Safety of polyethylene glycol 3350 solution in chronic constipation: randomized, placebo-controlled trial

OpenAIRE

McGraw, Thomas

2016-01-01

Thomas McGraw Global Medical Affairs, Merck & Co., Inc., Kenilworth, NJ, USA Purpose: To evaluate the safety and tolerability of aqueous solution concentrate (ASC) of polyethylene glycol (PEG) 3350 in patients with functional constipation.Patients and methods: The patients who met Rome III diagnostic criteria for functional constipation were randomized in this multicenter, randomized, placebo-controlled, single-blind study to receive once daily dose of PEG 3350 (17 g) ASC or ...

Pharmacokinetics and Safety of Intravenous Murepavadin Infusion in Healthy Adult Subjects Administered Single and Multiple Ascending Doses.

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Wach, Achim; Dembowsky, Klaus; Dale, Glenn E

2018-04-01

Murepavadin is the first in class of the outer membrane protein-targeting antibiotics (OMPTA) and a pathogen-specific peptidomimetic antibacterial with a novel, nonlytic mechanism of action targeting Pseudomonas aeruginosa Murepavadin is being developed for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). The pharmacokinetics (PK) and safety of single and multiple doses of murepavadin were investigated in healthy male subjects. Part A of the study was a double-blind, randomized, placebo-controlled, single-ascending-dose investigation in 10 sequential cohorts where each cohort comprised 6 healthy male subjects; 4 subjects were randomized to murepavadin, and 2 subjects were randomized to placebo. Part B was a double-blind, randomized, placebo-controlled, multiple-ascending-dose investigation in 3 sequential cohorts. After a single dose of murepavadin, the geometric mean half-life (2.52 to 5.30 h), the total clearance (80.1 to 114 ml/h/kg), and the volume of distribution (415 to 724 ml/kg) were consistent across dose levels. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Murepavadin was well tolerated, adverse events were transient and generally mild, and no dose-limiting toxicity was identified. Copyright © 2018 American Society for Microbiology.

Evaluation of Mangosteen juice blend on biomarkers of inflammation in obese subjects: a pilot, dose finding study

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Singh Betsy B

2009-10-01

Full Text Available Abstract Background The ability to reduce inflammation in overweight and obese individuals may be valuable in preventing the progression to metabolic syndrome with associated risks for heart disease and diabetes. The purpose of this study was to evaluate the effect of multiple dosages of a proprietary Mangosteen Juice blend on indicators of inflammation and antioxidant levels in obese patients with elevated C-reactive protein (CRP levels. Methods The study was an 8 week randomized, double-blind, placebo-controlled study with a pre-study 2 week washout period. The study included four groups including placebo and three difference doses of the test product, XanGo Juice™: 3, 6 or 9 oz twice daily. The primary outcome measure of this study was high-sensitivity (HS-CRP. Secondary outcome measures included other biochemical indicators of inflammation, anthropomorphic measures and a safety evaluation. Results One hundred twenty two (122 persons were screened for the study, 44 were randomized and 40 completed the study. HS-CRP measurements dropped after 8 weeks treatment compared to baseline in all 3 dose groups and increased in the placebo group. The changes from baseline were not significant but the comparison of change from baseline was significant for the 18 oz group when compared to placebo (p = 0.02. Other markers of inflammation (inflammatory cytokines and a marker for lipid peroxidation (F2 isoprostane did not show any significant differences when compared with placebo. There was a trend towards a decrease in BMI in the juice groups. There were no side effects reported in any of the groups and none of the laboratory or EKG safety assessments indicated clinically significant changes for any subject. Conclusion In this pilot, dose-finding study, a proprietary mangosteen juice blend (XanGo Juice™ reduced CRP levels (increased change from baseline compared to placebo for those taking the highest dose of 18 oz per day. Further studies with a

Evaluation of Mangosteen juice blend on biomarkers of inflammation in obese subjects: a pilot, dose finding study.

Science.gov (United States)

Udani, Jay K; Singh, Betsy B; Barrett, Marilyn L; Singh, Vijay J

2009-10-20

The ability to reduce inflammation in overweight and obese individuals may be valuable in preventing the progression to metabolic syndrome with associated risks for heart disease and diabetes. The purpose of this study was to evaluate the effect of multiple dosages of a proprietary Mangosteen Juice blend on indicators of inflammation and antioxidant levels in obese patients with elevated C-reactive protein (CRP) levels. The study was an 8 week randomized, double-blind, placebo-controlled study with a pre-study 2 week washout period. The study included four groups including placebo and three difference doses of the test product, XanGo Juice: 3, 6 or 9 oz twice daily. The primary outcome measure of this study was high-sensitivity (HS)-CRP. Secondary outcome measures included other biochemical indicators of inflammation, anthropomorphic measures and a safety evaluation. One hundred twenty two (122) persons were screened for the study, 44 were randomized and 40 completed the study. HS-CRP measurements dropped after 8 weeks treatment compared to baseline in all 3 dose groups and increased in the placebo group. The changes from baseline were not significant but the comparison of change from baseline was significant for the 18 oz group when compared to placebo (p = 0.02). Other markers of inflammation (inflammatory cytokines) and a marker for lipid peroxidation (F2 isoprostane) did not show any significant differences when compared with placebo. There was a trend towards a decrease in BMI in the juice groups. There were no side effects reported in any of the groups and none of the laboratory or EKG safety assessments indicated clinically significant changes for any subject. In this pilot, dose-finding study, a proprietary mangosteen juice blend (XanGo Juice) reduced CRP levels (increased change from baseline) compared to placebo for those taking the highest dose of 18 oz per day. Further studies with a larger population are required to confirm and further define the

Influence of random setup error on dose distribution

International Nuclear Information System (INIS)

Zhai Zhenyu

2008-01-01

Objective: To investigate the influence of random setup error on dose distribution in radiotherapy and determine the margin from ITV to PTV. Methods: A random sample approach was used to simulate the fields position in target coordinate system. Cumulative effect of random setup error was the sum of dose distributions of all individual treatment fractions. Study of 100 cumulative effects might get shift sizes of 90% dose point position. Margins from ITV to PTV caused by random setup error were chosen by 95% probability. Spearman's correlation was used to analyze the influence of each factor. Results: The average shift sizes of 90% dose point position was 0.62, 1.84, 3.13, 4.78, 6.34 and 8.03 mm if random setup error was 1,2,3,4,5 and 6 mm,respectively. Univariate analysis showed the size of margin was associated only by the size of random setup error. Conclusions: Margin of ITV to PTV is 1.2 times random setup error for head-and-neck cancer and 1.5 times for thoracic and abdominal cancer. Field size, energy and target depth, unlike random setup error, have no relation with the size of the margin. (authors)

Peritoneal Nebulization of Ropivacaine during Laparoscopic Cholecystectomy: Dose Finding and Pharmacokinetic Study

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Massimo Allegri

2017-01-01

Full Text Available Background. Intraperitoneal nebulization of ropivacaine reduces postoperative pain and morphine consumption after laparoscopic surgery. The aim of this multicenter double-blind randomized controlled trial was to assess the efficacy of different doses and dose-related absorption of ropivacaine when nebulized in the peritoneal cavity during laparoscopic cholecystectomy. Methods. Patients were randomized to receive 50, 100, or 150 mg of ropivacaine 1% by peritoneal nebulization through a nebulizer. Morphine consumption, pain intensity in the abdomen, wound and shoulder, time to unassisted ambulation, discharge time, and adverse effects were collected during the first 48 hours after surgery. The pharmacokinetics of ropivacaine was evaluated using high performance liquid chromatography. Results. Nebulization of 50 mg of ropivacaine had the same effect of 100 or 150 mg in terms of postoperative morphine consumption, shoulder pain, postoperative nausea and vomiting, activity resumption, and hospital discharge timing (>0.05. Plasma concentrations did not reach toxic levels in any patient, and no significant differences were observed between groups (P>0.05. Conclusions. There is no enhancement in analgesic efficacy with higher doses of nebulized ropivacaine during laparoscopic cholecystectomy. When administered with a microvibration-based aerosol humidification system, the pharmacokinetics of ropivacaine is constant and maintains an adequate safety profile for each dosage tested.

European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP): a randomized trial.

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Landolfi, R; Marchioli, R

1997-01-01

Thrombotic complications characterize the clinical course of polycythemia vera (PV) and represent the main cause of morbidity and mortality. However, uncertainty still exists as to the benefit/risk ratio of aspirin prophylaxis in this setting. In vivo platelet biosynthesis of thromboxane A2 is enhanced and can be suppressed by low-dose aspirin in PV, thus providing a rationale for assessing the efficacy and safety of a low-dose aspirin regimen in these patients. The Gruppo Italiano Studio Policitemia Vera has recently performed a pilot study on 112 patients randomized to receive aspirin, 40 mg daily, or placebo and followed for 16 +/- 6 months (mean +/- SD). This study showed that low-dose aspirin is well tolerated in PV patients, and that a large-scale efficacy trial is feasible in this setting. In this article we report the protocol of the European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study, which is a randomized trial designed to assess the risk/benefit ratio of low-dose aspirin in PV. To estimate the size and the follow-up duration required for the ECLAP trial, a retrospective analysis of the clinical epidemiology of a large PV population has recently been completed by the Gruppo Italiano Studio Policitemia Vera. On this basis, approximately 3500 patients will be enrolled in the ECLAP study with a follow-up of 3 to 4 years. The uncertainty principle will be used as the main eligibility criterion: Polycythemic patients of any age, having no clear indication for or contraindication to aspirin treatment, will be randomized in a double-blind fashion to receive oral aspirin (100 mg daily) or placebo. According to current therapeutic recommendations, the basic treatment of randomized patients should be aimed at maintaining the hematocrit value 50. Randomization will be stratified by participating center. The study is funded by the European Union BIOMED 2 program.

Efficacy and Safety of Multiple Doses of Exenatide Once-Monthly Suspension in Patients With Type 2 Diabetes: A Phase II Randomized Clinical Trial.

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Wysham, Carol H; MacConell, Leigh; Hardy, Elise

2016-10-01

This study investigated the efficacy and safety of multiple exenatide once-monthly suspension (QMS) doses of exenatide-containing microspheres in Miglyol referenced against the clinical dose of exenatide once-weekly (QW) microspheres in aqueous solution. In this phase II, randomized, controlled, single-blind study, 121 adults (∼30/arm) with type 2 diabetes and HbA1c 7.1-11.0% (54-97 mmol/mol) were randomized 1:1:1:1 to subcutaneous exenatide QW 2 mg (self-administered) or exenatide QMS 5, 8, or 11 mg (caregiver-administered) for 20 weeks. The primary end point was change in HbA1c. At baseline, mean age was 50 years, HbA1c was 8.5% (69 mmol/mol), fasting plasma glucose (FPG) was 184 mg/dL, and body weight was 98 kg. At week 20, mean ± SD HbA1c reductions were -1.54% ± 1.26% with exenatide QW and -1.29% ± 1.07%, -1.31% ± 1.66%, and -1.45% ± 0.93% with exenatide QMS 5, 8, and 11 mg, respectively (evaluable population: n = 110). There were no significant differences in HbA1c reductions among the exenatide QMS doses. FPG reductions were -34 ± 48 mg/dL with exenatide QW and -25 ± 43, -30 ± 52, and -49 ± 49 mg/dL with exenatide QMS 5, 8, and 11 mg, respectively. Weight decreased with all treatments. For exenatide QMS, nausea (16.7-23.3%) and headache (16.7-26.7%) were the most common adverse events. No major or minor hypoglycemia occurred. All doses of exenatide QMS resulted in efficacy and tolerability profiles consistent with exenatide QW. These results combined with pharmacokinetic and pharmacodynamic modeling could inform dose selection for further development. © 2016 by the American Diabetes Association.

ATG-Fresenius treatment and low-dose tacrolimus: results of a randomized controlled trial in liver transplantation.

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Benítez, C E; Puig-Pey, I; López, M; Martínez-Llordella, M; Lozano, J J; Bohne, F; Londoño, M C; García-Valdecasas, J C; Bruguera, M; Navasa, M; Rimola, A; Sánchez-Fueyo, A

2010-10-01

We report the results of a prospective randomized controlled trial in liver transplantation assessing the efficacy and safety of antithymocyte globulin (ATG-Fresenius) plus tacrolimus monotherapy at gradually decreasing doses. Patients were randomized to either: (a) standard-dose tacrolimus plus steroids;or (b) peritransplant ATG-Fresenius plus reduced-dose tacrolimus monotherapy followed by weaning of tacrolimus starting 3 months after transplantation. The primary end-point was the achievement of very low-dose tacrolimus (every-other-day or once daily dose with Fresenius group but no benefits in terms of improved renal function, lower metabolic complications or increased prevalence of tolerance-related biomarkers were observed. In conclusion, the use of ATG-Fresenius and tacrolimus at gradually decreasing doses was associated with a high rate of rejection, did not allow for the administration of very low doses of tacrolimus and failed to provide detectable clinical benefits. ClinicalTrials.gov identifier: NCT00436722. © 2010 The Authors Journal compilation © 2010 The American Society of Transplantation and the American Society of Transplant Surgeons.

Efficacy and safety of two doses of Norditropin® (somatropin) in short stature due to Noonan syndrome: a 2-year randomized, double-blind, multicenter trial in Japanese patients.

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Ozono, Keiichi; Ogata, Tsutomu; Horikawa, Reiko; Matsubara, Yoichi; Ogawa, Yoshihisa; Nishijima, Keiji; Yokoya, Susumu

2018-02-26

This randomized double-blind multicenter trial (NCT01927861) evaluated the growth-promoting effect and safety of Norditropin ® (NN220; somatropin) in Japanese children with short stature due to Noonan syndrome. Prepubertal children aged 3-Noonan syndrome were randomized to receive GH 0.033 mg/kg/day (n = 25, mean age 6.57 years, 11 females) or 0.066 mg/kg/day (n = 26, mean age 6.06 years, eight females) for 104 weeks. Change in height standard deviation score (HSDS) from baseline was analyzed based on an ANCOVA model. Baseline HSDS was -3.24. Estimated change in HSDS [95% CI] after 104 weeks' treatment was 0.84 [0.66, 1.02] and 1.47 [1.29, 1.64] for the lower and higher doses, respectively; estimated mean difference 0.63 [0.38, 0.88], p Noonan syndrome, with a favorable safety profile. The effect was greater with 0.066 mg/kg/day compared with 0.033 mg/kg/day.

Bioavailability and Safety of Vitamin D3 from Pizza Baked with Fortified Mozzarella Cheese: A Randomized Controlled Trial.

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Al-Khalidi, Banaz; Chiu, Winnie; Rousseau, Dérick; Vieth, Reinhold

2015-09-01

To assess the bioavailability and safety of vitamin D3 from fortified mozzarella cheese baked on pizza. In a randomized, double-blind trial, 96 apparently healthy, ethnically diverse adults were randomized to consume 200 IU or 28 000 IU vitamin D3 fortified mozzarella cheese with pizza once weekly for a total of 8 weeks. Blood and urine samples were collected at baseline (week 1) and final (week 10) visits for serum 25-hydroxyvitamin D and other biochemical measures. The primary outcome compared serum 25-hydroxyvitamin D between groups at 10 weeks. The secondary outcome evaluated the safety of vitamin D dosing protocol as measured by serum and urine calcium, phosphate, creatinine, and serum parathyroid hormone (PTH). Serum 25-hydroxyvitamin D increased by 5.1 ± 11 nmol/L in the low-dose group (n = 47; P = 0.003), and by 73 ± 22 nmol/L in the high-dose group (n = 49; P pizza.

Safety, tolerability, and pharmacokinetics of single oral doses of tofacitinib, a Janus kinase inhibitor, in healthy volunteers.

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Krishnaswami, Sriram; Boy, Mary; Chow, Vincent; Chan, Gary

2015-03-01

Tofacitinib is an oral Janus kinase inhibitor. This randomized, double-blind, parallel-group, placebo-controlled study was the first evaluation of tofacitinib in humans. The objectives were to characterize the safety and tolerability, pharmacokinetics (PK), and pharmacodynamics of escalating single tofacitinib doses in healthy subjects. Tofacitinib (0.1, 0.3, 1, 3, 10, 30, 60, and 100 mg) or placebo was administered as oral powder for constitution. For each dose, 7-9 subjects were randomized to tofacitinib and 3-5 subjects to placebo. Ninety-five males and females (age range 19-45) completed the study. Forty-nine treatment-emergent all-causality adverse events (AEs) were observed; nausea and headache were the most frequently reported. Tofacitinib PK was characterized by rapid absorption (time to peak serum concentration [Tmax ] 0.5-1 hour), rapid elimination (mean terminal half-lives 2.3-3.1 hours), and dose-proportional systemic exposures (peak serum concentration [Cmax ] and area under the serum concentration-time curve from time zero to infinity [AUC0-∞ ]). No appreciable correlation was observed between tofacitinib dose and lymphocyte subset counts. Single-dose tofacitinib up to 100 mg in healthy subjects had a safety profile of mostly mild AEs, and no deaths, serious AEs, severe AEs or discontinuations due to AEs. © 2014, The American College of Clinical Pharmacology.

Safety and pharmacodynamics of venetoclax (ABT-199) in a randomized single and multiple ascending dose study in women with systemic lupus erythematosus.

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Lu, P; Fleischmann, R; Curtis, C; Ignatenko, S; Clarke, S H; Desai, M; Wong, S L; Grebe, K M; Black, K; Zeng, J; Stolzenbach, J; Medema, J K

2018-02-01

Objective The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) may contribute to the pathogenesis of systemic lupus erythematosus. The safety, tolerability, and pharmacodynamics of the selective Bcl-2 inhibitor venetoclax (ABT-199) were assessed in women with systemic lupus erythematosus. Methods A phase 1, double-blind, randomized, placebo controlled study evaluated single ascending doses (10, 30, 90, 180, 300, and 500 mg) and multiple ascending doses (2 cycles; 30, 60, 120, 240, 400, and 600 mg for 1 week, and then 3 weeks off per cycle) of orally administered venetoclax. Eligible participants were aged 18-65 years with a diagnosis of systemic lupus erythematosus for 6 months or more receiving stable therapy for systemic lupus erythematosus (which could have included corticosteroids and/or stable antimalarials). Results All patients (48/48) completed the single ascending dose, 25 continued into the multiple ascending dose, and 44/50 completed the multiple ascending dose; two of the withdrawals (venetoclax 60 mg and 600 mg cohorts) were due to adverse events. Adverse event incidences were slightly higher in the venetoclax groups compared with the placebo groups, with no dose dependence. There were no serious adverse events with venetoclax. The most common adverse events were headache, nausea, and fatigue. Venetoclax 600 mg multiple ascending dose treatment depleted total lymphocytes and B cells by approximately 50% and 80%, respectively. Naive, switched memory, and memory B-cell subsets enriched in autoreactive B cells exhibited dose-dependent reduction of up to approximately 80%. There were no consistent or marked changes in neutrophils, natural killer cells, hemoglobin, or platelets. Conclusions Venetoclax was generally well tolerated in women with systemic lupus erythematosus and reduced total lymphocytes and disease-relevant subsets of antigen-experienced B cells. Registration ClinicalTrials.gov: NCT01686555.

A double-blind, randomized, pilot dose-finding study of maca root (L. meyenii) for the management of SSRI-induced sexual dysfunction.

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Dording, Christina M; Fisher, Lauren; Papakostas, George; Farabaugh, Amy; Sonawalla, Shamsah; Fava, Maurizio; Mischoulon, David

2008-01-01

We sought to determine whether maca, a Peruvian plant, is effective for selective-serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction. We conducted a double-blind, randomized, parallel group dose-finding pilot study comparing a low-dose (1.5 g/day) to a high-dose (3.0 g/day) maca regimen in 20 remitted depressed outpatients (mean age 36+/-13 years; 17 women) with SSRI-induced sexual dysfunction. The Arizona Sexual Experience Scale (ASEX) and the Massachusetts General Hospital Sexual Function Questionnaire (MGH-SFQ) were used to measure sexual dysfunction. Ten subjects completed the study, and 16 subjects (9 on 3.0 g/day; 7 on 1.5 g/day) were eligible for intent-to-treat (ITT) analyses on the basis of having had at least one postbaseline visit. ITT subjects on 3.0 g/day maca had a significant improvement in ASEX (from 22.8+/-3.8 to 16.9+/-6.2; z=-2.20, P=0.028) and in MGH-SFQ scores (from 24.1+/-1.9 to 17.0+/-5.7; z=-2.39, P=0.017), but subjects on 1.5 g/day maca did not. Libido improved significantly (PMaca was well tolerated. Maca root may alleviate SSRI-induced sexual dysfunction, and there may be a dose-related effect. Maca may also have a beneficial effect on libido.

Evaluation of the effect of multiple doses of lansoprazole on the pharmacokinetics and safety of ponatinib in healthy subjects.

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Narasimhan, Narayana I; Dorer, David J; Davis, Jeffrey; Turner, Christopher D; Sonnichsen, Daryl

2014-10-01

In vitro studies have demonstrated that the aqueous solubility of the tyrosine kinase inhibitor ponatinib decreases as pH increases. The primary aim of this study was to assess the effects of the gastric proton pump inhibitor lansoprazole on the pharmacokinetics of ponatinib. The single-dose safety profile of ponatinib with and without coadministration of lansoprazole was also characterized. This was a phase I, open-label, non-randomized, two-period crossover study in 20 healthy subjects aged 18-55 years. Subjects received a single oral dose of ponatinib 45 mg alone on day 1, an oral dose of lansoprazole 60 mg on day 14, and ponatinib 45 mg plus lansoprazole 60 mg on day 15. Lansoprazole coadministration resulted in a 1-h increase in the time to maximum plasma concentration (t max) of ponatinib (6 vs. 5 h post-dose; P lansoprazole versus ponatinib alone (40.67 vs. 53.96 ng/mL). Importantly, lansoprazole did not decrease the overall ponatinib systemic exposure as assessed by the ponatinib area under the plasma concentration-time curve from time zero to infinity (AUC∞ 1,153 ng·h/mL for lansoprazole + ponatinib vs. 1,222 ng·h/mL for ponatinib alone). The safety profile was considered acceptable when ponatinib was administered alone or with lansoprazole. Although coadministration of lansoprazole led to a modest, albeit statistically significant, reduction in ponatinib C max, overall systemic exposure to ponatinib did not change. The findings suggest that no dose adjustment is necessary when ponatinib is administered with drugs that increase gastric pH.

A phase 1, open-label, randomized study to compare the immunogenicity and safety of different administration routes and doses of virosomal influenza vaccine in elderly.

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Levin, Yotam; Kochba, Efrat; Shukarev, Georgi; Rusch, Sarah; Herrera-Taracena, Guillermo; van Damme, Pierre

2016-10-17

Influenza remains a significant problem in elderly despite widespread vaccination coverage. This randomized, phase-I study in elderly compared different strategies of improving vaccine immunogenicity. A total of 370 healthy participants (⩾65years) were randomized equally 1:1:1:1:1:1 to six influenza vaccine treatments (approximately 60-63 participants per treatment arm) at day 1 that consisted of three investigational virosomal vaccine formulations at doses of 7.5, 15, and 45μg HA antigen/strain administered intradermally (ID) by MicronJet600™ microneedle device (NanoPass Technologies) or intramuscularly (IM), and three comparator registered seasonal vaccines; Inflexal V™ (Janssen) and MF59 adjuvanted Fluad™ (Novartis) administered IM and Intanza™ (Sanofi Pasteur) administered ID via Soluvia™ prefilled microinjection system (BD). Serological evaluations were performed at days 22 and 90 and safety followed-up for 6months. Intradermal delivery of virosomal vaccine using MicronJet600™ resulted in significantly higher immunogenicity than the equivalent dose of virosomal Inflexal V™ administered intramuscularly across most of the parameters and strains, as well as in some of the readouts and strains as compared with the 45μg dose of virosomal vaccine formulation. Of 370 participants, 300 (81.1%) reported ⩾1 adverse event (AE); more participants reported solicited local AEs (72.2%) than solicited systemic AEs (12.2%). Intradermal delivery significantly improved influenza vaccine immunogenicity compared with intramuscular delivery. Triple dose (45μg) virosomal vaccine did not demonstrate any benefit on vaccine's immunogenicity over 15μg commercial presentation. All treatments were generally safe and well-tolerated. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Safety, pharmacokinetic, and functional effects of the nogo-a monoclonal antibody in amyotrophic lateral sclerosis: a randomized, first-in-human clinical trial.

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Vincent Meininger

Full Text Available The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS; it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1 to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg or placebo. In Part 2, 36 subjects were randomized (3∶1 to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG, and clinical laboratory tests. Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological, and biomarker parameters. Overall, ozanezumab treatment (0.01-15 mg/kg was well tolerated. The overall incidence of AEs in the repeat dose 2.5 mg/kg and 15 mg/kg ozanezumab groups was higher than in the repeat dose placebo group and repeat dose 0.5 mg/kg ozanezumab group. The majority were considered not related to study drug by the investigators. Six serious AEs were reported in three subjects receiving ozanezumab; none were considered related to study drug. No study drug-related patterns were identified for ECG, laboratory, or vital signs parameters. One subject (repeat dose 15 mg/kg ozanezumab showed a weak, positive anti-ozanezumab-antibody result. PK results were generally consistent with monoclonal antibody treatments. No apparent treatment effects were observed for functional endpoints or muscle biomarkers. Immunohistochemical staining showed dose-dependent co-localization of ozanezumab with Nogo-A in skeletal muscle. In conclusion, single and repeat dose ozanezumab treatment was well tolerated and demonstrated

Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials.

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Lee, Shing M; Backenroth, Daniel; Cheung, Ying Kuen Ken; Hershman, Dawn L; Vulih, Diana; Anderson, Barry; Ivy, Percy; Minasian, Lori

2016-04-20

The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on the cytotoxic chemotherapy paradigm. Molecularly targeted agents (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well as to late-onset and cumulative toxicities. Several approved MTAs have been poorly tolerated during long-term administration, leading to postmarketing dose optimization studies to re-evaluate the optimal treatment dose. Using data from completed bortezomib dose-finding trials, we explore its toxicity profile, optimize its dose, and examine the appropriateness of current designs for identifying an optimal dose. We classified the toxicities captured from 481 patients in 14 bortezomib dose-finding studies conducted through the National Cancer Institute Cancer Therapy Evaluation Program, computed the incidence of late-onset toxicities, and compared the incidence of dose-limiting toxicities (DLTs) among groups of patients receiving different doses of bortezomib. A total of 13,008 toxicities were captured: 46% of patients' first DLTs and 88% of dose reductions or discontinuations of treatment because of toxicity were observed after the first cycle. Moreover, for the approved dose of 1.3 mg/m(2), the estimated cumulative incidence of DLT was > 50%, and the estimated cumulative incidence of dose reduction or treatment discontinuation because of toxicity was nearly 40%. When considering the entire course of treatment, the approved bortezomib dose exceeds the conventional ceiling DLT rate of 20% to 33%. Retrospective analysis of trial data provides an opportunity for dose optimization of MTAs. Future dose-finding studies of MTAs should take into account late-onset toxicities to ensure that a tolerable dose is identified for future efficacy and comparative trials. © 2016 by American Society of Clinical Oncology.

Safety and pharmacokinetics of single and multiple intravenous bolus doses of diclofenac sodium compared with oral diclofenac potassium 50 mg: A randomized, parallel-group, single-center study in healthy subjects.

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Munjal, Sagar; Gautam, Anirudh; Okumu, Franklin; McDowell, James; Allenby, Kent

2016-01-01

In a randomized, parallel-group, single-center study in 42 healthy adults, the safety and pharmacokinetic parameters of an intravenous formulation of 18.75 and 37.5 mg diclofenac sodium (DFP-08) following single- and multiple-dose bolus administration were compared with diclofenac potassium 50 mg oral tablets. Mean AUC0-inf values for a 50-mg oral tablet and an 18.75-mg intravenous formulation were similar (1308.9 [393.0]) vs 1232.4 [147.6]). As measured by the AUC, DFP-08 18.75 mg and 37.5 mg demonstrated dose proportionality for extent of exposure. One subject in each of the placebo and DFP-08 18.75-mg groups and 2 subjects in the DFP-08 37.5-mg group reported adverse events that were considered by the investigator to be related to the study drug. All were mild in intensity and did not require treatment. Two subjects in the placebo group and 1 subject in the DFP-08 18.75-mg group reported grade 1 thrombophlebitis; no subjects reported higher than grade 1 thrombophlebitis after receiving a single intravenous dose. The 18.75- and 37.5-mg doses of intravenous diclofenac (single and multiple) were well tolerated for 7 days. Additional efficacy and safety studies are required to fully characterize the product. © 2015, The American College of Clinical Pharmacology.

Efficacy and Safety of OnabotulinumtoxinA Treatment of Forehead Lines: A Multicenter, Randomized, Dose-Ranging Controlled Trial.

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Solish, Nowell; Rivers, Jason K; Humphrey, Shannon; Muhn, Channy; Somogyi, Chris; Lei, Xiaofang; Bhogal, Meetu; Caulkins, Carrie

2016-03-01

Various onabotulinumtoxinA doses are effective in treating forehead lines (FHL), with a trend toward lower doses. To evaluate efficacy and safety of onabotulinumtoxinA dose-ranging treatment of FHL when the frontalis area and glabellar complex are treated together. Adults with moderate-to-severe FHL received onabotulinumtoxinA 40 U (FHL, 20 U; glabellar lines [GL], 20 U), 30 U (FHL, 10 U; GL, 20 U), or placebo. Response was assessed at weeks 1, 2, day 30, and monthly to day 180. Coprimary efficacy end points were investigator- and subject-assessed Facial Wrinkle Scale scores of none or mild (day 30). Patient-reported outcomes, onset/duration of effect, and adverse events (AEs) were evaluated. Responder rates (investigator/subject, respectively) were 40-U group, 91.2%/89.5%; 30-U group, 86.4%/81.4%; placebo, 1.7%/5.1%. OnabotulinumtoxinA resulted in significantly greater responder rates than placebo (p < .001). Adverse events were mild to moderate and similar between groups (most common AEs: nasopharyngitis [4.6%] and headache [4.0%]). Treatment of FHL with onabotulinumtoxinA 40 and 30 U (in frontalis and glabellar complex muscles) was tolerable, effective, and sustained. Both doses significantly reduced FHL severity; however, the 40-U dose demonstrated a trend toward greater sustained benefit and longer duration of effect versus the 30-U dose, with similar AE rates.

Strategies to reduce safety violations for working from heights in construction companies: study protocol for a randomized controlled trial.

Science.gov (United States)

van der Molen, Henk F; Frings-Dresen, Monique H W

2014-05-31

Safety measures should be applied to reduce work-related fatal and non-fatal fall injuries. However, according to the labor inspectorate, more than 80% of Dutch construction sites violate safety regulations for working from heights. To increase compliance with safety regulations, employers and workers have to select, implement and monitor safety measures. To facilitate this behavioral change, stimulating knowledge awareness and personalized feedback are frequently advocated behavior change techniques. For this study, two behavior change strategies have been developed in addition to the announcement of safety inspections by the labor inspectorate. These strategies consist of 1) face-to-face contacts with safety consultants and 2) direct mail with access to internet facilities. The objective of this study is to evaluate the effectiveness of these two strategies on the safety violations for working from heights, the process and the cost measures. This study is a block randomized intervention trial in 27 cities to establish the effects of the face-to-face guidance strategy (N = 9), a direct mailing strategy (N = 9) and a control condition of no guidance (N = 9) on safety violations to record by labor inspectors after three months. A process evaluation for both strategies will be performed to determine program implementation (reach, dose delivered and dose received), satisfaction, knowledge and perceived safety behavior. A cost analysis will be performed to establish the financial costs for both strategies. The present study is in accordance with the CONSORT statement. This study increases insight into performing practice-based randomized controlled trials. The outcome will help to evaluate the effect of two guidance strategies on safety violations. If these strategies are effective, implementation of these strategies through the national institute of safety and health or labor inspectorate can take place to guide construction companies in complying with

No-threshold dose-response curves for nongenotoxic chemicals: Findings and applications for risk assessment

International Nuclear Information System (INIS)

Sheehan, Daniel M.

2006-01-01

We tested the hypothesis that no threshold exists when estradiol acts through the same mechanism as an active endogenous estrogen. A Michaelis-Menten (MM) equation accounting for response saturation, background effects, and endogenous estrogen level fit a turtle sex-reversal data set with no threshold and estimated the endogenous dose. Additionally, 31 diverse literature dose-response data sets were analyzed by adding a term for nonhormonal background; good fits were obtained but endogenous dose estimations were not significant due to low resolving power. No thresholds were observed. Data sets were plotted using a normalized MM equation; all 178 data points were accommodated on a single graph. Response rates from ∼1% to >95% were well fit. The findings contradict the threshold assumption and low-dose safety. Calculating risk and assuming additivity of effects from multiple chemicals acting through the same mechanism rather than assuming a safe dose for nonthresholded curves is appropriate

Embracing model-based designs for dose-finding trials.

Science.gov (United States)

Love, Sharon B; Brown, Sarah; Weir, Christopher J; Harbron, Chris; Yap, Christina; Gaschler-Markefski, Birgit; Matcham, James; Caffrey, Louise; McKevitt, Christopher; Clive, Sally; Craddock, Charlie; Spicer, James; Cornelius, Victoria

2017-07-25

Dose-finding trials are essential to drug development as they establish recommended doses for later-phase testing. We aim to motivate wider use of model-based designs for dose finding, such as the continual reassessment method (CRM). We carried out a literature review of dose-finding designs and conducted a survey to identify perceived barriers to their implementation. We describe the benefits of model-based designs (flexibility, superior operating characteristics, extended scope), their current uptake, and existing resources. The most prominent barriers to implementation of a model-based design were lack of suitable training, chief investigators' preference for algorithm-based designs (e.g., 3+3), and limited resources for study design before funding. We use a real-world example to illustrate how these barriers can be overcome. There is overwhelming evidence for the benefits of CRM. Many leading pharmaceutical companies routinely implement model-based designs. Our analysis identified barriers for academic statisticians and clinical academics in mirroring the progress industry has made in trial design. Unified support from funders, regulators, and journal editors could result in more accurate doses for later-phase testing, and increase the efficiency and success of clinical drug development. We give recommendations for increasing the uptake of model-based designs for dose-finding trials in academia.

Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial.

Science.gov (United States)

Richardson, Paul G; Soiffer, Robert J; Antin, Joseph H; Uno, Hajime; Jin, Zhezhen; Kurtzberg, Joanne; Martin, Paul L; Steinbach, Gideon; Murray, Karen F; Vogelsang, Georgia B; Chen, Allen R; Krishnan, Amrita; Kernan, Nancy A; Avigan, David E; Spitzer, Thomas R; Shulman, Howard M; Di Salvo, Donald N; Revta, Carolyn; Warren, Diane; Momtaz, Parisa; Bradwin, Gary; Wei, L J; Iacobelli, Massimo; McDonald, George B; Guinan, Eva C

2010-07-01

Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for > or =14 days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day +100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day +100 survival, and decreased plasminogen activator inhibitor type 1 (PAI-1) during treatment was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD.

Safety of the Up-titration of Nifedipine GITS and Valsartan or Low-dose Combination in Uncontrolled Hypertension: the FOCUS Study.

Science.gov (United States)

Park, Jeong Bae; Shin, Joon-Han; Kim, Dong-Soo; Youn, Ho-Joong; Park, Seung Woo; Shim, Wan Joo; Park, Chang Gyu; Kim, Dong-Woon; Lee, Hae-Young; Choi, Dong-Ju; Rim, Se-Joong; Lee, Sung-Yun; Kim, Ju-Han

2016-04-01

Doubling the dose of antihypertensive drugs is necessary to manage hypertension in patients whose disease is uncontrolled. However, this strategy can result in safety issues. This study compared the safety and efficacy of up-titration of the nifedipine gastrointestinal therapeutic system (GITS) with up-titration of valsartan monotherapy; these were also compared with low-dose combinations of the two therapies. This prospective, open-label, randomized, active-controlled, multicenter study lasted 8 weeks. If patients did not meet the target blood pressure (BP) after 4 weeks of treatment with low-dose monotherapy, they were randomized to up-titration of the nifedipine GITS dose from 30 mg (N30) to 60 mg or valsartan from 80 mg to 160 mg or they were randomized to receive a low-dose combination of N30 and valsartan 80 mg for another 4 weeks. BP variability was assessed by using the SD or the %CV of the short-term BP measured at clinic. Of the 391 patients (20~70 years with stage II or higher hypertension) screened for study inclusion, 362 patients who had 3 BP measurements were enrolled. The reduction in the mean systolic/diastolic BP from baseline to week 4 was similar in both low-dose monotherapy groups with either N30 or valsartan 80 mg. BP variability (SD) was unchanged with either therapy, but the %CV was slightly increased in the N30 group. There was no significant difference in BP variability either in SD or %CV between responders and nonresponders to each monotherapy despite the significant difference in the mean BP changes. The up-titration effect of nifedipine GTS from 30 to 60 mg exhibited an additional BP reduction, but this effect was not shown in the up-titration of valsartan from 80 to 160 mg. Although the difference in BP was obvious between high-dose nifedipine GTS and valsartan, the BP variability was unchanged between the 2 drugs and was similar to the low-dose combinations. There was a low rate of adverse events in all treatment groups. In addition

Immunogenicity, reactogenicity and safety of 2 doses of an adjuvanted herpes zoster subunit vaccine administered 2, 6 or 12 months apart in older adults: Results of a phase III, randomized, open-label, multicenter study.

Science.gov (United States)

Lal, Himal; Poder, Airi; Campora, Laura; Geeraerts, Brecht; Oostvogels, Lidia; Vanden Abeele, Carline; Heineman, Thomas C

2018-01-02

In phase III trials, 2 doses of a herpes zoster (HZ) subunit vaccine (HZ/su; 50 µg varicella-zoster virus glycoprotein E [gE] and AS01 B Adjuvant System) administered 2-months apart in older adults (≥50 and ≥70 years) demonstrated >90% efficacy in preventing HZ and had a clinically acceptable safety profile. Here we report immunogenicity, reactogenicity and safety following administration of 2 HZ/su doses at intervals longer than 2 months. In this Phase III, open-label trial conducted in the US and Estonia, 354 adults ≥50 years were randomized 1:1:1 to receive 2 HZ/su doses 2, 6, or 12 months apart. gE-specific humoral immune responses were evaluated at pre-vaccination, 1 and 12 months post-dose 2. Co-primary objectives were to compare immune responses to HZ/su 1 month post-dose 2 when given 6-months or 12-months apart to those administered 2-months apart. For each participant, safety information was collected from dose 1 to 12 months post-dose 2. 346 participants completed the study and 343 were included in the according-to-protocol cohort for immunogenicity. One month post-dose 2, vaccine response rates were 96.5% (97.5% confidence interval [CI]: 90.4; 99.2) and 94.5% (97.5% CI: 87.6; 98.3) for the 0, 6- and 0, 12-month schedules, respectively, both schedules meeting the pre-defined criterion. Non-inferiority of anti-gE geometric mean concentrations was demonstrated for HZ/su administered on 0, 6-month compared to a 0, 2-month schedule; however, HZ/su administered on a 0, 12-month schedule did not meet the non-inferiority criterion. Injection site pain was the most commonly reported solicited adverse event (AE). 26 participants each reported at least 1 serious AE; none were assessed as related to vaccination. Immune responses to HZ/su administered at 0, 6-month were non-inferior to those elicited by a 0, 2-month schedule. HZ/su exhibited a clinically acceptable safety profile for all dosing intervals. Clinicaltrials.gov (NCT01751165

Analysis and planning of dose-finding studies with active control

International Nuclear Information System (INIS)

Helms, Hans-Joachim

2014-01-01

In the clinical development of radiopharmaceuticals the dose finding plays an important role. The contribution is focused on the evaluation and planning of dose finding studies with active control. It is of primary interest to find the lowest dose that yields the same efficacy as the active control. Besides the target dose confidence intervals are of importance to describe the quality of the target dose estimation. The calculation of case numbers and the determination of the dose steps to be studied are challenging under practical conditions. The contribution covers the demonstration of the statistical model the parameter estimation and the asymptotic properties based on maximum likelihood theory, the spline-based evaluation of nonlinear dose finding studies with active control and the planning of design and number of cases.

Utility of the sore throat pain model in a multiple-dose assessment of the acute analgesic flurbiprofen: a randomized controlled study.

Science.gov (United States)

Schachtel, Bernard; Aspley, Sue; Shephard, Adrian; Shea, Timothy; Smith, Gary; Schachtel, Emily

2014-07-03

The sore throat pain model has been conducted by different clinical investigators to demonstrate the efficacy of acute analgesic drugs in single-dose randomized clinical trials. The model used here was designed to study the multiple-dose safety and efficacy of lozenges containing flurbiprofen at 8.75 mg. Adults (n=198) with moderate or severe acute sore throat and findings of pharyngitis on a Tonsillo-Pharyngitis Assessment (TPA) were randomly assigned to use either flurbiprofen 8.75 mg lozenges (n=101) or matching placebo lozenges (n=97) under double-blind conditions. Patients sucked one lozenge every three to six hours as needed, up to five lozenges per day, and rated symptoms on 100-mm scales: the Sore Throat Pain Intensity Scale (STPIS), the Difficulty Swallowing Scale (DSS), and the Swollen Throat Scale (SwoTS). Reductions in pain (lasting for three hours) and in difficulty swallowing and throat swelling (for four hours) were observed after a single dose of the flurbiprofen 8.75 mg lozenge (Pflurbiprofen-treated patients experienced a 59% greater reduction in throat pain, 45% less difficulty swallowing, and 44% less throat swelling than placebo-treated patients (all Pflurbiprofen 8.75 mg lozenges were shown to be an effective, well-tolerated treatment for sore throat pain. Other pharmacologic actions (reduced difficulty swallowing and reduced throat swelling) and overall patient satisfaction from the flurbiprofen lozenges were also demonstrated in this multiple-dose implementation of the sore throat pain model. This trial was registered with ClinicalTrials.gov, registration number: NCT01048866, registration date: January 13, 2010.

A Randomized Dose-Ranging Study of Neuropeptide Y in Patients with Posttraumatic Stress Disorder.

Science.gov (United States)

Sayed, Sehrish; Van Dam, Nicholas T; Horn, Sarah R; Kautz, Marin M; Parides, Michael; Costi, Sara; Collins, Katherine A; Iacoviello, Brian; Iosifescu, Dan V; Mathé, Aleksander A; Southwick, Steven M; Feder, Adriana; Charney, Dennis S; Murrough, James W

2018-01-01

Anxiety and trauma-related disorders are among the most prevalent and disabling medical conditions in the United States, and posttraumatic stress disorder in particular exacts a tremendous public health toll. We examined the tolerability and anxiolytic efficacy of neuropeptide Y administered via an intranasal route in patients with posttraumatic stress disorder. Twenty-six individuals were randomized in a cross-over, single ascending dose study into 1 of 5 cohorts: 1.4 mg (n=3), 2.8 mg (n=6), 4.6 mg (n=5), 6.8 mg (n=6), and 9.6 mg (n=6). Each individual was dosed with neuropeptide Y or placebo on separate treatment days 1 week apart in random order under double-blind conditions. Assessments were conducted at baseline and following a trauma script symptom provocation procedure subsequent to dosing. Occurrence of adverse events represented the primary tolerability outcome. The difference between treatment conditions on anxiety as measured by the Beck Anxiety Inventory and the State-Trait Anxiety Inventory immediately following the trauma script represented efficacy outcomes. Twenty-four individuals completed both treatment days. Neuropeptide Y was well tolerated up to and including the highest dose. There was a significant interaction between treatment and dose; higher doses of neuropeptide Y were associated with a greater treatment effect, favoring neuropeptide Y over placebo on Beck Anxiety Inventory score (F1,20=4.95, P=.038). There was no significant interaction for State-Trait Anxiety Inventory score. Our study suggests that a single dose of neuropeptide Y is well tolerated up to 9.6 mg and may be associated with anxiolytic effects. Future studies exploring the safety and efficacy of neuropeptide Y in stress-related disorders are warranted. The reported study is registered at: http://clinicaltrials.gov (ID: NCT01533519). © The Author(s) 2017. Published by Oxford University Press on behalf of CINP.

Evaluation of the Efficacy, Safety, and Tolerability of 3 Dose Regimens of Topical Sodium Nitrite With Citric Acid in Patients With Anogenital Warts: A Randomized Clinical Trial.

Science.gov (United States)

Ormerod, Anthony D; van Voorst Vader, Pieter C; Majewski, Slovomir; Vanscheidt, Wolfgang; Benjamin, Nigel; van der Meijden, Willem

2015-08-01

Anogenital warts are a common disorder associated with significant physical and mental distress and a substantial cause of health care costs. To assess the efficacy of the topical application of nitric oxide delivered using acidified nitrite. A multicenter, randomized, controlled, dose-ranging clinical trial was conducted in European genitourinary medicine clinics between December 20, 2001, and January 14, 2003. Analysis was by intent to treat for all individuals initiating therapy. Participants included male and female volunteers older than 18 years with between 2 and 50 external anogenital warts. A total of 299 individuals from 40 centers were randomized to a control arm and a treatment arm that received 3 doses of acidified nitrite applied topically for 12 weeks with an additional 12 weeks of follow-up, with the final follow-up visit on January 14, 2003. Placebo nitrite cream and placebo citric acid cream were applied twice daily. Active treatment was divided as low dose (sodium nitrite, 3%, with citric acid, 4.5%, creams applied twice daily), middle dose (sodium nitrite, 6%, with citric acid, 9%, creams applied once daily at night, with placebo applied in the morning), and high dose (sodium nitrite, 6%, with citric acid, 9%, creams applied twice daily). The primary outcome was proportion of patients with complete clinical clearance of target warts; secondary outcomes were reduction in target wart area and safety. Complete clinical clearance at 12 weeks occurred in 10 of 74 patients (14%; 95% CI, 6%-21%) with placebo; 11 of 72 (15%; 95% CI, 7%-24%) with low-dose treatment; 17 of 74 (23%; 95% CI, 13%-33%) with middle-dose treatment; and 22 of 70 (31%; 95% CI, 21%-42%) with high-dose treatment (P = .01). Reduction in target wart area, time to clearance, and patient and investigator assessments supported the superiority of the high-dose therapy vs placebo. There were no systemic or serious adverse events associated with treatment. However, there was a dose

Randomized Trial of 2 Versus 1 Dose of Measles Vaccine

DEFF Research Database (Denmark)

Brønd, Marie; Martins, Cesario L; Byberg, Stine

2018-01-01

Background: Two doses of measles vaccine (MV) might reduce the nonmeasles mortality rate more than 1 dose of MV does. The effect of 2 versus 1 dose on morbidity has not been examined. Within a randomized trial of the effect of 2 doses versus 1 dose of MV on mortality in Guinea-Bissau, we investig...

The FIND-CKD study--a randomized controlled trial of intravenous iron versus oral iron in non-dialysis chronic kidney disease patients: background and rationale.

Science.gov (United States)

Macdougall, Iain C; Bock, Andreas; Carrera, Fernando; Eckardt, Kai-Uwe; Gaillard, Carlo; Van Wyck, David; Roubert, Bernard; Cushway, Timothy; Roger, Simon D

2014-04-01

Rigorous data are sparse concerning the optimal route of administration and dosing strategy for iron therapy with or without concomitant erythropoiesis-stimulating agent (ESA) therapy for the management of iron deficiency anaemia in patients with non-dialysis dependent chronic kidney disease (ND-CKD). FIND-CKD was a 56-week, open-label, multicentre, prospective, randomized three-arm study (NCT00994318) of 626 patients with ND-CKD and iron deficiency anaemia randomized to (i) intravenous (IV) ferric carboxymaltose (FCM) at an initial dose of 1000 mg iron with subsequent dosing as necessary to target a serum ferritin level of 400-600 µg/L (ii) IV FCM at an initial dose of 200 mg with subsequent dosing as necessary to target serum ferritin 100-200 µg/L or (iii) oral ferrous sulphate 200 mg iron/day. The primary end point was time to initiation of other anaemia management (ESA therapy, iron therapy other than study drug or blood transfusion) or a haemoglobin (Hb) trigger (two consecutive Hb values FIND-CKD was the longest randomized trial of IV iron therapy to date. Its findings will address several unanswered questions regarding iron therapy to treat iron deficiency anaemia in patients with ND-CKD. It was also the first randomized trial to utilize both a high and low serum ferritin target range to adjust IV iron dosing, and the first not to employ Hb response as its primary end point.

Safety and Effectiveness of two treatment regimes with tranexamic acid to minimize inflammatory response in elective cardiopulmonary bypass patients: a randomized double-blind, dose-dependent, phase IV clinical trial

Directory of Open Access Journals (Sweden)

Martín Beatriz

2011-10-01

Full Text Available Abstract Background In cardiopulmonary bypass (CPB patients, fibrinolysis may enhance postoperative inflammatory response. We aimed to determine whether an additional postoperative dose of antifibrinolytic tranexamic acid (TA reduced CPB-mediated inflammatory response (IR. Methods We performed a randomized, double-blind, dose-dependent, parallel-groups study of elective CPB patients receiving TA. Patients were randomly assigned to either the single-dose group (40 mg/Kg TA before CPB and placebo after CPB or the double-dose group (40 mg/Kg TA before and after CPB. Results 160 patients were included, 80 in each group. The incident rate of IR was significantly lower in the double-dose-group TA2 (7.5% vs. 18.8% in the single-dose group TA1; P = 0.030. After adjusting for hypertension, total protamine dose and temperature after CPB, TA2 showed a lower risk of IR compared with TA1 [OR: 0.29 (95% CI: 0.10-0.83, (P = 0.013]. Relative risk for IR was 2.5 for TA1 (95% CI: 1.02 to 6.12. The double-dose group had significantly lower chest tube bleeding at 24 hours [671 (95% CI 549-793 vs. 826 (95% CI 704-949 mL; P = 0.01 corrected-P significant] and lower D-dimer levels at 24 hours [489 (95% CI 437-540 vs. 621(95% CI: 563-679 ng/mL; P = 0.01 corrected-P significant]. TA2 required lower levels of norepinephrine at 24 h [0.06 (95% CI: 0.03-0.09 vs. 0.20(95 CI: 0.05-0.35 after adjusting for dobutamine [F = 6.6; P = 0.014 corrected-P significant]. We found a significant direct relationship between IL-6 and temperature (rho = 0.26; P P P P P P P Conclusions Prolonged inhibition of fibrinolysis, using an additional postoperative dose of tranexamic acid reduces inflammatory response and postoperative bleeding (but not transfusion requirements in CPB patients. A question which remains unanswered is whether the dose used was ideal in terms of safety, but not in terms of effectiveness. Current Controlled Trials number ISRCTN: ISRCTN84413719

Safety and immunogenicity of inactivated poliovirus vaccine made from Sabin strains: a phase II, randomized, positive-controlled trial.

Science.gov (United States)

Liao, Guoyang; Li, Rongcheng; Li, Changgui; Sun, Mingbo; Li, Yanping; Chu, Jiayou; Jiang, Shude; Li, Qihan

2012-01-15

The production of Sabin inactivated poliovirus vaccine (IPV) can reduce biosafety requirements in the posteradication/post-oral poliovirus vaccine (OPV) era. We conducted a phase II, randomized, positive-controlled trial to assess the safety and immunogenicity of Sabin IPV. The test groups (A, B, and C) received 3 doses of high, middle, and low D antigen (D Ag) of Sabin IPV at ages 2, 3, and 4 months, respectively. Infants in 2 control groups, group D and group E, received 3 doses of trivalent OPV and conventional IPV (cIPV), respectively, on the same schedule as that of groups A, B, and C. Serum samples were collected before and 30 days after the administration of the third dose. In total, 500 infants were randomly assigned to 5 groups, and 449 infants completed the vaccine series. No serious adverse events were associated with vaccinations. After 3 doses, the seroconversion rates in groups A, B, C, D, and E were 100%, 97.8%, 96.6%, 100%, and 90.1%, respectively, for type 1 poliovirus; 97.7%, 95.7%, 78.7%, 100%, and 90.1%, respectively, for type 2; and 98.8%, 98.9%, 93.3%, 100%, and 97.8%, respectively, for type 3. Sabin IPV has good safety characteristics. The seroconversion rates for type 1 poliovirus (most appropriate concentration, 15 D Ag units [DU]), type 2 (32 DU), and type 3 (45 DU) Sabin IPV were similar to those of the OPV and cIPV control groups. NCT01056705.

Identifying the most successful dose (MSD) in dose-finding studies in cancer.

Science.gov (United States)

Zohar, Sarah; O'Quigley, John

2006-01-01

For a dose finding study in cancer, the most successful dose (MSD), among a group of available doses, is that dose at which the overall success rate is the highest. This rate is the product of the rate of seeing non-toxicities together with the rate of tumor response. A successful dose finding trial in this context is one where we manage to identify the MSD in an efficient manner. In practice we may also need to consider algorithms for identifying the MSD which can incorporate certain restrictions, the most common restriction maintaining the estimated toxicity rate alone below some maximum rate. In this case the MSD may correspond to a different level than that for the unconstrained MSD and, in providing a final recommendation, it is important to underline that it is subject to the given constraint. We work with the approach described in O'Quigley et al. [Biometrics 2001; 57(4):1018-1029]. The focus of that work was dose finding in HIV where both information on toxicity and efficacy were almost immediately available. Recent cancer studies are beginning to fall under this same heading where, as before, toxicity can be quickly evaluated and, in addition, we can rely on biological markers or other measures of tumor response. Mindful of the particular context of cancer, our purpose here is to consider the methodology developed by O'Quigley et al. and its practical implementation. We also carry out a study on the doubly under-parameterized model, developed by O'Quigley et al. but not

Efficacy and safety of weight-based insulin glargine dose titration regimen compared with glucose level- and current dose-based regimens in hospitalized patients with type 2 diabetes: a randomized, controlled study.

Science.gov (United States)

Li, Xiaowei; Du, Tao; Li, Wangen; Zhang, Tong; Liu, Haiyan; Xiong, Yifeng

2014-09-01

Insulin glargine is widely used as basal insulin. However, published dose titration regimens for insulin glargine are complex. This study aimed to compare the efficacy and safety profile of a user-friendly, weight-based insulin glargine dose titration regimen with 2 published regimens. A total of 160 hospitalized patients with hyperglycemia in 3 medical centers were screened. Our inclusion criteria included age 18 to 80 years and being conscious. Exclusion criteria included pregnancy or breast-feeding and hepatic or renal dysfunction. A total of 149 patients were randomly assigned to receive weight-based, glucose level-based, or dose-based insulin glargine dose titration regimen between January 2011 and February 2013. The initial dose of insulin glargine was 0.2 U/kg. In the weight-based regimen (n = 49), the dose was titrated by increments of 0.1 U/kg daily. In the glucose level-based regimen (n = 51), the dose was titrated by 2, 4, 6, or 8 U daily when fasting blood glucose (FBG) was, respectively, between 7.0 and 7.9, 8.0 and 8.9, 9.0 and 9.9, or ≥10 mmol/L. In the current dose-based regimen (n = 49), titration was by daily increments of 20% of the current dose. The target FBG in all groups was ≤7.0 mmol/L. The incidence of hypoglycemia was recorded. One-way ANOVA and χ(2) test were used to compare data between the 3 groups. All but 1 patient who required additional oral antidiabetic medication completed the study. The mean (SD) time to achieve target FBG was 3.2 (1.2) days with the weight-based regimen and 3.7 (1.5) days with the glucose level-based regimen (P = 0.266). These times were both shorter than that achieved with the current dose-based regimen (4.8 [2.8] days; P = 0.0001 and P = 0.005, respectively). The daily doses of insulin glargine at the study end point were 0.43 (0.13) U/kg with the weight-based regimen, 0.50 (0.20) U/kg with the glucose level-based regimen, and 0.47 (0.23) U/kg with the current dose-based regimen (P = 0.184). The incidence

Safety, immunogenicity and dose ranging of a new Vi-CRM₁₉₇ conjugate vaccine against typhoid fever: randomized clinical testing in healthy adults.

Science.gov (United States)

van Damme, Pierre; Kafeja, Froukje; Anemona, Alessandra; Basile, Venere; Hilbert, Anne Katrin; De Coster, Ilse; Rondini, Simona; Micoli, Francesca; Qasim Khan, Rana M; Marchetti, Elisa; Di Cioccio, Vito; Saul, Allan; Martin, Laura B; Podda, Audino

2011-01-01

Typhoid fever causes more than 21 million cases of disease and 200,000 deaths yearly worldwide, with more than 90% of the disease burden being reported from Asia. Epidemiological data show high disease incidence in young children and suggest that immunization programs should target children below two years of age: this is not possible with available vaccines. The Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM₁₉₇) for infant vaccination concomitantly with EPI vaccines, either starting at 6 weeks with DTP or at 9 months with measles vaccine. We report the results from a Phase 1 and a Phase 2 dose ranging trial with Vi-CRM₁₉₇ in European adults. Following randomized blinded comparison of single vaccination with either Vi-CRM₁₉₇ or licensed polysaccharide vaccines (both containing 25·0 µg of Vi antigen), a randomised observer blinded dose ranging trial was performed in the same center to compare three concentrations of Vi-CRM₁₉₇ (1·25 µg, 5·0 µg and 12·5 µg of Vi antigen) with the polysaccharide vaccine. All vaccines were well tolerated. Compared to the polysaccharide vaccine, Vi-CRM₁₉₇ induced a higher incidence of mild to moderate short lasting local pain. All Vi-CRM₁₉₇ formulations induced higher Vi antibody levels compared to licensed control, with clear dose response relationship. Vi-CRM₁₉₇ did not elicit safety concerns, was highly immunogenic and is therefore suitable for further clinical testing in endemic populations of South Asia. ClinicalTrials.gov NCT01123941 NCT01193907.

A Dose-Finding Study of Dexketoprofen in Patients Undergoing Laparoscopic Cholecystectomy: A Randomized Clinical Trial on Effects on the Analgesic Concentration of Oxycodone.

Science.gov (United States)

Piirainen, Annika; Kokki, Hannu; Immonen, Satu; Eskelinen, Matti; Häkkinen, Merja R; Hautajärvi, Heidi; Kokki, Merja

2015-12-01

Dexketoprofen has been shown to provide efficient analgesia and an opioid-sparing effect after orthopedic surgery. In this dose-finding study, we evaluated the analgesic efficacy and opioid-sparing effect of dexketoprofen administered intravenously (i.v.) after laparoscopic cholecystectomy (LCC). Twenty-four patients undergoing LCC were randomized to receive dexketoprofen 10 or 50 mg i.v. 15 min before the end of the surgery. Subjects were provided with 0.2 mg/kg of oxycodone at anesthesia induction. In the recovery room, pain was assessed with an 11-point numerical rating scale (NRS; score of 0 = no pain, score of 10 = most severe pain) every 10 min. When the NRS score was ≥3/10 at rest or ≥5/10 at wound compression, a plasma sample was taken for analysis of oxycodone [to determine the minimum effective concentration (MEC)], its metabolites, and dexketoprofen. After that, subjects were titrated with oxycodone 2 or 3 mg i.v. every 10 min until the NRS score was dexketoprofen. At the onset of pain, the plasma oxycodone concentrations (MEC) were similar in the two groups: median 60 ng/mL (range 37-73) in the 10 mg group and median 52 ng/mL (range 24-79) in the 50 mg group. At the time of pain relief, the MEACs were 98 ng/mL (range 59-150) in the 10 mg group and 80 ng/mL (range 45-128) in the 50 mg group. The total doses of oxycodone needed to achieve pain relief were similar: 0.11 mg/kg (range 0-0.33) in the 10 mg group and 0.08 mg/kg (range 0-0.24) in the 50 mg group. Eleven subjects developed mild desaturation or a decreased respiratory rate after oxycodone titration. In the present double-blinded, randomized clinical trial, the need for a rescue opioid analgesic, oxycodone, was similar with the two dose levels of dexketoprofen-10 and 50 mg i.v.-after LCC.

Randomized, double-blind, placebo-controlled, crossover study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder: novel findings using a simulated adult workplace environment design

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Gao Joseph

2010-06-01

Full Text Available Abstract Background Duration of efficacy and safety of lisdexamfetamine dimesylate (LDX was assessed in adults (18-55 years with attention-deficit/hyperactivity disorder (ADHD using the simulated adult workplace environment. Methods After open-label dose optimization (4-week with LDX, 30-70 mg/d, subjects entered a 2-week randomized, double-blind, placebo-controlled crossover phase. Efficacy assessments included the Permanent Product Measure of Performance (PERMP total score (attempted+correct measured predose and from 2 to 14 hours postdose, averaged across postdose sessions (primary and at each time point vs placebo (secondary, and ADHD Rating Scale IV (ADHD-RS-IV with adult prompts at baseline and crossover visits. Safety assessments included treatment-emergent adverse events (TEAEs, vital signs, and electrocardiograms. Results Of 127 randomized subjects, 105 were in the intention-to-treat population and 103 completed the study. While receiving LDX vs placebo, adults had greater improvement (P P ≤ .0017 for each time point and change from predose (P P Conclusions LDX significantly improved PERMP scores vs placebo and maintained improvement throughout the day from the first (2 hours to last (14 hours postdose time point vs placebo in adults with ADHD. Trial Registration ClinicalTrials.gov Identifier: NCT00697515 Safety and Efficacy Workplace Environment Study of Lisdexamfetamine Dimesylate (LDX in Adults With Attention-Deficit Hyperactivity Disorder (ADHD http://www.clinicaltrials.gov/ct2/show/NCT00697515?term=NCT00697515&rank=1

Randomized Crossover Comparison of the Short-Term Efficacy and Safety of Single Half-Dose Silodosin and Tamsulosin Hydrochoride in Men With Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia.

Science.gov (United States)

Takeshita, Hideki; Moriyama, Shingo; Arai, Yoshiaki; Washino, Satoshi; Saito, Kimitoshi; Chiba, Koji; Horiuchi, Susumu; Noro, Akira

2016-01-01

To compare the efficacy and safety of single half-dose silodosin and single full-dose tamsulosin in Japanese men with lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH). Japanese men aged ≥50 years with LUTS/BPH and an International Prostate Symptom Score (IPSS) of ≥8 were enrolled in the randomized crossover study and divided into silodosin-preceding (S-T) and tamsulosin-preceding (T-S) groups. The S-T group received 4 mg silodosin once daily for 4 weeks followed by 0.2 mg tamsulosin once daily for 4 weeks. The T-S group received the reverse treatment sequence. A washout period prior to drug crossover was not included. Subjective and objective efficacy parameters including IPSS, quality of life (QOL) index, uroflowmetry, and safety were compared between the two groups. Thirty of 34 men (S-T group n = 16; T-S group n = 14) completed the study. Both drugs significantly improved all IPSS items and QOL index in the first treatment period. Subjective improvement in nocturia by silodosin was observed in both the first and crossover treatment periods. Objective improvement in maximum flow rate by silodosin was only observed in the first treatment period. Adverse events occurred more frequently with silodosin than with tamsulosin; however, none of the adverse events required treatment discontinuation. Ejaculation disorders occurred in three participants (10%) and were associated with silodosin use. Single half-dose silodosin has a similar efficacy to full-dose tamsulosin in Japanese men with LUTS/BPH and thus, may represent an effective, safe, and affordable treatment option. © 2015 Wiley Publishing Asia Pty Ltd.

A randomized, phase 1/2 trial of the safety, tolerability, and immunogenicity of bivalent rLP2086 meningococcal B vaccine in healthy infants.

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Martinon-Torres, Federico; Gimenez-Sanchez, Francisco; Bernaola-Iturbe, Enrique; Diez-Domingo, Javier; Jiang, Qin; Perez, John L

2014-09-08

Neisseria meningitidis serogroup B (MnB) is a major cause of invasive meningococcal disease in infants. A conserved, surface-exposed lipoprotein, LP2086 (a factor H-binding protein [fHBP]), is a promising MnB vaccine target. A bivalent, recombinant vaccine targeting the fHBP (rLP2086) of MnB was developed. This phase 1/2 clinical study was designed to assess the immunogenicity, safety, and tolerability of a 4-dose series of the rLP2086 vaccine at 20-, 60-, 120-, or 200-μg dose levels in vaccine-naive infants when given with routine childhood vaccines. The study was to consist of two phases: a single-blind sentinel phase and an open-label full enrollment phase. During the sentinel phase, randomization of subjects to the next higher dose was delayed pending a 14-day safety review of dose 1 of the preceding dose cohort. The full enrollment phase was to occur after completion of the sentinel phase. Local reactions were generally mild and adverse events infrequent; however, after only 46 infants were randomized into the study, fever rates were 64% and 90% in subjects receiving one 20- or 60-μg rLP2086 dose, respectively. Most fevers were group and 1 subject in the 60-μg group experienced fevers >39.0°C; no fevers were >40.0°C. Due to these high fever rates, the study was terminated early. No immunogenicity data were collected. This report discusses the safety and acceptability of rLP2086 in infants after one 20- or 60-μg dose. Due to the high fever rate experienced in the 20- and 60-μg groups, rLP2086 in the current formulation may not be acceptable for infants. Copyright © 2014. Published by Elsevier Ltd.

Relative safety profiles of high dose statin regimens

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Carlos Escobar

2008-06-01

Full Text Available Carlos Escobar, Rocio Echarri, Vivencio BarriosDepartment of Cardiology, Hospital Ramón y Cajal, Madrid, SpainAbstract: Recent clinical trials recommend achieving a low-density lipoprotein cholesterol level of <100 mg/dl in high-risk and <70 mg/dl in very high risk patients. To attain these goals, however, many patients will need statins at high doses. The most frequent side effects related to the use of statins, myopathy, rhabdomyolysis, and increased levels of transaminases, are unusual. Although low and moderate doses show a favourable profile, there is concern about the tolerability of higher doses. During recent years, numerous trials to analyze the efficacy and tolerability of high doses of statins have been published. This paper updates the published data on the safety of statins at high doses.Keywords: statins, high doses, tolerability, liver, muscle

Dose and Fractionation in Radiation Therapy of Curative Intent for Non-Small Cell Lung Cancer: Meta-Analysis of Randomized Trials

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Ramroth, Johanna; Cutter, David J.; Darby, Sarah C. [Nuffield Department of Population Health, University of Oxford, Oxford, Oxfordshire (United Kingdom); Higgins, Geoff S. [Department of Oncology, University of Oxford, Oxford, Oxfordshire (United Kingdom); McGale, Paul [Nuffield Department of Population Health, University of Oxford, Oxford, Oxfordshire (United Kingdom); Partridge, Mike [CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, Oxfordshire (United Kingdom); Taylor, Carolyn W., E-mail: carolyn.taylor@ndph.ox.ac.uk [Nuffield Department of Population Health, University of Oxford, Oxford, Oxfordshire (United Kingdom)

2016-11-15

Purpose: The optimum dose and fractionation in radiation therapy of curative intent for non-small cell lung cancer remains uncertain. We undertook a published data meta-analysis of randomized trials to examine whether radiation therapy regimens with higher time-corrected biologically equivalent doses resulted in longer survival, either when given alone or when given with chemotherapy. Methods and Materials: Eligible studies were randomized comparisons of 2 or more radiation therapy regimens, with other treatments identical. Median survival ratios were calculated for each comparison and pooled. Results: 3795 patients in 25 randomized comparisons of radiation therapy dose were studied. The median survival ratio, higher versus lower corrected dose, was 1.13 (95% confidence interval [CI] 1.04-1.22) when radiation therapy was given alone and 0.83 (95% CI 0.71-0.97) when it was given with concurrent chemotherapy (P for difference=.001). In comparisons of radiation therapy given alone, the survival benefit increased with increasing dose difference between randomized treatment arms (P for trend=.004). The benefit increased with increasing dose in the lower-dose arm (P for trend=.01) without reaching a level beyond which no further survival benefit was achieved. The survival benefit did not differ significantly between randomized comparisons where the higher-dose arm was hyperfractionated and those where it was not. There was heterogeneity in the median survival ratio by geographic region (P<.001), average age at randomization (P<.001), and year trial started (P for trend=.004), but not for proportion of patients with squamous cell carcinoma (P=.2). Conclusions: In trials with concurrent chemotherapy, higher radiation therapy doses resulted in poorer survival, possibly caused, at least in part, by high levels of toxicity. Where radiation therapy was given without chemotherapy, progressively higher radiation therapy doses resulted in progressively longer survival, and no

Dose and Fractionation in Radiation Therapy of Curative Intent for Non-Small Cell Lung Cancer: Meta-Analysis of Randomized Trials

International Nuclear Information System (INIS)

Ramroth, Johanna; Cutter, David J.; Darby, Sarah C.; Higgins, Geoff S.; McGale, Paul; Partridge, Mike; Taylor, Carolyn W.

2016-01-01

Purpose: The optimum dose and fractionation in radiation therapy of curative intent for non-small cell lung cancer remains uncertain. We undertook a published data meta-analysis of randomized trials to examine whether radiation therapy regimens with higher time-corrected biologically equivalent doses resulted in longer survival, either when given alone or when given with chemotherapy. Methods and Materials: Eligible studies were randomized comparisons of 2 or more radiation therapy regimens, with other treatments identical. Median survival ratios were calculated for each comparison and pooled. Results: 3795 patients in 25 randomized comparisons of radiation therapy dose were studied. The median survival ratio, higher versus lower corrected dose, was 1.13 (95% confidence interval [CI] 1.04-1.22) when radiation therapy was given alone and 0.83 (95% CI 0.71-0.97) when it was given with concurrent chemotherapy (P for difference=.001). In comparisons of radiation therapy given alone, the survival benefit increased with increasing dose difference between randomized treatment arms (P for trend=.004). The benefit increased with increasing dose in the lower-dose arm (P for trend=.01) without reaching a level beyond which no further survival benefit was achieved. The survival benefit did not differ significantly between randomized comparisons where the higher-dose arm was hyperfractionated and those where it was not. There was heterogeneity in the median survival ratio by geographic region (P<.001), average age at randomization (P<.001), and year trial started (P for trend=.004), but not for proportion of patients with squamous cell carcinoma (P=.2). Conclusions: In trials with concurrent chemotherapy, higher radiation therapy doses resulted in poorer survival, possibly caused, at least in part, by high levels of toxicity. Where radiation therapy was given without chemotherapy, progressively higher radiation therapy doses resulted in progressively longer survival, and no

Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in healthy Japanese subjects.

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Sarashina, Akiko; Koiwai, Kazuki; Seman, Leo J; Yamamura, Norio; Taniguchi, Atsushi; Negishi, Takahiro; Sesoko, Shogo; Woerle, Hans J; Dugi, Klaus A

2013-01-01

This randomized, placebo-controlled within dose groups, double-blind, single rising dose study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of 1 mg to 100 mg doses of empagliflozin in 48 healthy Japanese male subjects. Empagliflozin was rapidly absorbed, reaching peak levels in 1.25 to 2.50 h; thereafter, plasma concentrations declined in a biphasic fashion, with mean terminal elimination half-life ranging from 7.76 to 11.7 h. Increase in empagliflozin exposure was proportional to dose. Oral clearance was dose independent and ranged from 140 to 172 mL/min. In the 24 h following 100 mg empagliflozin administration, the mean (%CV) amount of glucose excreted in urine was 74.3 (17.1) g. The amount and the maximum rate of glucose excreted via urine increased with dose of empagliflozin. Nine adverse events, all of mild intensity, were reported by 8 subjects (7 with empagliflozin and 1 with the placebo). No hypoglycemia was reported. In conclusion, 1 mg to 100 mg doses of empagliflozin had a good safety and tolerability profile in healthy Japanese male subjects. Exposure to empagliflozin was dose proportional. The amount and rate of urinary glucose excretion were higher with empagliflozin than with the placebo, and increased with empagliflozin dose.

Safety, immunogenicity and dose ranging of a new Vi-CRM₁₉₇ conjugate vaccine against typhoid fever: randomized clinical testing in healthy adults.

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Pierre van Damme

Full Text Available Typhoid fever causes more than 21 million cases of disease and 200,000 deaths yearly worldwide, with more than 90% of the disease burden being reported from Asia. Epidemiological data show high disease incidence in young children and suggest that immunization programs should target children below two years of age: this is not possible with available vaccines. The Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM₁₉₇ for infant vaccination concomitantly with EPI vaccines, either starting at 6 weeks with DTP or at 9 months with measles vaccine. We report the results from a Phase 1 and a Phase 2 dose ranging trial with Vi-CRM₁₉₇ in European adults.Following randomized blinded comparison of single vaccination with either Vi-CRM₁₉₇ or licensed polysaccharide vaccines (both containing 25·0 µg of Vi antigen, a randomised observer blinded dose ranging trial was performed in the same center to compare three concentrations of Vi-CRM₁₉₇ (1·25 µg, 5·0 µg and 12·5 µg of Vi antigen with the polysaccharide vaccine.All vaccines were well tolerated. Compared to the polysaccharide vaccine, Vi-CRM₁₉₇ induced a higher incidence of mild to moderate short lasting local pain. All Vi-CRM₁₉₇ formulations induced higher Vi antibody levels compared to licensed control, with clear dose response relationship.Vi-CRM₁₉₇ did not elicit safety concerns, was highly immunogenic and is therefore suitable for further clinical testing in endemic populations of South Asia.ClinicalTrials.gov NCT01123941 NCT01193907.

77 FR 2606 - Pipeline Safety: Random Drug Testing Rate

Science.gov (United States)

2012-01-18

... DEPARTMENT OF TRANSPORTATION Pipeline and Hazardous Materials Safety Administration [Docket ID PHMSA-2012-0004] Pipeline Safety: Random Drug Testing Rate AGENCY: Pipeline and Hazardous Materials... pipelines and operators of liquefied natural gas facilities must select and test a percentage of covered...

75 FR 9018 - Pipeline Safety: Random Drug Testing Rate

Science.gov (United States)

2010-02-26

... DEPARTMENT OF TRANSPORTATION Pipeline and Hazardous Materials Safety Administration [Docket ID PHMSA-2010-0034] Pipeline Safety: Random Drug Testing Rate AGENCY: Pipeline and Hazardous Materials... pipelines and operators of liquefied natural gas facilities must select and test a percentage of covered...

Pharmacokinetics and Safety of Amenamevir in Healthy Subjects: Analysis of Four Randomized Phase 1 Studies.

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Kusawake, Tomohiro; Keirns, James J; Kowalski, Donna; den Adel, Martin; Groenendaal-van de Meent, Dorien; Takada, Akitsugu; Ohtsu, Yoshiaki; Katashima, Masataka

2017-12-01

Amenamevir (ASP2151) is a nonnucleoside antiherpesvirus compound available for the treatment of varicella-zoster virus infections. In this article we summarize the findings of four phase 1 studies in healthy participants. Four randomized phase 1 studies investigated the safety and pharmacokinetics of single and multiple doses of amenamevir, including the assessment of age group effect (nonelderly vs elderly), food effect, and the relative bioavailability of two formulations. Amenamevir was administered orally at various doses as a single dose (5-2400 mg) or daily (300 or 600 mg/day) for 7 days. Following single and multiple oral doses, amenamevir demonstrated a less than dose proportional increase in the pharmacokinetic parameters area under the plasma drug concentration versus time curve from time zero to infinity (AUC inf ) and C max . After single and multiple oral 300-mg doses of amenamevir, no apparent differences in pharmacokinetics were observed between nonelderly and elderly participants. In contrast, with the amenamevir 600-mg dose both the area under the plasma drug concentration versus time curve from time zero to 24 h and C max were slightly increased and renal clearance was decreased in elderly participants. The pharmacokinetics of amenamevir was affected by food, with AUC inf increased by about 90%. In the bioavailability study, AUC inf and C max were slightly lower following tablet versus capsule administration (decreased by 14 and 12%, respectively), with relative bioavailability of 86%. The different amenamevir doses and formulations were safe and well tolerated; no deaths or serious adverse events were reported. Amenamevir had less than dose proportional pharmacokinetic characteristics. Age may have an influence on amenamevir pharmacokinetics; however, the effect was considered minimal. The pharmacokinetics of amenamevir were affected by food, with AUC inf almost doubling when amenamevir was administered with food. The concentration versus

Standardized dose factors for dose calculations - 1982 SRP reactor safety analysis report tritium, iodine, and noble gases

International Nuclear Information System (INIS)

Pillinger, W.L.; Marter, W.L.

1982-01-01

Standardized dose constants are recommended for calculation of offsite doses in the 1982 SRP Reactor Safety Analysis Report (SAR). Dose constants are proposed for inhalation of tritium and radioiodines and for submersion in a semi-infinite cloud of radioiodines and noble gases. The proposed constants, based on ICRP2 methodology for internal dose and methodology recommended by the US Nuclear Regulatory Commission for external dose, are compatible with dose calculational methods used at the Savannah River Plant and Savannah River Laboratory for normal releases of radioactivity. 8 references

Safety of polyethylene glycol 3350 solution in chronic constipation: randomized, placebo-controlled trial.

Science.gov (United States)

McGraw, Thomas

2016-01-01

To evaluate the safety and tolerability of aqueous solution concentrate (ASC) of polyethylene glycol (PEG) 3350 in patients with functional constipation. The patients who met Rome III diagnostic criteria for functional constipation were randomized in this multicenter, randomized, placebo-controlled, single-blind study to receive once daily dose of PEG 3350 (17 g) ASC or placebo solution for 14 days. The study comprised a screening period (visit 1), endoscopy procedure (visits 2 and 3), and followup telephone calls 30 days post-treatment. Safety end points included adverse events (AEs), clinical laboratory evaluations, vital signs, and others. The primary end points were the proportion of patients with abnormalities of the oral and esophageal mucosa, detected by visual and endoscopic examination of the oral cavity and esophagus, respectively, compared with placebo. A secondary objective was to compare the safety and tolerability of ASC by evaluating AEs or adverse drug reactions. A total of 65 patients were enrolled in this study, 31 were randomized to PEG 3350 ASC and 34 were randomized to placebo, of which 62 patients completed the study. No patients in either group showed abnormalities in inflammation of the oral mucosa during visit 2 (before treatment) or visit 3 (after treatment). Fewer abnormalities of the esophageal mucosa were observed in the PEG 3350 ASC group than in the placebo group on visit 3, with no significant difference in the proportion of abnormalities between the treatment groups. Overall, 40 treatment-emergent AEs were observed in 48.4% of patients treated with PEG 3350 ASC, and 41 treatment-emergent AEs were observed in 55.9% of patients treated with placebo - nonsignificant difference of -7.5% (95% CI: -21.3, 6.3) between treatment groups. No serious AEs or deaths were reported, and no patient discontinued because of an AE. PEG 3350 ASC is safe and well tolerated in patients with functional constipation (NCT01885104).

Dental radiographic units - radiation safety and patient doses

International Nuclear Information System (INIS)

Nagpal, J.S.; Varadharajan, Geetha

2001-01-01

Three models of dental radiographic machines have been examined for radiation safety. Using TL dosemeters, doses received by the patients at chest level and the gonads have been estimated. Care should be taken to shield gonads during dental radiographic examinations. (author)

An accelerated dose escalation with a grass pollen allergoid is safe and well-tolerated: a randomized open label phase II trial.

Science.gov (United States)

Chaker, A M; Al-Kadah, B; Luther, U; Neumann, U; Wagenmann, M

2015-01-01

The number of injections in the dose escalation of subcutaneous immunotherapy (SCIT) is small for some currently used hypoallergenic allergoids, but can still be inconvenient to patients and can impair compliance. The aim of this trial was to compare safety and tolerability of an accelerated to the conventional dose escalation scheme of a grass pollen allergoid. In an open label phase II trial, 122 patients were 1:1 randomized for SCIT using a grass pollen allergoid with an accelerated dose escalation comprising only 4 weekly injections (Group I) or a conventional dose escalation including 7 weekly injections (Group II). Safety determination included the occurrence of local and systemic adverse events. Tolerability was assessed by patients and physicians. Treatment-related adverse events were observed in 22 (36.1 %) patients in Group I and 15 (24.6 %) in Group II. Local reactions were reported by 18 patients in Group I and 11 in Group II. Five Grade 1 systemic reactions (WAO classification) were observed in Group I and 2 in Group II. Grade 2 reactions occurred 3 times in Group I and 2 times in Group II. Tolerability was rated as "good" or "very good" by 53 (86.9 %) patients in Group I and 59 (100 %) in Group II by investigators. Forty-eight patients in Group I (80.0 %) and 54 in Group II (91.5 %) rated tolerability as "good" or "very good". The dose escalation of a grass pollen allergoid can be accelerated with safety and tolerability profiles comparable to the conventional dose escalation.

A Phase Ib open label, randomized, safety study of SANGUINATE™ in patients with sickle cell anemia

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Hemant Misra

Full Text Available Abstract Background: Treatment of sickle cell anemia is a challenging task and despite the well understood genetic and biochemical pathway of sickle hemoglobin, current therapy continues to be limited to the symptomatic treatment of pain, supplemental oxygen, antibiotics, red blood cell transfusions and hydroxyurea. SANGUINATE is a carbon monoxide releasing molecule and oxygen transfer agent under clinical development for the treatment of sickle cell anemia and comorbidities. Methods: An open-label randomized Phase Ib study was performed in adult sickle cell anemia patients. Two dose levels of SANGUINATE were compared to hydroxyurea in 24 homozygotes for Hb SS. Twelve subjects received either a low dose (160 mg/kg of SANGUINATE or 15 mg/kg hydroxyurea. Another 12 subjects received either a high dose (320 mg/kg of SANGUINATE or 15 mg/kg hydroxyurea. The primary endpoint was the safety of SANGUINATE versus hydroxyurea in sickle cell anemia patients. Secondary endpoints included determination of the plasma pharmacokinetics and assessment of hematologic measurements. Results: Musculoskeletal related adverse events were the most common. Transient troponin I levels increased in three patients, one of whom had an increase in tricuspid regurgitant velocity; however, no clinical signs were noted. Following an assessment of vital signs, tricuspid regurgitant velocity, electrocardiogram, serum biochemistry, hematology, urinalysis, and analysis of reported adverse events, SANGUINATE was found to be safe in stable sickle cell anemia patients. Conclusions: The clinical trial met its primary objective of demonstrating an acceptable safety profile for SANGUINATE in patients with sickle cell anemia. This trial established the safety of SANGUINATE at both dose levels and permitted its advance to Phase II trials.

Phase 2 Randomized, Dose-Ranging Study of Oxymetazoline Cream for Treatment of Persistent Facial Erythema Associated With Rosacea.

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DuBois, Janet; Dover, Jeffrey S; Jones, Terry M; Weiss, Robert A; Berk, David R; Ahluwalia, Gurpreet

2018-03-01

Rosacea is a chronic dermatologic condition with limited treatment options. This phase 2 study evaluated the optimal oxymetazoline dosing regimen in patients with moderate to severe persistent facial erythema of rosacea. Patients were randomly assigned to oxymetazoline cream, 0.5%, 1.0%, or 1.5%, or vehicle, administered once daily (QD) or twice daily (BID) for 28 consecutive days. The primary efficacy endpoint was the proportion of patients with ≥2-grade improvement from baseline on the Clinician Erythema Assessment (CEA) and the Subject Self-Assessment of erythema (SSA-1) on day 28. Safety assessments included treatment-emergent adverse events and dermal tolerability. A total of 356 patients were treated (mean age, 50.0 years; 80.1% female). The proportions of patients achieving the primary endpoint were significantly higher with oxymetazoline 0.5% QD (P=0.049), 1.0% QD (P=0.006), 1.5% QD (P=0.012), 1.0% BID (P=0.021), and 1.5% BID (P=0.006) versus their respective vehicles. For both QD and BID dosing, the efficacy of oxymetazoline 1.0% was greater than the 0.5% dose and comparable to the 1.5% dose. Safety and application-site tolerability were similar across groups. Short-term treatment period. Oxymetazoline 1.0% QD provided the optimal dosing regimen and was selected for evaluation in phase 3 clinical studies. J Drugs Dermatol. 2018;17(3):308-316.

Dose-associated changes in safety and efficacy parameters observed in a 24-week maintenance trial of olanzapine long-acting injection in patients with schizophrenia

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Watson Susan B

2011-02-01

Full Text Available Abstract Background In a recently published 24-week maintenance study of olanzapine long-acting injection (LAI in schizophrenia (Kane et al., 2010, apparent dose-associated changes were noted in both efficacy and safety parameters. To help clinicians balance safety and efficacy when choosing a dose of olanzapine LAI, we further studied these changes. Methods Outpatients with schizophrenia who had maintained stability on open-label oral olanzapine for 4 to 8 weeks were randomly assigned to "low" (150 mg/2 weeks; N = 140, "medium" (405 mg/4 weeks; N = 318, or "high" (300 mg/2 weeks; N = 141 dosages of olanzapine LAI for 24 weeks. Potential relationships between dose and several safety or efficacy measures were examined via regression analysis, the Jonckheere-Terpstra test (continuous data, or the Cochran-Armitage test (categorical data. Results Safety parameters statistically significantly related to dose were mean weight change (low: +0.67 [SD = 4.38], medium: +0.89 [SD = 3.87], high: +1.70 [SD = 4.14] kg, p = .024; effect size [ES] = 0.264 high vs. low dose, mean change in prolactin (low: -5.61 [SD = 12.49], medium: -2.76 [SD = 19.02], high: +3.58 [SD = 33.78] μg/L, p = .001; ES = 0.410 high vs. low dose, fasting triglycerides change from normal at baseline to high (low: 3.2%, medium: 6.0%, high: 18.9%, p = .001; NNT = 7 high vs. low dose and fasting high-density lipoprotein cholesterol change from normal at baseline to low (low: 13.8%, medium: 19.6%, high: 30.7%, p = .019; NNT = 6 high vs. low dose. Efficacy measures significantly related to dose included Positive and Negative Syndrome Scale total score mean change (low: +2.66 [SD = 14.95], medium: -0.09 [SD = 13.47], high: -2.19 [SD = 13.11], p Conclusions Analyses of several safety and efficacy parameters revealed significant associations with dose of olanzapine LAI, with the highest dose generally showing greater efficacy as well as greater adverse changes in metabolic safety measures. When

Pharmacokinetics, pharmacodynamics, efficacy, and safety of a new recombinant asparaginase preparation in children with previously untreated acute lymphoblastic leukemia: A randomized phase 2 clinical trial

NARCIS (Netherlands)

R. Pieters (Rob); I.M. Appel (Inge); H.J. Kuehnel; I. Tetzlaff-Fohr (Iris); U. Pichlmeier (Uwe); I. van der Vaart (Inekee); E. Visser (Eline); R.L. Stigter

2008-01-01

textabstractThe pharmacokinetics, pharmacodynam-ics, efficacy, and safety of a new recom-binant Escherichia coli - asparaginase preparation was compared withAsparagi-nase medac. Thirty-two children with acute lymphoblastic leukemia were randomized to receive one of both agents at a dose of 5000

Safety and Efficacy of Rocuronium With Sugammadex Reversal Versus Succinylcholine in Outpatient Surgery-A Multicenter, Randomized, Safety Assessor-Blinded Trial.

Science.gov (United States)

Soto, Roy; Jahr, Jonathan S; Pavlin, Janet; Sabo, Daniel; Philip, Beverly K; Egan, Talmage D; Rowe, Everton; de Bie, Joris; Woo, Tiffany

Complex surgical procedures are increasingly performed in an outpatient setting, with emphasis on rapid recovery and case turnover. In this study, the combination of rocuronium for neuromuscular blockade (NMB) reversed by single-dose sugammadex was compared with succinylcholine followed by spontaneous recovery in outpatient surgery. This multicenter, randomized, safety assessor-blinded study enrolled adults undergoing a short elective outpatient surgical procedure requiring NMB and tracheal intubation. Patients were randomized to NMB with either rocuronium 0.6 mg/kg for tracheal intubation with incremental doses of rocuronium 0.15 mg/kg and subsequent reversal with sugammadex 4.0 mg/kg at 1-2 posttetanic counts or succinylcholine 1.0 mg/kg for intubation with spontaneous recovery. The primary efficacy end point was the time from sugammadex administration to recovery of the train-of-four ratio to 0.9; for succinylcholine, time from administration to recovery of the first twitch (T1) to 90% was assessed. From 167 patients enrolled, 150 received treatment. The all-subjects-treated population comprised 70 patients in the rocuronium-sugammadex group and 80 in the succinylcholine group. Geometric mean (95% confidence interval) time from the start of sugammadex administration to recovery of the train-of-four ratio to 0.9 was 1.8 (1.6-2.0) minutes. Geometric mean (95% confidence interval) time from succinylcholine administration to recovery of T1 to 90% was 10.8 (10.1-11.5) minutes. Health outcome variables were similar between the groups. Adverse events were reported in 87.1% and 93.8% of patients for rocuronium-sugammadex and succinylcholine, respectively. In conclusion, rocuronium for intubation followed by sugammadex for reversal of NMB offers a viable treatment option in outpatient surgery without prolonging recovery duration or jeopardizing safety.

Safety assessments of subcutaneous doses of aragonite calcium carbonate nanocrystals in rats

Science.gov (United States)

Jaji, Alhaji Zubair; Zakaria, Zuki Abu Bakar; Mahmud, Rozi; Loqman, Mohamad Yusof; Hezmee, Mohamad Noor Mohamad; Abba, Yusuf; Isa, Tijani; Mahmood, Saffanah Khuder

2017-05-01

Calcium carbonate nanoparticles have shown promising potentials in the delivery of drugs and metabolites. There is however, a paucity of information on the safety of their intentional or accidental over exposures to biological systems and general health safety. To this end, this study aims at documenting information on the safety of subcutaneous doses of biogenic nanocrystals of aragonite polymorph of calcium carbonate derived from cockle shells (ANC) in Sprague-Dawley (SD) rats. ANC was synthesized using the top-down method, characterized using the transmission electron microscopy and field emission scanning electron microscope and its acute and repeated dose 28-day trial toxicities were evaluated in SD rats. The results showed that the homogenous 30 ± 5 nm-sized spherical pure aragonite nanocrystals were not associated with mortality in the rats. Severe clinical signs and gross and histopathological lesions, indicating organ toxicities, were recorded in the acute toxicity (29,500 mg/m2) group and the high dose (5900 mg/m2) group of the repeated dose 28-day trial. However, the medium- (590 mg/m2 body weight) and low (59 mg/m2)-dose groups showed moderate to mild lesions. The relatively mild lesions observed in the low toxicity dosage group marked the safety margin of ANC in SD rats. It was concluded from this study that the toxicity of CaCO3 was dependent on the particulate size (30 ± 5 nm) and concentration and the route of administration used.

Pharmacokinetics and safety of fentanyl sublingual spray and fentanyl citrate intravenous: a multiple ascending dose study in opioid-naïve healthy volunteers.

Science.gov (United States)

Rauck, Richard L; Oh, D Alexander; Singla, Neil; Koch, Christian; Parikh, Neha; Nalamachu, Srinivas; Wilson, Daniel; Yu, Jin; Vetticaden, Santosh

2017-11-01

Fentanyl sublingual spray, with its rapid onset for pain relief, may be efficacious in the management of acute or post-operative pain. Because patients in these settings may be opioid-naïve, the study was conducted to determine the safety, tolerability, and pharmacokinetics of multiple dose administration of fentanyl sublingual spray in an opioid-naïve population. Fentanyl sublingual spray (100 mcg, 200 mcg, and 400 mcg) and fentanyl citrate intravenous (IV; 50 mcg) were administered every 0.5, 1.0, 2.0, and 4.0 h for up to three doses per cohort in opioid-naïve subjects (ClinicalTrials.gov identifier: NCT02641340). Eight subjects in each cohort were randomly assigned (six subjects received fentanyl sublingual spray; two subjects received fentanyl citrate IV). Pharmacokinetic and safety-related pharmacodynamic assessments were performed through 24 h post-first dose. Safety assessments were collected through Day 7. Ninety-six opioid-naïve subjects, aged 20-55 years, with a body mass index of 18.7-31.5 kg/m 2 , participated in the study. Multiple doses of fentanyl sublingual spray (100, 200, and 400 mcg) were generally well tolerated. Hypoxia, observed in the 200-mcg and 400-mcg dose groups, increased with increasing doses and higher dosing frequency, but was readily managed by nasal cannula oxygenation. Overall, nausea increased with increasing doses, and ∼52.6% (10 out of 19) cases of nausea that occurred at the highest dose of 400 mcg were treated with concomitant medication. Overall, the reported adverse events were consistent with the known safety profile of fentanyl. Fentanyl sublingual spray (100 mcg, 200 mg, and 400 mcg) administered every 0.5, 1, 2, and 4 h was generally well tolerated in an opioid-naïve population. The results suggest that doses of 200 mcg or lower may be safe for use in an opioid-naïve population.

Switching to aripiprazole in outpatients with schizophrenia experiencing insufficient efficacy and/or safety/tolerability issues with risperidone: a randomized, multicentre, open-label study.

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Ryckmans, V; Kahn, J P; Modell, S; Werner, C; McQuade, R D; Kerselaers, W; Lissens, J; Sanchez, R

2009-05-01

This study evaluated the safety/tolerability and effectiveness of aripiprazole titrated-dose versus fixed-dose switching strategies from risperidone in patients with schizophrenia experiencing insufficient efficacy and/or safety/tolerability issues. Patients were randomized to an aripiprazole titrated-dose (starting dose 5 mg/day) or fixed-dose (dose 15 mg/day) switching strategy with risperidone down-tapering. Primary endpoint was rate of discontinuation due to adverse events (AEs) during the 12-week study. Secondary endpoints included positive and negative syndrome scale (PANSS), clinical global impressions - improvement of illness scale (CGI-I), preference of medication (POM), subjective well-being under neuroleptics (SWN-K) and GEOPTE (Grupo Español para la Optimización del Tratamiento de la Esquizofrenia) scales. Rates of discontinuations due to AEs were similar between titrated-dose and fixed-dose strategies (3.5% vs. 5.0%; p=0.448). Improvements in mean PANSS total scores were similar between aripiprazole titrated-dose and fixed-dose strategies (-14.8 vs. -17.2; LOCF), as were mean CGI-I scores (2.9 vs. 2.8; p=0.425; LOCF) and SWN-K scores (+8.6 vs.+10.3; OC,+7.8 vs.+9.8; LOCF). Switching can be effectively and safely achieved through a titrated-dose or fixed-dose switching strategy for aripiprazole, with down-titration of risperidone.

Sensitivity of dose-finding studies to observation errors.

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Zohar, Sarah; O'Quigley, John

2009-11-01

The purpose of Phase I designs is to estimate the MTD (maximum tolerated dose, in practice a dose with some given acceptable rate of toxicity) while, at the same time, minimizing the number of patients treated at doses too far removed from the MTD. Our purpose here is to investigate the sensitivity of conclusions from dose-finding designs to recording or observation errors. Certain toxicities may go undetected and, conversely, certain non-toxicities may be incorrectly recorded as dose-limiting toxicities. Recording inaccuracies would be expected to have an influence on final and within trial recommendations and, in this paper, we study in greater depth this question. We focus, in particular on three designs used currently; the standard '3+3' design, the grouped up-and-down design [M. Gezmu, N. Flournoy, Group up-and-down designs for dose finding. Journal of Statistical Planning and Inference 2006; 136 (6): 1749-1764.] and the continual reassessment method (CRM, [J. O'Quigley, M. Pepe, L. Fisher, Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Biometrics 1990; 46 (1): 33-48.]). A non-toxicity incorrectly recorded as a toxicity (error of first kind) has a greater influence in general than the converse (error of second kind). These results are illustrated via figures which suggest that the standard '3+3' design in particular is sensitive to errors of the second kind. Such errors can have a very important impact on drug development in that, if carried through to the Phase 2 and Phase 3 studies, we can significantly increase the probability of failure to detect efficacy as a result of having delivered an inadequate dose.

Safety and immunogenicity of an intramuscular quadrivalent influenza vaccine in children 3 to 8 y of age: A phase III randomized controlled study.

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Pepin, Stephanie; Szymanski, Henryk; Rochín Kobashi, Ilya Angélica; Villagomez Martinez, Sandra; González Zamora, José Francisco; Brzostek, Jerzy; Huang, Li-Min; Chiu, Cheng-Hsun; Chen, Po-Yen; Ahonen, Anitta; Forstén, Aino; Seppä, Ilkka; Quiroz, René Farfán; Korhonen, Tiina; Rivas, Enrique; Monfredo, Celine; Hutagalung, Yanee; Menezes, Josemund; Vesikari, Timo

2016-12-01

A quadrivalent, inactivated, split-virion influenza vaccine containing a strain from both B lineages (IIV4) has been developed, but its safety and immunogenicity in young children has not been described. This was a phase III, randomized, double-blind, active-controlled, multi-center study to examine the immunogenicity and safety of IIV4 in children 3-8 y of age (EudraCT no. 2011-005374-33). Participants were randomized 5:1:1 to receive the 2013/2014 Northern Hemisphere formulation of IIV4, an investigational trivalent comparator (IIV3) containing the B/Victoria lineage strain, or the licensed Northern Hemisphere IIV3 containing the B/Yamagata lineage strain. Participants who had not previously received a full influenza vaccination schedule received 2 doses of vaccine 28 d apart; all others received a single dose. 1242 children were included. For all 4 strains, IIV4 induced geometric mean haemagglutination inhibition titres non-inferior to those induced by the IIV3 comparators. For both B strains, geometric mean antibody titres induced by IIV4 were superior to those induced by the IIV3 with the alternative lineage strain. Similar proportions of participants vaccinated with IIV4 and IIV3 reported solicited injection-site reactions, solicited systemic reactions, and vaccine-related adverse events. A single vaccine-related serious adverse event, thrombocytopenia, was reported 9 d after vaccination with IIV4 and resolved without sequelae. In conclusion, in children aged 3-8 y who received one dose or 2 doses 28 d apart, IIV4 had an acceptable safety profile, was as immunogenic as IIV3 for the shared strains, and had superior immunogenicity for the additional B strain.

Radiation safety program in a high dose rate brachytherapy facility

International Nuclear Information System (INIS)

Rodriguez, L.V.; Hermoso, T.M.; Solis, R.C.

2001-01-01

The use of remote afterloading equipment has been developed to improve radiation safety in the delivery of treatment in brachytherapy. Several accidents, however, have been reported involving high dose-rate brachytherapy system. These events, together with the desire to address the concerns of radiation workers, and the anticipated adoption of the International Basic Safety Standards for Protection Against Ionizing Radiation (IAEA, 1996), led to the development of the radiation safety program at the Department of Radiotherapy, Jose R. Reyes Memorial Medical Center and at the Division of Radiation Oncology, St. Luke's Medical Center. The radiation safety program covers five major aspects: quality control/quality assurance, radiation monitoring, preventive maintenance, administrative measures and quality audit. Measures for evaluation of effectiveness of the program include decreased unnecessary exposures of patients and staff, improved accuracy in treatment delivery and increased department efficiency due to the development of staff vigilance and decreased anxiety. The success in the implementation required the participation and cooperation of all the personnel involved in the procedures and strong management support. This paper will discuss the radiation safety program for a high dose rate brachytherapy facility developed at these two institutes which may serve as a guideline for other hospitals intending to install a similar facility. (author)

A randomized controlled trial of vitamin D dosing strategies after acute hip fracture: No advantage of loading doses over daily supplementation

Directory of Open Access Journals (Sweden)

Farrauto Leonardo

2011-06-01

Full Text Available Abstract Background There remains uncertainty regarding the appropriate therapeutic management of hip fracture patients. The primary aim of our study was to examine whether large loading doses in addition to daily vitamin D offered any advantage over a simple daily low-dose vitamin D regimen for increasing vitamin D levels. Methods In this randomized controlled study, patients over age 50 with an acute fragility hip fracture were enrolled from two hospital sites in Ontario, Canada. Participants were randomized to one of three loading dose groups: placebo; 50,000 IU vitamin D2; or 100,000 IU D2. Following a placebo/loading dose, all patients received a daily tablet of 1,000 IU vitamin D3 for 90 days. Serum 25-hydroxy vitamin D (25-OHD was measured at baseline, discharge from acute care (approximately 4-weeks, and 3-months. Results Sixty-five patients were enrolled in the study (44% male. An immediate rise in 25-OHD occurred in the 100,000 group, however there were no significant differences in 25-OHD between the placebo, 50,000 and 100,000 loading dose groups after 4-weeks (69.3, 84.5, 75.6 nmol/L, p = 0.15 and 3-months (86.7, 84.2, 73.3 nmol/L, p = 0.09, respectively. At the end of the study, approximately 75% of the placebo and 50,000 groups had reached the target therapeutic range (75 nmol/L, and 44% of the 100,000 group. Conclusions In correcting vitamin D insufficiency/deficiency in elderly patients with hip fracture, our findings suggest that starting with a lower daily dose of Vitamin D3 achieved similar results as providing an additional large loading dose of Vitamin D2. At the end of the study, all three groups were equally effective in attaining improvement in 25-OHD levels. Given that a daily dose of 1,000 IU vitamin D3 (with or without a loading dose resulted in at least 25% of patients having suboptimal vitamin D status, patients with acute hip fracture may benefit from a higher daily dose of vitamin D. Trial registration Clinical

Safety, tolerability, and immunogenicity of the novel antituberculous vaccine RUTI: randomized, placebo-controlled phase II clinical trial in patients with latent tuberculosis infection.

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Nell, Andre S; D'lom, Eva; Bouic, Patrick; Sabaté, Montserrat; Bosser, Ramon; Picas, Jordi; Amat, Mercè; Churchyard, Gavin; Cardona, Pere-Joan

2014-01-01

To evaluate the safety, tolerability and immunogenicity of three different doses (5, 25 and 50 µg) of the novel antituberculous vaccine RUTI compared to placebo in subjects with latent tuberculosis infection. Double-blind, randomized, placebo-controlled Phase II Clinical Trial (95 patients randomized). Three different RUTI doses and placebo were tested, randomized both in HIV-positive (n = 47) and HIV-negative subjects (n = 48), after completion of one month isoniazid (INH) pre-vaccination. Each subject received two vaccine administrations, 28 Days apart. Five patients withdrew and 90 patients completed the study. Assessment of safety showed no deaths during study. Two subjects had serious adverse events one had a retinal detachment while taking INH and was not randomized and the other had a severe local injection site abscess on each arm and was hospitalized; causality was assessed as very likely and by the end of the study the outcome had resolved. All the patients except 5 (21%) patients of the placebo group (3 HIV+ and 2 HIV-) reported at least one adverse event (AE) during the study. The most frequently occurring AEs among RUTI recipients were (% in HIV+/-): injection site reactions [erythema (91/92), induration (94/92), local nodules (46/25), local pain (66/75), sterile abscess (6/6), swelling (74/83), ulcer (20/11), headache (17/22) and nasopharyngitis (20/5)]. These events were mostly mild and well tolerated. Overall, a polyantigenic response was observed, which differed by HIV- status. The best polyantigenic response was obtained when administrating 25 µg RUTI, especially in HIV-positive subjects which was not increased after the second inoculation. This Phase II clinical trial demonstrates reasonable tolerability of RUTI. The immunogenicity profile of RUTI vaccine in LTBI subjects, even being variable among groups, allows us considering one single injection of one of the highest doses in future trials, preceded by an extended safety clinical

Optimal dose selection accounting for patient subpopulations in a randomized Phase II trial to maximize the success probability of a subsequent Phase III trial.

Science.gov (United States)

Takahashi, Fumihiro; Morita, Satoshi

2018-02-08

Phase II clinical trials are conducted to determine the optimal dose of the study drug for use in Phase III clinical trials while also balancing efficacy and safety. In conducting these trials, it may be important to consider subpopulations of patients grouped by background factors such as drug metabolism and kidney and liver function. Determining the optimal dose, as well as maximizing the effectiveness of the study drug by analyzing patient subpopulations, requires a complex decision-making process. In extreme cases, drug development has to be terminated due to inadequate efficacy or severe toxicity. Such a decision may be based on a particular subpopulation. We propose a Bayesian utility approach (BUART) to randomized Phase II clinical trials which uses a first-order bivariate normal dynamic linear model for efficacy and safety in order to determine the optimal dose and study population in a subsequent Phase III clinical trial. We carried out a simulation study under a wide range of clinical scenarios to evaluate the performance of the proposed method in comparison with a conventional method separately analyzing efficacy and safety in each patient population. The proposed method showed more favorable operating characteristics in determining the optimal population and dose.

An information and communication technology-based centralized clinical trial to determine the efficacy and safety of insulin dose adjustment education based on a smartphone personal health record application: a randomized controlled trial.

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Kim, Gyuri; Bae, Ji Cheol; Yi, Byoung Kee; Hur, Kyu Yeon; Chang, Dong Kyung; Lee, Moon-Kyu; Kim, Jae Hyeon; Jin, Sang-Man

2017-07-18

A Personal Health Record (PHR) is an online application that allows patients to access, manage, and share their health data. PHRs not only enhance shared decision making with healthcare providers, but also enable remote monitoring and at-home-collection of detailed data. The benefits of PHRs can be maximized in insulin dose adjustment for patients starting or intensifying insulin regimens, as frequent self-monitoring of glucose, self-adjustment of insulin dose, and precise at-home data collection during the visit-to-visit period are important for glycemic control. The aim of this study is to examine the efficacy and safety of insulin dose adjustment based on a smartphone PHR application in patients with diabetes mellitus (DM) and to confirm the validity and stability of an information and communication technology (ICT)-based centralized clinical trial monitoring system. This is a 24-week, open-label, randomized, multi-center trial. There are three follow-up measures: baseline, post-intervention at week 12, and at week 24. Subjects diagnosed with type 1 DM, type 2 DM, and/or post-transplant DM who initiate basal insulin or intensify their insulin regimen to a basal-bolus regimen are included. After education on insulin dose titration and prevention for hypoglycemia and a 1-week acclimation period, subjects are randomized in a 1:1 ratio to either an ICT-based intervention group or a conventional intervention group. Subjects in the conventional intervention group will save and send their health information to the server via a PHR application, whereas those in ICT-based intervention group will receive additional algorithm-based feedback messages. The health information includes level of blood glucose, insulin dose, details on hypoglycemia, food diary, and step count. The primary outcome will be the proportion of patients who reach an optimal insulin dose within 12 weeks of study enrollment, without severe hypoglycemia or unscheduled clinic visits. This clinical trial

Pharmacokinetics and safety of fentanyl sublingual spray and fentanyl citrate intravenous: a single ascending dose study in opioid-naïve healthy volunteers.

Science.gov (United States)

Rauck, Richard; Oh, D Alexander; Parikh, Neha; Koch, Christian; Singla, Neil; Yu, Jin; Nalamachu, Srinivas; Vetticaden, Santosh

2017-11-01

Fentanyl sublingual spray offers rapid pain relief in opioid-tolerant cancer patients, and may be useful in acute or post-operative pain. Both opioid-naïve and non-tolerant patients are likely to receive opioids in these settings. Understanding the relationship between systemic exposure of fentanyl sublingual spray and effects on respiratory function in opioid-naïve or non-tolerant populations is important to ensure patient safety. This study evaluated single-dose fentanyl sublingual spray in opioid-naïve participants. Participants were randomized to receive single-dose fentanyl sublingual spray (100, 200, 400, 600, 800 mcg) or fentanyl citrate IV in one of five cohorts. Dosing occurred following a 10-h fast, with fasting continuing for 4 h post-dose. Dose proportionality was assessed using analysis of variance and linear regression techniques. PK assessments and safety monitoring were performed through 24 h post-dose. Safety assessments, including adverse event (AE) monitoring, occurred from dosing through Day 7. Fifty participants (19-53 years) received fentanyl sublingual spray or fentanyl citrate IV. Mean maximum plasma concentrations were reached between 0.27-0.60 h post-dose for fentanyl sublingual spray. Peak (C max ) and total (AUC 0- t , AUC 0-∞ ) fentanyl exposures increased in a linear, but more than dose-proportional manner, with higher doses. The most common AEs were somnolence, nausea, and vomiting. All AEs were mild or moderate in severity. Doses at 400, 600, and 800 mcg were associated with nausea and vomiting, requiring pharmacologic intervention. Hypoxia episodes requiring nasal cannula oxygenation were observed with 600mcg and 800mcg doses. Overall, single-dose fentanyl sublingual spray (100-800 mcg) was generally well tolerated, with greater incidences of AEs (e.g. nausea, vomiting, hypoxia) at higher doses. Doses up to 200 mcg may be safely administered to healthy opioid-naïve individuals with routine monitoring; doses

Safety of polyethylene glycol 3350 solution in chronic constipation: randomized, placebo-controlled trial

Directory of Open Access Journals (Sweden)

McGraw T

2016-07-01

Full Text Available Thomas McGraw Global Medical Affairs, Merck & Co., Inc., Kenilworth, NJ, USA Purpose: To evaluate the safety and tolerability of aqueous solution concentrate (ASC of polyethylene glycol (PEG 3350 in patients with functional constipation.Patients and methods: The patients who met Rome III diagnostic criteria for functional constipation were randomized in this multicenter, randomized, placebo-controlled, single-blind study to receive once daily dose of PEG 3350 (17 g ASC or placebo solution for 14 days. The study comprised a screening period (visit 1, endoscopy procedure (visits 2 and 3, and follow-up telephone calls 30 days post-treatment. Safety end points included adverse events (AEs, clinical laboratory evaluations, vital signs, and others. The primary end points were the proportion of patients with abnormalities of the oral and esophageal mucosa, detected by visual and endoscopic examination of the oral cavity and esophagus, respectively, compared with placebo. A secondary objective was to compare the safety and tolerability of ASC by evaluating AEs or adverse drug reactions.Results: A total of 65 patients were enrolled in this study, 31 were randomized to PEG 3350 ASC and 34 were randomized to placebo, of which 62 patients completed the study. No patients in either group showed abnormalities in inflammation of the oral mucosa during visit 2 (before treatment or visit 3 (after treatment. Fewer abnormalities of the esophageal mucosa were observed in the PEG 3350 ASC group than in the placebo group on visit 3, with no significant difference in the proportion of abnormalities between the treatment groups. Overall, 40 treatment-emergent AEs were observed in 48.4% of patients treated with PEG 3350 ASC, and 41 treatment-emergent AEs were observed in 55.9% of patients treated with placebo – nonsignificant difference of -7.5% (95% CI: -21.3, 6.3 between treatment groups. No serious AEs or deaths were reported, and no patient discontinued because

Efficacy and safety of escitalopram versus citalopram in major depressive disorder: a 6-week, multicenter, randomized, double-blind, flexible-dose study.

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Ou, Jian-Jun; Xun, Guang-Lei; Wu, Ren-Rong; Li, Le-Hua; Fang, Mao-Sheng; Zhang, Hong-Geng; Xie, Shi-Ping; Shi, Jian-Guo; Du, Bo; Yuan, Xue-Qin; Zhao, Jing-Ping

2011-02-01

S-citalopram (escitalopram) is the very active moiety of citalopram. It has been shown in many studies to be an effective and safe antidepressant for treating major depressive disorder (MDD). The aim of our study was to compare the efficacy and safety of escitalopram vs citalopram in Chinese MDD patients. In the double-blind study, 240 MDD patients were randomly assigned to treatment for 6 weeks either with escitalopram (10-20 mg/d) or citalopram (20-40 mg/d). The primary efficacy measurement was the change of 17-item Hamilton Depression Rating Scale (HAMD-17) total score from baseline to the end of study. The secondary efficacy measurements were response and remission rates. The adverse events (AEs) were recorded by the investigator. Two hundred and three (85%) patients completed the trial. The average dose was 13.9 mg/d in the escitalopram group and 27.6 mg/d in the citalopram group. No significant differences were found between the two groups in the change in HAMD-17 total score, response, and remission rate. These results were similar in severe MDD patients. No significant differences were found between the two groups in AEs. No serious AEs were observed in this study. The study suggests that escitalopram 10-20 mg/d are as effective and safe as citalopram 20-40 mg/d in the short-term treatment for Chinese MDD patients.

Safety and Immunogenicity of Full-Dose Trivalent Inactivated Influenza Vaccine (TIV) Compared With Half-Dose TIV Administered to Children 6 Through 35 Months of Age.

Science.gov (United States)

Halasa, Natasha B; Gerber, Michael A; Berry, Andrea A; Anderson, Edwin L; Winokur, Patricia; Keyserling, Harry; Eckard, Allison Ross; Hill, Heather; Wolff, Mark C; McNeal, Monica M; Edwards, Kathryn M; Bernstein, David I

2015-09-01

Children 6 through 35 months of age are recommended to receive half the dose of influenza vaccine compared with older children and adults. This was a 6-site, randomized 2:1, double-blind study comparing full-dose (0.5 mL) trivalent inactivated influenza vaccine (TIV) with half-dose (0.25 mL) TIV in children 6 through 35 months of age. Children previously immunized with influenza vaccine (primed cohort) received 1 dose, and those with no previous influenza immunizations (naive cohort) received 2 doses of TIV. Local and systemic adverse events were recorded. Sera were collected before immunization and 1 month after last dose of TIV. Hemagglutination inhibition antibody testing was performed. Of the 243 subjects enrolled (32 primed, 211 naive), data for 232 were available for complete analysis. No significant differences in local or systemic reactions were observed. Few significant differences in immunogenicity to the 3 vaccine antigens were noted. The immune response to H1N1 was significantly higher in the full-dose group among primed subjects. In the naive cohort, the geometric mean titer for all 3 antigens after 2 doses of TIV were significantly higher in the 12 through 35 months compared with the 6 through 11 months age group. Our study confirms the safety of full-dose TIV given to children 6 through 35 months of age. An increase in antibody responses after full- versus half-dose TIV was not observed, except for H1N1 in the primed group. Larger studies are needed to clarify the potential for improved immunogenicity with higher vaccine doses. Recommending the same dose could simplify the production, storage, and administration of influenza vaccines.

Sleep-Related Safety Behaviors and Dysfunctional Beliefs Mediate the Efficacy of Online CBT for Insomnia: A Randomized Controlled Trial.

Science.gov (United States)

Lancee, Jaap; Eisma, Maarten C; van Straten, Annemieke; Kamphuis, Jan H

2015-01-01

Several trials have demonstrated the efficacy of online cognitive behavioral therapy (CBT) for insomnia. However, few studies have examined putative mechanisms of change based on the cognitive model of insomnia. Identification of modifiable mechanisms by which the treatment works may guide efforts to further improve the efficacy of insomnia treatment. The current study therefore has two aims: (1) to replicate the finding that online CBT is effective for insomnia and (2) to test putative mechanism of change (i.e., safety behaviors and dysfunctional beliefs). Accordingly, we conducted a randomized controlled trial in which individuals with insomnia were randomized to either online CBT for insomnia (n = 36) or a waiting-list control group (n = 27). Baseline and posttest assessments included questionnaires assessing insomnia severity, safety behaviors, dysfunctional beliefs, anxiety and depression, and a sleep diary. Three- and six-month assessments were administered to the CBT group only. Results show moderate to large statistically significant effects of the online treatment compared to the waiting list on insomnia severity, sleep measures, sleep safety behaviors, and dysfunctional beliefs. Furthermore, dysfunctional beliefs and safety behaviors mediated the effects of treatment on insomnia severity and sleep efficiency. Together, these findings corroborate the efficacy of online CBT for insomnia, and suggest that these effects were produced by changing maladaptive beliefs, as well as safety behaviors. Treatment protocols for insomnia may specifically be enhanced by more focused attention on the comprehensive fading of sleep safety behaviors, for instance through behavioral experiments.

The effectiveness of low-dose and high-dose tranexamic acid in posterior lumbar interbody fusion: a double-blinded, placebo-controlled randomized study.

Science.gov (United States)

Kim, Ki-Tack; Kim, Cheung-Kue; Kim, Yong-Chan; Juh, Hyung-Suk; Kim, Hyo-Jong; Kim, Hyeon-Soo; Hong, Se Jung; Hey, Hwee Weng Dennis

2017-11-01

Tranexamic acid is a proven drug used for reduction of intraoperative blood loss in spinal surgery. However, optimal dosing considering risk/benefits is not well established owing to the heterogeneity in patient selection and surgical procedures of previous studies. This study aimed to evaluate the effectiveness and safety of various tranexamic acid regimens in reducing perioperative blood loss in single-level posterior lumbar interbody fusion (PLIF). Patients were randomly grouped into three different interventions: low-dose tranexamic acid (LD), high-dose tranexamic acid (HD), and placebo-controlled (PC) groups. The HD and LD groups received 10 and 5 mg/kg of bolus loading dose and 2 and 1 mg/kg of continuous infusion until 5 h after surgery, respectively. Data on patient demographics and preoperative and 24-h postoperative laboratory values were collected. Outcome parameters include intraoperative blood loss, 24-h postoperative blood loss, and blood loss during removal of the last drain. Seventy-two patients (mean age 63.3 ± 7.6 years) showed similar baseline characteristics. Intraoperatively, blood loss was reduced by the administration of tranexamic acid (P = 0.04), contributed predominantly by a difference between the LD and HD groups (123 mL; P tranexamic acid use were noted. Tranexamic acid administration for single-level PLIF was effective and safe in reducing perioperative blood loss in a dose-dependent manner. An HD regimen comprising 10 mg/kg of bolus loading dose and 2 mg/kg/h of continuous infusion is recommended. Level 1 study according to Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence.

Safety and convenience of once-weekly somapacitan in adult GH deficiency: a 26-week randomized, controlled trial.

Science.gov (United States)

Johannsson, Gudmundur; Feldt-Rasmussen, Ulla; Håkonsson, Ida Holme; Biering, Henrik; Rodien, Patrice; Tahara, Shigeyuki; Toogood, Andrew; Rasmussen, Michael Højby

2018-05-01

Somapacitan is a reversible albumin-binding growth hormone (GH) derivative, developed for once-weekly administration. This study aimed to evaluate the safety of once-weekly somapacitan vs once-daily Norditropin ® . Local tolerability and treatment satisfaction were also assessed. 26-week randomized, controlled phase 3 safety and tolerability trial in six countries (Nbib2382939). Male or female patients aged 18-79 years with adult GH deficiency (AGHD), treated with once-daily GH for ≥6 months, were randomized to once-weekly somapacitan ( n  = 61) or once-daily Norditropin ( n  = 31) administered subcutaneously by pen. Both treatments were dose titrated for 8 weeks to achieve insulin-like growth factor I (IGF-I) standard deviation score (SDS) levels within the normal range, and then administered at a fixed dose. Outcome measures were adverse events (AEs), including injection site reactions; occurrence of anti-somapacitan/anti-GH antibodies and change in treatment satisfaction, assessed using the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). Mean IGF-I SDS remained between 0 and 2 SDS throughout the trial in both groups. AEs were mostly mild or moderate and transient in nature. The most common AEs were nasopharyngitis, headache and fatigue in both groups. More than 1500 somapacitan injections were administered and no clinically significant injection site reactions were reported. No anti-somapacitan or anti-GH antibodies were detected. The TSQM-9 score for convenience increased significantly more with somapacitan vs Norditropin ( P  = 0.0171). In this 26-week trial in patients with AGHD, somapacitan was well tolerated and no safety issues were identified. Once-weekly somapacitan was reported to be more convenient than once-daily Norditropin. © 2018 The authors.

Prospective open randomized study comparing efficacies and safeties of a 3-day course of azithromycin and a 10-day course of erythromycin in children with community-acquired acute lower respiratory tract infections

NARCIS (Netherlands)

Roord, JJ; Goossens, MMHT; Kimpen, JLL; Wolf, B.H.

1996-01-01

The efficacies and safeties of a 3-day, 3-dose course of azithromycin (10 mg/kg of body weight per day) and a 10-day, 30-dose course of erythromycin (40 mg/kg/day) for the treatment of acute lower respiratory tract infections in children were compared in an open randomized multicenter study.

Efficacy of prokinetics with a split-dose of polyethylene glycol in bowel preparation for morning colonoscopy: a randomized controlled trial.

Science.gov (United States)

Kim, Hyoung Jun; Kim, Tae Oh; Shin, Bong Chul; Woo, Jae Gon; Seo, Eun Hee; Joo, Hee Rin; Heo, Nae-Yun; Park, Jongha; Park, Seung Ha; Yang, Sung Yeon; Moon, Young Soo; Shin, Jin-Yong; Lee, Nae Young

2012-01-01

Currently, a split-dose of polyethylene glycol (PEG) is the mainstay of bowel preparation due to its tolerability, bowel-cleansing action, and safety. However, bowel preparation with PEG is suboptimal because residual fluid reduces the polyp detection rate and requires a more thorough colon inspection. The aim of our study was to demonstrate the efficacy of a sufficient dose of prokinetics on bowel cleansing together with split-dose PEG. A prospective endoscopist-blinded study was conducted. Patients were randomly allocated to two groups: prokinetic with split-dose PEG or split-dose PEG alone. A prokinetic [100 mg itopride (Itomed)], was administered twice simultaneously with each split-dose of PEG. Bowel-cleansing efficacy was measured by endoscopists using the Ottawa scale and the segmental fluidity scale score. Each participant completed a bowel preparation survey. Mean scores from the Ottawa scale, segmental fluid scale, and rate of poor preparation were compared between both groups. Patients in the prokinetics with split-dose PEG group showed significantly lower total Ottawa and segmental fluid scores compared with patients in the split-dose of PEG alone group. A sufficient dose of prokinetics with a split-dose of PEG showed efficacy in bowel cleansing for morning colonoscopy, largely due to the reduction in colonic fluid. Copyright © 2012 S. Karger AG, Basel.

The SHIELD (Safety & Health Improvement: Enhancing Law Enforcement Departments Study: Feasibility and Findings

Directory of Open Access Journals (Sweden)

Kerry Stephen Kuehl

2014-05-01

Full Text Available This randomized prospective trial aimed to assess the feasibility and efficacy of a team-based worksite health and safety intervention for law enforcement personnel. Four-hundred and eight subjects were enrolled and half were randomized to meet participants met for weekly, peer-led sessions delivered from a scripted team-based health and safety curriculum. Curriculum addressed: exercise, nutrition, stress, sleep, body weight, injury, and other unhealthy lifestyle behaviours such as smoking and heavy alcohol use. Health and safety questionnaires administered before and after the intervention found significant improvements for increased fruit and vegetable consumption, overall healthy eating, increased sleep quantity and sleep quality, and reduced personal stress.

Safety and immunogenicity of an AMA-1 malaria vaccine in Malian adults: results of a phase 1 randomized controlled trial.

Directory of Open Access Journals (Sweden)

Mahamadou A Thera

2008-01-01

Full Text Available The objective was to evaluate the safety, reactogenicity and immunogenicity of the AMA-1-based blood-stage malaria vaccine FMP2.1/AS02A in adults exposed to seasonal malaria.A phase 1 double blind randomized controlled dose escalation trial was conducted in Bandiagara, Mali, West Africa, a rural town with intense seasonal transmission of Plasmodium falciparum malaria. The malaria vaccine FMP2.1/AS02A is a recombinant protein (FMP2.1 based on apical membrane antigen-1 (AMA-1 from the 3D7 clone of P. falciparum, adjuvanted with AS02A. The comparator vaccine was a cell-culture rabies virus vaccine (RabAvert. Sixty healthy, malaria-experienced adults aged 18-55 y were recruited into 2 cohorts and randomized to receive either a half dose or full dose of the malaria vaccine (FMP2.1 25 microg/AS02A 0.25 mL or FMP2.1 50 microg/AS02A 0.5 mL or rabies vaccine given in 3 doses at 0, 1 and 2 mo, and were followed for 1 y. Solicited symptoms were assessed for 7 d and unsolicited symptoms for 30 d after each vaccination. Serious adverse events were assessed throughout the study. Titers of anti-AMA-1 antibodies were measured by ELISA and P. falciparum growth inhibition assays were performed on sera collected at pre- and post-vaccination time points. Transient local pain and swelling were common and more frequent in both malaria vaccine dosage groups than in the comparator group. Anti-AMA-1 antibodies increased significantly in both malaria vaccine groups, peaking at nearly 5-fold and more than 6-fold higher than baseline in the half-dose and full-dose groups, respectively.The FMP2.1/AS02A vaccine had a good safety profile, was well-tolerated, and was highly immunogenic in malaria-exposed adults. This malaria vaccine is being evaluated in Phase 1 and 2 trials in children at this site.

Immunogenicity and safety of combined adsorbed low-dose diphtheria, tetanus and inactivated poliovirus vaccine (REVAXIS®) versus combined diphtheria, tetanus and inactivated poliovirus vaccine (DT Polio®) given as a booster dose at 6 years of age

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Gajdos, Vincent; Soubeyrand, Benoit; Vidor, Emmanuel; Richard, Patrick; Boyer, Julie; Sadorge, Christine

2011-01-01

This randomized, comparative, phase-IIIb study conducted in France aimed to demonstrate whether seroprotection against diphtheria, tetanus and poliomyelitis 1 month after a single dose of REVAXIS (low-dose diphtheria) is non-inferior to seroprotection 1 month after a single dose of DT Polio (standard-dose diphtheria), both vaccines being given as a second booster to healthy children at 6 years of age. Children were randomly assigned to receive a single intramuscular dose of REVAXIS or DT Polio. Primary endpoints were the 1-month post-booster seroprotection rates for diphtheria, tetanus and poliovirus type-1, -2 and -3 antigens. Secondary endpoints were immunogenicity and safety observations. Of 788 children screened, 760 were randomized: REVAXIS group, 384 children; DT Polio group, 376 children. No relevant difference in demographic characteristics at baseline was observed between REVAXIS and DT Polio groups. Noninferiority of REVAXIS compared with DT Polio for seroprotection was demonstrated against diphtheria (respectively 98.6% and 99.3%), tetanus (respectively 99.6% and 100%) and poliovirus antigens (100% for each types in both groups). No allergic reactions to REVAXIS were reported. A benefit/risk ratio in favor of REVAXIS was suggested by the trend towards a better tolerability of REVAXIS compared with DT Polio regarding the rate of severe solicited injection-site reactions. The results support the use of REVAXIS as a booster at 6 years of age in infants who previously received a three-dose primary series within the first 6 months of life and a first booster including diphtheria, tetanus and poliovirus vaccine(s) given before 2 years of age. PMID:21441781

The effect of dose on the safety and immunogenicity of the VSV Ebola candidate vaccine: a randomised double-blind, placebo-controlled phase 1/2 trial.

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Huttner, Angela; Dayer, Julie-Anne; Yerly, Sabine; Combescure, Christophe; Auderset, Floriane; Desmeules, Jules; Eickmann, Markus; Finckh, Axel; Goncalves, Ana Rita; Hooper, Jay W; Kaya, Gürkan; Krähling, Verena; Kwilas, Steve; Lemaître, Barbara; Matthey, Alain; Silvera, Peter; Becker, Stephan; Fast, Patricia E; Moorthy, Vasee; Kieny, Marie Paule; Kaiser, Laurent; Siegrist, Claire-Anne

2015-10-01

Safe and effective vaccines against Ebola could prevent or control outbreaks. The safe use of replication-competent vaccines requires a careful dose-selection process. We report the first safety and immunogenicity results in volunteers receiving 3 × 10(5) plaque-forming units (pfu) of the recombinant vesicular stomatitis virus-based candidate vaccine expressing the Zaire Ebola virus glycoprotein (rVSV-ZEBOV; low-dose vaccinees) compared with 59 volunteers who had received 1 ×10(7) pfu (n=35) or 5 × 10(7) pfu (n=16) of rVSV-ZEBOV (high-dose vaccinees) or placebo (n=8) before a safety-driven study hold. The Geneva rVSV-ZEBOV study, an investigator-initiated phase 1/2, dose-finding, placebo-controlled, double-blind trial conducted at the University Hospitals of Geneva, Switzerland, enrolled non-pregnant, immunocompetent, and otherwise healthy adults aged 18-65 years. Participants from the low-dose group with no plans to deploy to Ebola-aff5cted regions (non-deployable) were randomised 9:1 in a double-blind fashion using randomly permuted blocks of varying sizes to a single injection of 3 × 10(5) pfu or placebo, whereas deployable participants received single-injection 3 × 10(5) pfu open-label. Primary safety and immunogenicity outcomes were the incidence of adverse events within 14 days of vaccination and day-28 antibody titres, respectively, analysed by intention to treat. After viral oligoarthritis was observed in 11 of the first 51 vaccinees (22%) receiving 10(7) or 5 × 10(7) pfu, 56 participants were given a lower dose (3 × 10(5) pfu, n=51) or placebo (n=5) to assess the effect of dose reduction on safety and immunogenicity. This trial is ongoing with a follow-up period of 12 months; all reported results are from interim databases. This study is registered with ClinicalTrials.gov, number NCT02287480. Between Jan 5 and Jan 26, 2015, 43 non-deployable participants received low-dose rVSV-ZEBOV (3 × 10(5) pfu) or placebo in a

17DD yellow fever vaccine: a double blind, randomized clinical trial of immunogenicity and safety on a dose-response study.

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Martins, Reinaldo M; Maia, Maria de Lourdes S; Farias, Roberto Henrique G; Camacho, Luiz Antonio B; Freire, Marcos S; Galler, Ricardo; Yamamura, Anna Maya Yoshida; Almeida, Luiz Fernando C; Lima, Sheila Maria B; Nogueira, Rita Maria R; Sá, Gloria Regina S; Hokama, Darcy A; de Carvalho, Ricardo; Freire, Ricardo Aguiar V; Pereira Filho, Edson; Leal, Maria da Luz Fernandes; Homma, Akira

2013-04-01

To verify if the Bio-Manguinhos 17DD yellow fever vaccine (17DD-YFV) used in lower doses is as immunogenic and safe as the current formulation. Doses from 27,476 IU to 587 IU induced similar seroconversion rates and neutralizing antibodies geometric mean titers (GMTs). Immunity of those who seroconverted to YF was maintained for 10 mo. Reactogenicity was low for all groups. Young and healthy adult males (n = 900) were recruited and randomized into 6 groups, to receive de-escalating doses of 17DD-YFV, from 27,476 IU to 31 IU. Blood samples were collected before vaccination (for neutralization tests to yellow fever, serology for dengue and clinical chemistry), 3 to 7 d after vaccination (for viremia and clinical chemistry) and 30 d after vaccination (for new yellow fever serology and clinical chemistry). Adverse events diaries were filled out by volunteers during 10 d after vaccination. Volunteers were retested for yellow fever and dengue antibodies 10 mo later. Seropositivity for dengue was found in 87.6% of volunteers before vaccination, but this had no significant influence on conclusions. In young healthy adults Bio-Manguinhos/Fiocruz yellow fever vaccine can be used in much lower doses than usual. INTERNATIONAL REGISTER: ISRCTN 38082350.

A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Oral ELND005 (scyllo-Inositol) in Young Adults with Down Syndrome without Dementia.

Science.gov (United States)

Rafii, Michael S; Skotko, Brian G; McDonough, Mary Ellen; Pulsifer, Margaret; Evans, Casey; Doran, Eric; Muranevici, Gabriela; Kesslak, Patrick; Abushakra, Susan; Lott, Ira T

2017-01-01

ELND005 (scyllo-Inositol; cyclohexane-1,2,3,4,5,6-hexol) has been evaluated as a potential disease-modifying treatment for Alzheimer's disease (AD). Individuals with Down syndrome (DS) have an increased risk for developing AD dementia. To evaluate the safety and tolerability of ELND005 and to determine its pharmacokinetics (PK) and relationship between PK parameters, safety outcome measures, and exploratory efficacy outcome measures in young adults with DS without dementia. This was a prospective, randomized, double-blind, placebo-controlled, parallel-group, three-arm, multicenter Phase II study of the safety and pharmacokinetics of ELND005 administered orally for 4 weeks (ClinicalTrials.gov NCT01791725). Participants who met study eligibility criteria were randomly assigned in a 2 : 1:1 ratio to receive ELND005 at either 250 mg twice daily (BID) or 250 mg once daily (QD) or matching placebo for 4 weeks. There were no apparent treatment group-related trends on cognitive or behavioral measures and there were no SAEs and no deaths in the study. Overall, mean changes from baseline in clinical laboratory parameters, vital sign measurements, electrocardiogram results, and other physical findings were unremarkable. ELND005 accumulation averaged approximately 2-fold with QD dosing, and 3- to 4-fold with BID dosing. Overall, treatment of adults with DS with ELND005 at both doses was well tolerated, achieved measurable blood levels and demonstrated no safety findings. Further studies will be needed to test efficacy.

Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial.

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Choueiri, Toni K; Larkin, James; Oya, Mototsugu; Thistlethwaite, Fiona; Martignoni, Marcella; Nathan, Paul; Powles, Thomas; McDermott, David; Robbins, Paul B; Chism, David D; Cho, Daniel; Atkins, Michael B; Gordon, Michael S; Gupta, Sumati; Uemura, Hirotsugu; Tomita, Yoshihiko; Compagnoni, Anna; Fowst, Camilla; di Pietro, Alessandra; Rini, Brian I

2018-04-01

The combination of an immune checkpoint inhibitor and a VEGF pathway inhibitor to treat patients with advanced renal-cell carcinoma might increase the clinical benefit of these drugs compared with their use alone. Here, we report preliminary results for the combination of avelumab, an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF receptor inhibitor approved for second-line treatment of advanced renal-cell carcinoma, in treatment-naive patients with advanced renal-cell carcinoma. The JAVELIN Renal 100 study is an ongoing open-label, multicentre, dose-finding, and dose-expansion, phase 1b study, done in 14 centres in the USA, UK, and Japan. Eligible patients were aged 18 years or older (≥20 years in Japan) and had histologically or cytologically confirmed advanced renal-cell carcinoma with clear-cell component, life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 1 or less, received no previous systemic treatment for advanced renal cell carcinoma, and had a resected primary tumour. Patients enrolled into the dose-finding phase received 5 mg axitinib orally twice daily for 7 days, followed by combination therapy with 10 mg/kg avelumab intravenously every 2 weeks and 5 mg axitinib orally twice daily. Based on the pharmacokinetic data from the dose-finding phase, ten additional patients were enrolled into the dose-expansion phase and assigned to this regimen. The other patients in the dose-expansion phase started taking combination therapy directly. The primary endpoint was dose-limiting toxicities in the first 4 weeks (two cycles) of treatment with avelumab plus axitinib. Safety and antitumour activity analyses were done in all patients who received at least one dose of avelumab or axitinib. This trial is registered with ClinicalTrials.gov, number NCT02493751. Between Oct 30, 2015, and Sept 30, 2016, we enrolled six patients into the dose-finding phase and 49 into the

Immunogenicity and safety evaluation of bivalent types 1 and 3 oral poliovirus vaccine by comparing different poliomyelitis vaccination schedules in China: A randomized controlled non-inferiority clinical trial.

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Qiu, Jingjun; Yang, Yunkai; Huang, Lirong; Wang, Ling; Jiang, Zhiwei; Gong, Jian; Wang, Wei; Wang, Hongyan; Guo, Shaohong; Li, Chanjuan; Wei, Shuyuan; Mo, Zhaojun; Xia, Jielai

2017-06-03

The type 2 component of the oral poliovirus vaccine is targeted for global withdrawal through a switch from the trivalent oral poliovirus vaccine (tOPV) to a bivalent oral poliovirus vaccine (bOPV). The switch is intended to prevent paralytic polio caused by circulating vaccine-derived poliovirus type 2. We aimed to assess the immunogenicity and safety profile of 6 vaccination schedules with different sequential doses of inactivated poliovirus vaccine (IPV), tOPV, or bOPV. A randomized controlled trial was conducted in China in 2015. Healthy newborn babies randomly received one of the following 6 vaccination schedules: cIPV-bOPV-bOPV(I-B-B), cIPV-tOPV-tOPV(I-T-T), cIPV-cIPV-bOPV(I-I-B), cIPV-cIPV-tOPV(I-I-T), cIPV-cIPV-cIPV(I-I-I), or tOPV-tOPV-tOPV(T-T-T). Doses were administered sequentially at 4-6 week intervals after collecting baseline blood samples. Patients were proactively followed up for observation of adverse events after the first dose and 30 days after all doses. The primary study objective was to investigate the immunogenicity and safety profile of different vaccine schedules, evaluated by seroconversion, seroprotection and antibody titer against poliovirus types 1, 2, and 3 in the per-protocol population. Of 600 newborn babies enrolled, 504 (84.0%) were included in the per-protocol population. For type 1 poliovirus, the differences in the seroconversion were 1.17% (95% CI = -2.74%, 5.08%) between I-B-B and I-T-T and 0.00% (95% CI: -6.99%, 6.99%) between I-I-B and I-I-T; for type 3 poliovirus, differences in the seroconversion were 3.49% (95% CI: -1.50%, 8.48%) between I-B-B and I-T-T and -2.32% (95% CI: -5.51%, 0.86%) between I-I-B and I-I-T. The non-inferiority conclusion was achieved in both poliovirus type 1 and 3 with the margin of -10%. Of 24 serious adverse events reported, no one was vaccine-related. The vaccination schedules with bOPV followed by one or 2 doses of IPV were recommended to substitute for vaccinations involving tOPV without

Case study: Findings and lessons learned from investigating a uranium intake and the corresponding dose calculations

International Nuclear Information System (INIS)

Beeslaar, Frik; Niekerk, Santie van; Steenkamp, Harry; Visagie, Abrie

2008-01-01

Full text: Purpose: To discuss the findings of an investigation into uranium intake and to discuss the lessons learned from the subsequent bioassay monitoring and dose calculations. Method: An investigation was held to determine direct and root causes after elevated air concentration levels were reported during the execution of an ad-hoc task. A programme of bioassay monitoring (urine sampling and lung counts) was implemented for the involved staff and committed effective doses were calculated. Major findings of the investigation: a) Inadequate pre-task assessment led to hazards not being identified and subsequently proper control measures were not implemented; b) Inadequate localised control of contamination led to contamination of worker's clothes and faces and contamination of rest of area; c) Workers were complacent which led to a lapse in safety awareness and subsequently they removed their face masks during the task. Problems experienced with bioassay monitoring and dose calculations: a) Some bioassay samples were not taken or were given incorrectly; b) Calculating doses were difficult due to lack of information regarding date of intake; whether there were other possible intakes; and the physiochemical nature of the uranium; c) Weak correlation between predicted and actual bioassay data; d) Period between starting bioassay monitoring and the actual event was too long. Conclusions: a) Shortcomings in the control of contamination with protective clothing and during the execution of ad-hoc tasks; b) Identifying hazards and assessing it is extremely dependant on the skill and capabilities if the Radiation Protection Officers; c) Instructions to workers regarding sampling of urine and arrangements around the sampling should be very specific with only one person responsible for managing the process; d) Be aware of the psychological impact on the affected workers; e) 2 nd Independent dose calculation important for verifying doses; f) Detection capabilities and

Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity

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Huss M

2017-07-01

Full Text Available Michael Huss,1 Praveen Duhan,2 Preetam Gandhi,3 Chien-Wei Chen,4 Carsten Spannhuth,3 Vinod Kumar5 1Child and Adolescent Psychiatry, University Medicine, Mainz, Germany; 2Global Medical Affairs, Novartis Healthcare Pvt. Ltd., Hyderabad, India; 3Development Franchise, Established Medicine Neuroscience, Novartis Pharma AG, Basel, Switzerland; 4Biostatistics Cardio-Metabolic & Established Medicine, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 5Established Medicines, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Abstract: Attention-deficit/hyperactivity disorder (ADHD is a chronic psychiatric disorder characterized by hyperactivity and/or inattention and is often associated with a substantial impact on psychosocial functioning. Methylphenidate (MPH, a central nervous system stimulant, is commonly used for pharmacological treatment of adults and children with ADHD. Current practice guidelines recommend optimizing MPH dosage to individual patient needs; however, the clinical benefits of individual dose optimization compared with fixed-dose regimens remain unclear. Here we review the available literature on MPH dose optimization from clinical trials and real-world experience on ADHD management. In addition, we report safety and efficacy data from the largest MPH modified-release long-acting Phase III clinical trial conducted to examine benefits of dose optimization in adults with ADHD. Overall, MPH is an effective ADHD treatment with a good safety profile; data suggest that dose optimization may enhance the safety and efficacy of treatment. Further research is required to establish the extent to which short-term clinical benefits of MPH dose optimization translate into improved long-term outcomes for patients with ADHD. Keywords: methylphenidate, dose optimization, attention-deficit/hyperactivity disorder, ADHD

Towards tracer dose reduction in PET studies: Simulation of dose reduction by retrospective randomized undersampling of list-mode data.

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Gatidis, Sergios; Würslin, Christian; Seith, Ferdinand; Schäfer, Jürgen F; la Fougère, Christian; Nikolaou, Konstantin; Schwenzer, Nina F; Schmidt, Holger

2016-01-01

Optimization of tracer dose regimes in positron emission tomography (PET) imaging is a trade-off between diagnostic image quality and radiation exposure. The challenge lies in defining minimal tracer doses that still result in sufficient diagnostic image quality. In order to find such minimal doses, it would be useful to simulate tracer dose reduction as this would enable to study the effects of tracer dose reduction on image quality in single patients without repeated injections of different amounts of tracer. The aim of our study was to introduce and validate a method for simulation of low-dose PET images enabling direct comparison of different tracer doses in single patients and under constant influencing factors. (18)F-fluoride PET data were acquired on a combined PET/magnetic resonance imaging (MRI) scanner. PET data were stored together with the temporal information of the occurrence of single events (list-mode format). A predefined proportion of PET events were then randomly deleted resulting in undersampled PET data. These data sets were subsequently reconstructed resulting in simulated low-dose PET images (retrospective undersampling of list-mode data). This approach was validated in phantom experiments by visual inspection and by comparison of PET quality metrics contrast recovery coefficient (CRC), background-variability (BV) and signal-to-noise ratio (SNR) of measured and simulated PET images for different activity concentrations. In addition, reduced-dose PET images of a clinical (18)F-FDG PET dataset were simulated using the proposed approach. (18)F-PET image quality degraded with decreasing activity concentrations with comparable visual image characteristics in measured and in corresponding simulated PET images. This result was confirmed by quantification of image quality metrics. CRC, SNR and BV showed concordant behavior with decreasing activity concentrations for measured and for corresponding simulated PET images. Simulation of dose

Efficacy of Single-Dose and Triple-Dose Albendazole and Mebendazole against Soil-Transmitted Helminths and Taenia spp.: A Randomized Controlled Trial

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Steinmann, Peter; Utzinger, Jürg; Du, Zun-Wei; Jiang, Jin-Yong; Chen, Jia-Xu; Hattendorf, Jan; Zhou, Hui; Zhou, Xiao-Nong

2011-01-01

Background The control of soil-transmitted helminth (STH) infections currently relies on the large-scale administration of single-dose oral albendazole or mebendazole. However, these treatment regimens have limited efficacy against hookworm and Trichuris trichiura in terms of cure rates (CR), whereas fecal egg reduction rates (ERR) are generally high for all common STH species. We compared the efficacy of single-dose versus triple-dose treatment against hookworm and other STHs in a community-based randomized controlled trial in the People's Republic of China. Methodology/Principal findings The hookworm CR and fecal ERR were assessed in 314 individuals aged ≥5 years who submitted two stool samples before and 3–4 weeks after administration of single-dose oral albendazole (400 mg) or mebendazole (500 mg) or triple-dose albendazole (3×400 mg over 3 consecutive days) or mebendazole (3×500 mg over 3 consecutive days). Efficacy against T. trichiura, Ascaris lumbricoides, and Taenia spp. was also assessed. Albendazole cured significantly more hookworm infections than mebendazole in both treatment regimens (single dose: respective CRs 69% (95% confidence interval [CI]: 55–81%) and 29% (95% CI: 20–45%); triple dose: respective CRs 92% (95% CI: 81–98%) and 54% (95% CI: 46–71%)). ERRs followed the same pattern (single dose: 97% versus 84%; triple dose: 99.7% versus 96%). Triple-dose regimens outperformed single doses against T. trichiura; three doses of mebendazole – the most efficacious treatment tested – cured 71% (95% CI: 57–82%). Both single and triple doses of either drug were highly efficacious against A. lumbricoides (CR: 93–97%; ERR: all >99.9%). Triple dose regimens cured all Taenia spp. infections, whereas single dose applications cured only half of them. Conclusions/Significance Single-dose oral albendazole is more efficacious against hookworm than mebendazole. To achieve high CRs against both hookworm and T. trichiura, triple-dose regimens are

A phase 2a randomized, parallel group, dose-ranging study of molindone in children with attention-deficit/hyperactivity disorder and persistent, serious conduct problems.

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Stocks, Jennifer Dugan; Taneja, Baldeo K; Baroldi, Paolo; Findling, Robert L

2012-04-01

To evaluate safety and tolerability of four doses of immediate-release molindone hydrochloride in children with attention-deficit/hyperactivity disorder (ADHD) and serious conduct problems. This open-label, parallel-group, dose-ranging, multicenter trial randomized children, aged 6-12 years, with ADHD and persistent, serious conduct problems to receive oral molindone thrice daily for 9-12 weeks in four treatment groups: Group 1-10 mg (5 mg if weight conduct problems. Secondary outcome measures included change in Nisonger Child Behavior Rating Form-Typical Intelligence Quotient (NCBRF-TIQ) Conduct Problem subscale scores, change in Clinical Global Impressions-Severity (CGI-S) and -Improvement (CGI-I) subscale scores from baseline to end point, and Swanson, Nolan, and Pelham rating scale-revised (SNAP-IV) ADHD-related subscale scores. The study randomized 78 children; 55 completed the study. Treatment with molindone was generally well tolerated, with no clinically meaningful changes in laboratory or physical examination findings. The most common treatment-related adverse events (AEs) included somnolence (n=9), weight increase (n=8), akathisia (n=4), sedation (n=4), and abdominal pain (n=4). Mean weight increased by 0.54 kg, and mean body mass index by 0.24 kg/m(2). The incidence of AEs and treatment-related AEs increased with increasing dose. NCBRF-TIQ subscale scores improved in all four treatment groups, with 34%, 34%, 32%, and 55% decreases from baseline in groups 1, 2, 3, and 4, respectively. CGI-S and SNAP-IV scores improved over time in all treatment groups, and CGI-I scores improved to the greatest degree in group 4. Molindone at doses of 5-20 mg/day (children weighing <30 kg) and 20-40 mg (≥ 30 kg) was well tolerated, and preliminary efficacy results suggest that molindone produces dose-related behavioral improvements over 9-12 weeks. Additional double-blind, placebo-controlled trials are needed to further investigate molindone in this pediatric population.

An open-label, sequential, dose-finding study of peginesatide for the maintenance treatment of anemia in chronic hemodialysis patients

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Besarab Anatole

2012-08-01

Full Text Available Abstract Background Peginesatide is a peptide-based erythropoiesis-stimulating agent that was designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis. The primary objective of this phase 2 dose-finding study was to determine the once-monthly peginesatide dosing strategy that would maintain hemoglobin within ±1.0 g/dL of baseline values after conversion from epoetin alfa; the safety of peginesatide was evaluated concurrently. Methods Chronic hemodialysis patients on stable regimens of epoetin alfa were sequentially assigned to cohorts that differed on (1 how the peginesatide starting dose was determined (using a single epoetin alfa–to-peginesatide dose conversion ratio or a tiered, weight-based or absolute-dose conversion table and on (2 whether or not a 1-week erythropoiesis-stimulating agent-free interval was used. Peginesatide doses were titrated to maintain hemoglobin levels within ±1.0 g/dL from baseline. Results A total of 164 patients were enrolled and received intravenous peginesatide every 4 weeks for up to 6 doses; the duration of the study including follow-up was ≤29 weeks. Overall, the proportion of patients with hemoglobin levels within ±1.0 g/dL of baseline increased over the course of the study from 39% (Weeks 2–13 to 54% (Weeks 18–25. Cohorts that used tiered dose conversion tables trended towards having more stable peginesatide doses than did those cohorts that used a single dose conversion ratio. Moreover, cohorts that used an erythropoiesis-stimulating agent-free interval did not have the substantial initial increase in hemoglobin levels that was seen in those cohorts that did not use such an interval. In this study, the safety profile of peginesatide was consistent with those of marketed erythropoiesis-stimulating agents. Conclusions The results of this study were used to guide the dosing regimens used subsequently in phase 3 studies. Once

Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial.

Science.gov (United States)

Atkins, Michael B; Plimack, Elizabeth R; Puzanov, Igor; Fishman, Mayer N; McDermott, David F; Cho, Daniel C; Vaishampayan, Ulka; George, Saby; Olencki, Thomas E; Tarazi, Jamal C; Rosbrook, Brad; Fernandez, Kathrine C; Lechuga, Mariajose; Choueiri, Toni K

2018-03-01

Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma. In this ongoing, open-label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0-1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a dose-finding phase to estimate the maximum tolerated dose, and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment. The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02133742. Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose-expansion phase. All 52 patients were analysed together. No unexpected toxicities were

Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial.

Science.gov (United States)

Jacobson, Ira M; Brown, Robert S; Freilich, Bradley; Afdhal, Nezam; Kwo, Paul Y; Santoro, John; Becker, Scott; Wakil, Adil E; Pound, David; Godofsky, Eliot; Strauss, Robert; Bernstein, David; Flamm, Steven; Pauly, Mary Pat; Mukhopadhyay, Pabak; Griffel, Louis H; Brass, Clifford A

2007-10-01

This prospective, multicenter, community-based and academic-based, open-label, investigator-initiated, U.S. study evaluated efficacy and safety of pegylated interferon (PEG-IFN) alfa-2b plus a flat or weight-based dose of ribavirin (RBV) in adults with chronic hepatitis C. Patients (n = 5027) were randomly assigned to receive PEG-IFN alfa-2b 1.5 microg/kg/week plus flat-dose (800 mg/day) or weight-based (800-1400 mg/day) RBV for 48 weeks (patients with genotype 1, 4, 5, or 6) and for 24 or 48 weeks (genotype 2/3 patients). Primary end point was sustained virologic response (undetectable [<125 IU/mL] serum hepatitis C virus RNA at 24-week follow-up). Sustained virologic response, but not end-of-treatment, rates were significantly higher with weight-based than with flat-dose RBV (44.2% versus 40.5%; P = 0.008). Sustained virologic response rates by intention-to-treat analysis were 34.0% and 28.9%, respectively, in genotype 1 patients (P = 0.005) and 31.2% and 26.7%, respectively, in genotype 1 patients with high baseline viral load (P = 0.056). In genotype 2/3 patients, rates were not significantly different (61.8% and 59.5%, respectively) regardless of treatment duration. Besides greater hemoglobin reductions with weight-based RBV, safety profiles were similar across RBV dosing groups, including the 1400-mg/day group. PEG-IFN alfa-2b plus weight-based RBV is more effective than flat-dose RBV, particularly in genotype 1 patients, providing equivalent efficacy across all weight groups. RBV 1400 mg/day is appropriate for patients 105 to 125 kg. For genotype 2/3 patients, 24 weeks of treatment with flat-dose RBV is adequate; no evidence of additional benefit of extending treatment to 48 weeks was demonstrated.

Safety of high-dose daptomycin in patients with severe renal impairment

Directory of Open Access Journals (Sweden)

Tai CH

2018-03-01

Full Text Available Chih-Hsun Tai,1 Chi-Hao Shao,2 Chen-You Chen,2 Shu-Wen Lin,1–3 Chien-Chih Wu1,2 1Department of Pharmacy, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan; 2School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; 3Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan Background: Treatment options are limited for infections due to multidrug-resistant Gram-positive pathogens. Daptomycin is a lipopeptide antibiotic with concentration-dependent killing characteristic and dose-dependent post-antibiotic effect. To achieve optimized pharmacodynamic effect, some experts advocated using a high dose of daptomycin (≥9 mg/kg for severe infections. However, the safety of high-dose therapy in patients with renal impairment remains unknown. This study was aimed to evaluate the safety of daptomycin in patients with severe renal impairment. Methods: This was a retrospective study performed by reviewing electronic medical records. Patients with severe renal impairment who were treated with daptomycin in a tertiary teaching hospital between January 1, 2013, and June 30, 2016, were included for evaluation. The incidence rates of creatine kinase (CK elevation between high-dose (≥9 mg/kg and standard-dose (<9 mg/kg groups were compared. Results: Overall, 164 patients met the inclusion criteria, and 114 (69.5% of them were on renal replacement therapy. Vancomycin-resistant enterococci were the most common pathogens (61.3% of the patients with documented pathogens. The treatment success rate was 51.6% in the 91 patients with bacteremia. The average dose of daptomycin was 8.0±2.3 mg/kg, and 37 (22.6% patients received ≥9 mg/kg. CK levels were followed in 108 (65.9% patients. Significantly higher incidence of CK elevation was found in the high-dose group compared with that in the standard-dose group (10.8% vs 1.6%, P<0.05. Moreover

A randomized, double-blind, multicentre study comparing daily 2 and 5 mg of tropisetron for the control of nausea and vomiting induced by low-dose cisplatin- or non-cisplatin-containing chemotherapy

NARCIS (Netherlands)

Wymenga, ANM; vanderGraaf, WTA; Wils, JA; vanHeukelom, LS; vanderLinden, GHM; DullemondWestland, AC; Nooy, M; vanderHeul, C; deBruijn, KM; deVries, EGE

Background: This study compares efficacy safety and tolerability of 2 and 5 mg tropisetron in prevention of nausea and vomiting induced by low-dose cisplatin- or non-cisplatin-containing chemotherapy. Patients and methods: 152 chemotherapy-naive cancer patients were randomized in a double-blind

Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine : efficacy, safety and dosing

NARCIS (Netherlands)

van den Broek, Marcel P. H.; Rademaker, Carin M. A.; van Straaten, Henrica L. M.; Huitema, Alwin D. R.; Toet, Mona C.; de Vries, Linda S.; Egberts, Antoine C. G.; Groenendaal, Floris

BACKGROUND: Lidocaine is an antiarrythmicum used as an anticonvulsant for neonatal seizures, also during therapeutic hypothermia following (perinatal) asphyxia. Hypothermia may affect the efficacy, safety and dosing of lidocaine in these patients. OBJECTIVE: To study the efficacy and safety of

LD-aminopterin in the canine homologue of human atopic dermatitis: a randomized, controlled trial reveals dosing factors affecting optimal therapy.

Science.gov (United States)

Zebala, John A; Mundell, Alan; Messinger, Linda; Griffin, Craig E; Schuler, Aaron D; Kahn, Stuart J

2014-01-01

Options are limited for patients with atopic dermatitis (AD) who do not respond to topical treatments. Antifolate therapy with systemic methotrexate improves the disease, but is associated with adverse effects. The investigational antifolate LD-aminopterin may offer improved safety. It is not known how antifolate dose and dosing frequency affect efficacy in AD, but a primary mechanism is thought to involve the antifolate-mediated accumulation of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). However, recent in vitro studies indicate that AICAR increases then decreases as a function of antifolate concentration. To address this issue and understand how dosing affects antifolate efficacy in AD, we examined the efficacy and safety of different oral doses and schedules of LD-aminopterin in the canine model of AD. This was a multi-center, double-blind trial involving 75 subjects with canine AD randomized to receive up to 12 weeks of placebo, once-weekly (0.007, 0.014, 0.021 mg/kg) or twice-weekly (0.007 mg/kg) LD-aminopterin. The primary efficacy outcome was the Global Score (GS), a composite of validated measures of disease severity and itch. GS improved in all once-weekly cohorts, with 0.014 mg/kg being optimal and significant (43%, P<0.01). The majority of improvement was seen by 8 weeks. In contrast, GS in the twice-weekly cohort was similar to placebo and worse than all once-weekly cohorts. Adverse events were similar across all treated cohorts and placebo. Once-weekly LD-aminopterin was safe and efficacious in canine AD. Twice-weekly dosing negated efficacy despite having the same daily and weekly dose as effective once-weekly regimens. Optimal dosing in this homologue of human AD correlated with the concentration-selective accumulation of AICAR in vitro, consistent with AICAR mediating LD-aminopterin efficacy in AD.

LD-aminopterin in the canine homologue of human atopic dermatitis: a randomized, controlled trial reveals dosing factors affecting optimal therapy.

Directory of Open Access Journals (Sweden)

John A Zebala

Full Text Available Options are limited for patients with atopic dermatitis (AD who do not respond to topical treatments. Antifolate therapy with systemic methotrexate improves the disease, but is associated with adverse effects. The investigational antifolate LD-aminopterin may offer improved safety. It is not known how antifolate dose and dosing frequency affect efficacy in AD, but a primary mechanism is thought to involve the antifolate-mediated accumulation of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR. However, recent in vitro studies indicate that AICAR increases then decreases as a function of antifolate concentration. To address this issue and understand how dosing affects antifolate efficacy in AD, we examined the efficacy and safety of different oral doses and schedules of LD-aminopterin in the canine model of AD.This was a multi-center, double-blind trial involving 75 subjects with canine AD randomized to receive up to 12 weeks of placebo, once-weekly (0.007, 0.014, 0.021 mg/kg or twice-weekly (0.007 mg/kg LD-aminopterin. The primary efficacy outcome was the Global Score (GS, a composite of validated measures of disease severity and itch. GS improved in all once-weekly cohorts, with 0.014 mg/kg being optimal and significant (43%, P<0.01. The majority of improvement was seen by 8 weeks. In contrast, GS in the twice-weekly cohort was similar to placebo and worse than all once-weekly cohorts. Adverse events were similar across all treated cohorts and placebo.Once-weekly LD-aminopterin was safe and efficacious in canine AD. Twice-weekly dosing negated efficacy despite having the same daily and weekly dose as effective once-weekly regimens. Optimal dosing in this homologue of human AD correlated with the concentration-selective accumulation of AICAR in vitro, consistent with AICAR mediating LD-aminopterin efficacy in AD.

Safety of low-dose aspirin in endovascular treatment for intracranial atherosclerotic stenosis.

Directory of Open Access Journals (Sweden)

Ning Ma

Full Text Available OBJECTIVES: To evaluate the safety of low-dose aspirin plus clopidogrel versus high-dose aspirin plus clopidogrel in prevention of vascular risk within 90 days of duration of dual antiplatelet therapy in patients treated with intracranial endovascular treatment. METHODS: From January 2012 to December 2013, this prospective and observational study enrolled 370 patients with symptomatic intracranial atherosclerotic stenosis of ≥70% with poor collateral undergoing intracranial endovascular treatment. Antiplatelet therapy consists of aspirin, at a low-dose of 100 mg or high-dose of 300 mg daily; clopidogrel, at a dose of 75 mg daily for 5 days before endovascular treatment. The dual antiplatelet therapy continued for 90 days after intervention. The study endpoints include acute thrombosis, subacute thrombosis, stroke or death within 90 days after intervention. RESULTS: Two hundred and seventy three patients received low-dose aspirin plus clopidogrel and 97 patients received high-dose aspirin plus clopidogrel before intracranial endovascular treatment. Within 90 days after intervention, there were 4 patients (1.5% with acute thrombosis, 5 patients (1.8% with subacute thrombosis, 17 patients (6.2% with stroke, and 2 death (0.7% in low-dose aspirin group, compared with no patient (0% with acute thrombosis, 2 patient (2.1% with subacute thrombosis, 6 patients (6.2% with stroke, and 2 death (2.1% in high-dose aspirin group, and there were no significant difference in all study endpoints between two groups. CONCLUSION: Low-dose aspirin plus clopidogrel is comparative in safety with high-dose aspirin plus clopidogrel within 90 days of duration of dual antiplatelet therapy in patients treated with intracranial endovascular treatment.

Immunogenicity, Safety and Reactogenicity of a Booster Dose of the 10-Valent Pneumococcal Nontypeable H. influenzae Protein D Conjugate Vaccine Coadministered With DTPa-IPV-Hib in Dutch Children: A Randomized Controlled Trial.

Science.gov (United States)

van den Bergh, Menno R; Spijkerman, Judith; François, Nancy; Swinnen, Kristien; Borys, Dorota; Schuerman, Lode; Veenhoven, Reinier H; Sanders, Elisabeth A M

2016-07-01

Immune responses and safety profiles may be affected when vaccines are coadministered. We evaluated the immunogenicity, safety and reactogenicity of a booster dose of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D-conjugate (PHiD-CV; Synflorix GSK Vaccines) and DTPa-IPV-Hib (Pediacel Sanofi Pasteur MSD) when coadministered. We performed booster assessment in a randomized controlled trial in the Netherlands. Of 780 enrolled healthy infants, 774 toddlers participated in the booster phase and received (1:1:1) (1) PHiD-CV + DTPa-HBV-IPV/Hib (Infanrix hexa, GSK Vaccines), (2) PHiD-CV + DTPa-IPV-Hib, or (3) 7-valent pneumococcal conjugate vaccine (7vCRM, Prevenar/Prevnar, Pfizer, Inc.) + DTPa-IPV-Hib at 2, 3, 4 and 11-13 months old. Blood samples were taken postprimary, prebooster, 1 and 12 months postbooster. Antipneumococcal antibody responses were comparable between both PHiD-CV groups, except for serotype 18C (conjugated to tetanus toxoid). Anti-18C antibody geometric mean concentrations (GMCs) were higher when coadministered with DTPa-HBV-IPV/Hib. For each vaccine serotype, the percentages of children with antibody concentration ≥ 0.20 μg/mL were within the same ranges between PHiD-CV groups (93.8%-100%). The same was observed for the percentages of participants with opsonophagocytic activity titer ≥ 8 (90.9%-100%). When comparing both DTPa-IPV-Hib groups, postbooster antidiphtheria antibody GMCs were higher when coadministered with 7vCRM, while antitetanus and antipolyribosyl-ribitol phosphate antibody GMCs were higher with PHiD-CV coadministration. Regardless, antibody levels to these antigens were well above thresholds. Safety and reactogenicity profiles were comparable between groups. Coadministration of a booster dose of PHiD-CV and DTPa-IPV-Hib was immunogenic and well tolerated.

A Randomized, Controlled Clinical Trial Comparing Efficacy, Safety ...

African Journals Online (AJOL)

A Randomized, Controlled Clinical Trial Comparing Efficacy, Safety and Cost Effectiveness of Lornoxicam with Diclofenac Sodium in Patients of Osteoarthritis Knee. ... All patients were assessed with visual analogue scale and 100 meter walking test before starting of therapy, at 15 days and at 1, 2 and 3 months of therapy.

Maximum tolerable radiation doses recommended by the Israel Advisory Committee on nuclear safety

International Nuclear Information System (INIS)

Tadmor, J.; Litai, D.; Lubin, E.

1978-01-01

Maximum tolerable doses have been recommended by the Israel Advisory Committee on Nuclear Safety. The recommendations which are based on a comparison with risks tolerated in other human activities, are for doses to radiation workers, for individual members of the population at the fence of a nuclear installation, and for the population at large, for both normal operating and accident conditions. Tolerable whole-body doses and doses to different critical organs are listed

Safety and PK/PD correlation of TV-1106, a recombinant fused human albumin-growth hormone, following repeat dose administration to monkeys.

Science.gov (United States)

Ashkenazi, Nurit; Rosenstock, Moti; Hallak, Hussein; Bassan, Merav; Rasamoelisolo, Michele; Leuschner, Jost; Shinar, Doron

TV-1106 is a recombinant human albumin genetically fused to growth hormone which is intended to reduce the frequency of injections for GH therapy users. We report the safety, tolerability, pharmacokinetics and pharmacodynamics of repeated subcutaneous injections of TV-1106 in Cynomolgus monkeys. Cynomolgus monkeys received four weekly subcutaneous injections of 0, 5, 10 or 20mg/kg TV-1106 and were monitored for safety signals throughout the study. Serum levels of TV-1106 and insulin-like growth factor 1 (IGF-1) were assayed. Treated animals showed no adverse effects or histopathological changes. TV-1106 serum concentrations showed sustained exposure to the drug. Exposure increased in a dose-dependent manner with peak concentrations at approximately 24h post-dosing and elimination half-lives in the range of 12 to 24h. IGF-1 serum concentrations were elevated throughout the entire study duration, indicative of the pharmacological response. There was a clear correlation between change in IGF-1 levels and dose or exposure to TV-1106. The safety, pharmacokinetic and pharmacodynamic findings support the further development of TV-1106 as a once-weekly administered treatment for patients with GHD. Copyright © 2016 Elsevier Ltd. All rights reserved.

Dose finding study of granisetron in patients receiving high-dose cisplatin chemotherapy. The Granisetron Study Group.

Science.gov (United States)

Riviere, A.

1994-01-01

The efficacy and safety of three different doses of granisetron (2 micrograms kg-1, group A; 10 micrograms kg-1, group B; 40 micrograms kg-1, group C) were compared in a randomised, double-blind study of 157 patients due to receive high-dose cisplatin therapy (mean dose > 97 mg m-2). In each group, up to two 3 mg rescue doses of granisetron were allowed if more than mild nausea or vomiting occurred. In group A 30.8%, in group B 61.5% and in group C 67.9% of patients were complete responders (i.e. no vomiting or nothing worse than mild nausea) during the first 24 h. These differences are significant between groups A and B, and A and C. There were no statistically significant differences in any efficacy variable between the 10 micrograms kg-1 and 40 micrograms kg-1 groups, although in each case the trend favoured the higher dose. Additional rescue doses resulted in resolved or improved symptoms in 95.3% for the first rescue dose and 93.3% for the second. Over the 7 days of the study, 82.7%, 82.7% and 86.8% of patients in groups A, B and C respectively were treated with granisetron alone. Headache was the most common side-effect, reported by 9.6% of patients; the majority of headaches were mild. There was no difference between the treatment groups regarding the adverse event rate. We concluded that prophylactic doses of 10 or 40 micrograms kg-1 lead to a safe and satisfactory degree of control of nausea and vomiting induced by high-dose cisplatin. PMID:8180032

Immunogenicity and safety of purified chick-embryo cell rabies vaccine under Zagreb 2-1-1 or 5-dose Essen regimen in Chinese children 6 to 17 years old and adults over 50 years: a randomized open-label study.

Science.gov (United States)

Li, RongCheng; Li, YanPing; Wen, ShuQing; Wen, HuiChun; Nong, Yi; Mo, Zhaojun; Xie, Fang; Pellegrini, Michele

2015-01-01

The aim of this Phase IIIb, open-label, randomized study was to demonstrate the non-inferiority of immune responses and to assess the safety of a purified chick-embryo cell rabies vaccine (PCECV) in healthy Chinese children (6 to 17 years) and older adults (≥51 years) following 2 alternative intramuscular (IM) simulated post-exposure prophylaxis (PEP) regimens: 4-dose Zagreb or 5-dose Essen regimen. Serum samples were collected prior to vaccination on Days 1 and 15 and on day 43 to assess immune response by rabies virus neutralizing antibody (RVNA) concentrations. Solicited adverse events (AEs) were recorded for up to 7 days following each vaccine dose, and unsolicited AEs throughout the entire study period. PCECV vaccination induced a strong immune response at Day 15, and the non-inferiority in immune response of the Zagreb vs. the Essen regimen was demonstrated in children and older adults. At Day 15,100% of children (N = 224), and 99% of subjects ≥51 years of age (N = 376) developed adequate RVNA concentrations (≥0.5 IU/mL); at Day 43 all subjects achieved RVNA concentrations ≥0.5 IU/mL, for both PEP regimens. The well-known tolerability and safety profile of the PCECV was again observed in this study following either Zagreb or Essen regimens. Rabies PEP vaccination with PCECV following a Zagreb regimen induced immune responses non-inferior to those of the Essen regimen, and had a similar safety and tolerability profile to the Essen regimen in Chinese children, adolescents, and adults over 51 years. ClinicalTrials.gov identifier: NCT01680016.

Radiation safety program in high dose rate brachytherapy facility at INHS Asvini

Directory of Open Access Journals (Sweden)

Kirti Tyagi

2014-01-01

Full Text Available Brachytherapy concerns primarily the use of radioactive sealed sources which are inserted into catheters or applicators and placed directly into tissue either inside or very close to the target volume. The use of radiation in treatment of patients involves both benefits and risks. It has been reported that early radiation workers had developed radiation induced cancers. These incidents lead to continuous work for the improvement of radiation safety of patients and personnel The use of remote afterloading equipment has been developed to improve radiation safety in the delivery of treatment in brachytherapy. The widespread adoption of high dose rate brachytherapy needs appropriate quality assurance measures to minimize the risks to both patients and medical staff. The radiation safety program covers five major aspects: quality control, quality assurance, radiation monitoring, preventive maintenance, administrative measures and quality audit. This paper will discuss the radiation safety program developedfor a high dose rate brachytherapy facility at our centre which may serve as a guideline for other centres intending to install a similar facility.

A dose-finding, cross-over study to evaluate the effect of a Nestorone®/Estradiol transdermal gel delivery on ovulation suppression in normal ovulating women.

Science.gov (United States)

Brache, Vivian; Merkatz, Ruth; Kumar, Narender; Jesam, Cristian; Sussman, Heather; Hoskin, Elena; Roberts, Kevin; Alami, Mohcine; Taylor, Deshawn; Jorge, Aidelis; Croxatto, Horacio; Lorange, Ellen; Mishell, Daniel R; Sitruk-Ware, Regine

2015-10-01

This study aims to determine the lowest effective of three Nestorone (NES)/estradiol (E2) transdermal gel doses to ensure ovulation suppression in 90-95% of cycles. This was a randomized, open-label, three-treatment-period cross-over study to evaluate the effects of NES/E2 transdermal gel on ovulation inhibition, suppression of follicular growth and pharmacokinetic parameters. The doses were low (1.5 mg NES/0.5 mg E2), medium (3.0 mg NES/1.0 mg E2) and high (4.5 mg NES/1.5 mg E2). Participants applied gel daily to a fixed area on the abdomen for 21 consecutive days. They were interviewed regarding their experiences using the gel. Eighteen participants were randomized; 16 completed the study. Median NES C(max) values for low, medium and high dose groups at day 21 were 318.6 pmol/L, 783.0 pmol/L and 1063.8 pmol/L, respectively. Median maximum follicular diameter was higher with the lowest dose with 16.2 mm versus 10.0 and 10.4 mm with the medium and high doses, respectively. Among adherent participants, ovulation was inhibited in all dose groups, except for one participant in the medium dose (6.7%) that had luteal activity and an ultrasound image suggestive of a luteinized unruptured follicle. There were few reports of unscheduled bleeding, with more episodes reported for the lower dose. Adverse events were mild, and no skin irritation was reported from gel application. While all three doses blocked ovulation effectively and were evaluated as safe and acceptable, the medium dose was considered the lowest effective dose based on a more adequate suppression of follicular development. Further development of this novel contraceptive delivering NES and E2 is warranted and has potential for improved safety compared to ethinyl-estradiol-based methods. Copyright © 2015 Elsevier Inc. All rights reserved.

Safety, dose, and timing of reteplase in treating occluded central venous catheters in children with cancer.

Science.gov (United States)

Terrill, Kelly R; Lemons, Richard S; Goldsby, Robert E

2003-11-01

Recombinant tissue plasminogen activator, alteplase, began to be commonly used to restore the patency of occluded central venous catheters (CVCs) as urokinase production was halted in the late 1990s. However, alteplase often requires an extended dwell time to restore patency to occluded CVCs. In adults, reteplase, a newer thrombolytic agent, has been reported to restore patency to CVCs in 30 minutes. The authors prospectively evaluated the safety and efficacy of reteplase in restoring patency to occluded CVCs in children with cancer. This was a dose escalation trial. The dose of reteplase was initiated at 0.1 units and increased by increments of 0.1 units to a maximum dose of 0.4 units. Each dose was tested on at least three participants. Time to patency after reteplase administration was recorded by nurses caring for the patients. Attempts to access the line occurred every 15 minutes for 1 hour. CVCs that remained occluded after 1 hour were treated with alteplase. Reteplase was administered to 15 clotted CVCs. Twelve of the 15 were cleared with an average dwell time of 38 minutes. The time to patency did not appear to correlate with the dose. No adverse events were reported. Reteplase can restore patency to occluded CVCs in a pediatric population. Reteplase appears to have comparable efficacy with alteplase, but reteplase may require shorter dwell times. A prospective, randomized, clinical trial is warranted to determine whether reteplase is as effective as alteplase in restoring patency to occluded CVCs.

Analgesic efficacy and safety of intravenous paracetamol (acetaminophen) administered as a 2g starting dose following third molar surgery

DEFF Research Database (Denmark)

Juhl, Gitte Irene; Nørholt, Sven E.; Tønnesen, Else Kirstine

2006-01-01

BACKGROUND: The recommended dose for intravenous (IV) paracetamol injection in adults is 1g, however pharmacokinetic and pharmacodynamic findings suggest that a better analgesia could be obtained with a 2g starting dose. METHODS: A single-centre, randomised, double-blind, placebo-controlled, 3......-parallel group study was performed to demonstrate the analgesic efficacy and safety of IV paracetamol 2g. Following third molar surgery, patients reporting moderate to severe pain received a single 15-min infusion of either IV paracetamol 2g, IV paracetamol 1g or placebo. Efficacy and safety were evaluated...... over 8h. Laboratory tests were performed before and 48h after drug administration. RESULTS: Two hundred and ninety seven patients (132=IV paracetamol 2g; 132=IV paracetamol 1g; 33=placebo) were randomised and completed the study. The summed pain relief over 6h (TOTPAR6) was significantly superior...

Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial.

Science.gov (United States)

Thaçi, Diamant; Simpson, Eric L; Beck, Lisa A; Bieber, Thomas; Blauvelt, Andrew; Papp, Kim; Soong, Weily; Worm, Margitta; Szepietowski, Jacek C; Sofen, Howard; Kawashima, Makoto; Wu, Richard; Weinstein, Steven P; Graham, Neil M H; Pirozzi, Gianluca; Teper, Ariel; Sutherland, E Rand; Mastey, Vera; Stahl, Neil; Yancopoulos, George D; Ardeleanu, Marius

2016-01-02

Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis, evidenced by marked improvement after treatment with dupilumab, a fully-human monoclonal antibody that blocks both pathways. We aimed to assess the efficacy and safety of several dose regimens of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments. In this randomised, placebo-controlled, double-blind study, we enrolled patients aged 18 years or older who had an Eczema Area and Severity Index (EASI) score of 12 or higher at screening (≥16 at baseline) and inadequate response to topical treatments from 91 study centres, including hospitals, clinics, and academic institutions, in Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Patients were randomly assigned (1:1:1:1:1:1), stratified by severity (moderate or severe, as assessed by Investigator's Global Assessment) and region (Japan vs rest of world) to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or placebo once a week for 16 weeks. We used a central randomisation scheme, provided by an interactive voice response system. Drug kits were coded, providing masking to treatment assignment, and allocation was concealed. Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) from baseline to week 16. Analyses included all randomly assigned patients who received one or more doses of study drug. This trial is registered with ClinicalTrials.gov, number NCT01859988. Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were randomly assigned. 379 patients received one or more

Open-Label Single-Sequence Crossover Study Evaluating Pharmacokinetics, Efficacy, and Safety of Once-Daily Dosing of Nitisinone in Patients with Hereditary Tyrosinemia Type 1.

Science.gov (United States)

Guffon, Nathalie; Bröijersén, Anders; Palmgren, Ingrid; Rudebeck, Mattias; Olsson, Birgitta

2018-01-01

Although nitisinone is successfully used to treat hereditary tyrosinemia type 1 (HT-1) with the recommended twice-daily dosing, data describing a long half-life motivate less frequent dosing. Therefore, in agreement with the Pharmacovigilance Risk Assessment Committee at the European Medicines Agency, this study was performed to investigate the switch to once-daily dosing. This open-label, non-randomized, single-sequence crossover study evaluated the pharmacokinetics, efficacy, and safety of once-daily compared to twice-daily dosing of nitisinone in patients with HT-1 (NCT02323529). Well-controlled patients of dry blood spots by tandem mass spectrometry. The primary endpoint was C min of nitisinone after ≥4 weeks of treatment on each dosing regimen. Secondary objectives were evaluation of efficacy and safety during each dosing regimen. In total, 19 patients were enrolled and 17 included in the per-protocol analysis set. The mean (SD) nitisinone C min decreased by 23%, from 26.4 (10.2) to 21.2 (9.9) μmol/L in dry blood spot samples (not equivalent to plasma concentrations), when patients switched from twice- to once-daily dosing. There was no apparent age- or bodyweight-related trend in the degree of C min decrease. No patient had quantifiable succinylacetone levels during the once-daily treatment period, indicating efficacious treatment. All adverse events were mild or moderate and judged unrelated to nitisinone. The switch to once-daily treatment with nitisinone appeared efficacious and safe in the treatment of patients with HT-1.

Dose-Weighted Adjusted Mantel-Haenszel Tests for Numeric Scaled Strata in a Randomized Trial

Science.gov (United States)

Gansky, Stuart A.; Cheng, Nancy F.; Koch, Gary G.

2011-01-01

A recent three-arm parallel groups randomized clinical prevention trial had a protocol deviation causing participants to have fewer active doses of an in-office treatment than planned. The original statistical analysis plan stipulated a minimal assumption randomization-based extended Mantel-Haenszel (EMH) trend test of the high frequency, low frequency, and zero frequency treatment groups and a binary outcome. Thus a dose-weighted adjusted EMH (DWAEMH) test was developed with an extra set of weights corresponding to the number of active doses actually available, in the spirit of a pattern mixture model. The method can easily be implemented using standard statistical software. A set of Monte Carlo simulations using a logistic model was undertaken with (and without) actual dose-response effects through 1000 replicates for empirical power estimates (and 2100 for empirical size). Results showed size was maintained and power was improved for DWAEMH versus EMH and logistic regression Wald tests in the presence of a dose effect and treatment by dose interaction. PMID:21709814

Value of public health and safety actions and radiation dose avoided

Energy Technology Data Exchange (ETDEWEB)

Baum, J.W. [Brookhaven National Lab., Upton, NY (United States)

1994-05-01

The values judged best to reflect the willingness of society to pay for the avoidance or reduction of risk were deduced from studies of costs of health care, transportation safety, consumer product safety, government agency actions, wage-risk compensation, consumer behavior (market) studies, and willingness-to-pay surveys. The results ranged from $1,400,000 to $2,700,000 per life saved. Applying the mean of these values ($2,100,000) and the latest risk per unit dose coefficients used by the ICRP (1991), which take into account risks to the general public, including genetic effects and nonfatal cancers, yields a value of dose avoided of $750 to $1,500 per person-cSv for public exposures. The lower value applies if adjustments are made for years of life lost per fatality. A nominal value of $1,000 per person-cSv seems appropriate in light of the many uncertainties involved in deducing these values. These values are consistent with values recommended by several European countries for individual doses in the region of 1 mSv/y (100 mrem/y). Below this dose rate, most countries have values a factor of 7 to 10 lower, based on the assumption that society is less concerned with fatality risks below about 10{sup {minus}4}/y.

Value of public health and safety actions and radiation dose avoided

International Nuclear Information System (INIS)

Baum, J.W.

1994-05-01

The values judged best to reflect the willingness of society to pay for the avoidance or reduction of risk were deduced from studies of costs of health care, transportation safety, consumer product safety, government agency actions, wage-risk compensation, consumer behavior (market) studies, and willingness-to-pay surveys. The results ranged from $1,400,000 to $2,700,000 per life saved. Applying the mean of these values ($2,100,000) and the latest risk per unit dose coefficients used by the ICRP (1991), which take into account risks to the general public, including genetic effects and nonfatal cancers, yields a value of dose avoided of $750 to $1,500 per person-cSv for public exposures. The lower value applies if adjustments are made for years of life lost per fatality. A nominal value of $1,000 per person-cSv seems appropriate in light of the many uncertainties involved in deducing these values. These values are consistent with values recommended by several European countries for individual doses in the region of 1 mSv/y (100 mrem/y). Below this dose rate, most countries have values a factor of 7 to 10 lower, based on the assumption that society is less concerned with fatality risks below about 10 -4 /y

Low or High Fractionation Dose {beta}-Radiotherapy for Pterygium? A Randomized Clinical Trial

Energy Technology Data Exchange (ETDEWEB)

Viani, Gustavo Arruda, E-mail: gusviani@gmail.com [Department of Radiation Oncology, Marilia Medicine School, Sao Paulo, SP (Brazil); De Fendi, Ligia Issa; Fonseca, Ellen Carrara [Department of Ophthalmology, Marilia Medicine School, Sao Paulo, SP (Brazil); Stefano, Eduardo Jose [Department of Radiation Oncology, Marilia Medicine School, Sao Paulo, SP (Brazil)

2012-02-01

Purpose: Postoperative adjuvant treatment using {beta}-radiotherapy (RT) is a proven technique for reducing the recurrence of pterygium. A randomized trial was conducted to determine whether a low fractionation dose of 2 Gy within 10 fractions would provide local control similar to that after a high fractionation dose of 5 Gy within 7 fractions for surgically resected pterygium. Methods: A randomized trial was conducted in 200 patients (216 pterygia) between February 2006 and July 2007. Only patients with fresh pterygium resected using a bare sclera method and given RT within 3 days were included. Postoperative RT was delivered using a strontium-90 eye applicator. The pterygia were randomly treated using either 5 Gy within 7 fractions (Group 1) or 2 Gy within 10 fractions (Group 2). The local control rate was calculated from the date of surgery. Results: Of the 216 pterygia included, 112 were allocated to Group 1 and 104 to Group 2. The 3-year local control rate for Groups 1 and 2 was 93.8% and 92.3%, respectively (p = .616). A statistically significant difference for cosmetic effect (p = .034), photophobia (p = .02), irritation (p = .001), and scleromalacia (p = .017) was noted in favor of Group 2. Conclusions: No better local control rate for postoperative pterygium was obtained using high-dose fractionation vs. low-dose fractionation. However, a low-dose fractionation schedule produced better cosmetic effects and resulted in fewer symptoms than high-dose fractionation. Moreover, pterygia can be safely treated in terms of local recurrence using RT schedules with a biologic effective dose of 24-52.5 Gy{sub 10.}.

Safety, dose optimisation and security: the quadrature of the circle

Energy Technology Data Exchange (ETDEWEB)

Hardeman, Frank; Vermeersch, Fernand [Belgian Nuclear Research Centre (SCK.CEN), Boeretang 200, BE-2400 Mol (Belgium)

2010-07-01

The growing concern for potential terrorist acts has lead to a number of new ideas about storing radiological and nuclear materials that are not always compatible with existing practices or infrastructures. This is valid in routine circumstances, but especially poses problems in case of accidents. As such, the management of nuclear safety, radiological protection and security within an evolving world such as a nuclear research centre sometimes looks like implementing the quadrature of the circle. International guidance exists, but is not always easily converted into an adequate policy comprehensible to all levels in a plant, from management to the work floor. Some examples. 1. infrastructure related problems: from a security point of view, fuels are better stored in the heart of a protected zone, while in case of criticality, fire... a more peripheral location is appropriate. 2. Safety related problems: Protection infrastructure may lead to difficulties of evacuation in case of emergencies; access limitations may be a burden in the management of safety interventions, maintenance... 3. Administrative contradictions: inventories of fuel storages and high active sealed sources are a cornerstone of inspections and verifications; yet, this information is a treasure for terrorists aiming at actions to obtain special materials. 4. Dose management: measures taken to secure sources may lead to a dose increase (e.g. labelling of old sources). However, the main difficulty is related to the 'cultural' aspect. There are synergies between safety culture, 'ALARA' culture and security culture. An individual aspect of desirable behaviour (e.g. questioning attitude), complemented with an organisational dimension (e.g. training, raising awareness) are obviously common. The objective is also in line: to avoid reduction of well-being of people, to protect the environment, to prevent damage to facilities. The main difficulties arise however because of the fundamental

Safety, dose optimisation and security: the quadrature of the circle

International Nuclear Information System (INIS)

Hardeman, Frank; Vermeersch, Fernand

2010-01-01

The growing concern for potential terrorist acts has lead to a number of new ideas about storing radiological and nuclear materials that are not always compatible with existing practices or infrastructures. This is valid in routine circumstances, but especially poses problems in case of accidents. As such, the management of nuclear safety, radiological protection and security within an evolving world such as a nuclear research centre sometimes looks like implementing the quadrature of the circle. International guidance exists, but is not always easily converted into an adequate policy comprehensible to all levels in a plant, from management to the work floor. Some examples. 1. infrastructure related problems: from a security point of view, fuels are better stored in the heart of a protected zone, while in case of criticality, fire... a more peripheral location is appropriate. 2. Safety related problems: Protection infrastructure may lead to difficulties of evacuation in case of emergencies; access limitations may be a burden in the management of safety interventions, maintenance... 3. Administrative contradictions: inventories of fuel storages and high active sealed sources are a cornerstone of inspections and verifications; yet, this information is a treasure for terrorists aiming at actions to obtain special materials. 4. Dose management: measures taken to secure sources may lead to a dose increase (e.g. labelling of old sources). However, the main difficulty is related to the 'cultural' aspect. There are synergies between safety culture, 'ALARA' culture and security culture. An individual aspect of desirable behaviour (e.g. questioning attitude), complemented with an organisational dimension (e.g. training, raising awareness) are obviously common. The objective is also in line: to avoid reduction of well-being of people, to protect the environment, to prevent damage to facilities. The main difficulties arise however because of the fundamental differences being

Phase I dose-finding study of cabazitaxel administered weekly in patients with advanced solid tumours

International Nuclear Information System (INIS)

Fumoleau, Pierre; Trigo, Jose Manuel; Isambert, Nicolas; Sémiond, Dorothée; Gupta, Sunil; Campone, Mario

2013-01-01

Cabazitaxel is approved in patients with metastatic hormone-refractory prostate cancer previously treated with a docetaxel-containing regimen. This study evaluated a weekly cabazitaxel dosing regimen. Primary objectives were to report dose-limiting toxicities (DLTs) and to determine the maximum tolerated dose (MTD). Efficacy, safety and pharmacokinetics were secondary objectives. Cabazitaxel was administered weekly (1-hour intravenous infusion at 1.5–12 mg/m2 doses) for the first 4 weeks of a 5-week cycle in patients with solid tumours. Monitoring of DLTs was used to determine the MTD and the recommended weekly dose. Thirty-one patients were enrolled. Two of six patients experienced DLTs at 12 mg/m 2 , which was declared the MTD. Gastrointestinal disorders were the most common adverse event. Eight patients developed neutropenia (three ≥ Grade 3); one occurrence of febrile neutropenia was reported. There were two partial responses (in breast cancer) and 13 patients had stable disease (median duration of 3.3 months). Increases in C max and AUC 0–t were dose proportional for the 6–12 mg/m 2 doses. The MTD of weekly cabazitaxel was 12 mg/m 2 and the recommended weekly dose was 10 mg/m 2 . The observed safety profile and antitumour activity of cabazitaxel were consistent with those observed with other taxanes in similar dosing regimens. The study was registered with ClinicalTrials.gov as http://www.clinicaltrials.gov/ct2/show/NCT01755390

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the CGRP Binding Monoclonal Antibody LY2951742 (Galcanezumab in Healthy Volunteers

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David Monteith

2017-10-01

Full Text Available Background: Calcitonin gene-related peptide (CGRP is pivotal in the pathophysiology of migraine headaches and represents a promising target for migraine treatment. The humanized monoclonal antibody galcanezumab (LY2951742 binds to CGRP and may be effective in migraine prophylaxis.Objectives: The primary objective was to evaluate the safety and tolerability of single and multiple doses of galcanezumab in humans. Secondary objectives included assessing the pharmacokinetics and evaluating target engagement.Methods: A double-blind, randomized, placebo-controlled study (NCT 01337596 with single escalating and multiple subcutaneous (SC doses of galcanezumab was performed in healthy male volunteers. Single doses of 1, 5, 25, 75, 200, and 600 mg of galcanezumab (n = 7/dose or placebo (n = 2/dose were injected SC in six consecutive cohorts of nine subjects each. One cohort of nine subjects received multiple (4 150 mg doses of galcanezumab or placebo every other week. Target engagement was evaluated by measuring inhibition of capsaicin-induced increase in dermal blood flow (DBF.Findings: Sixty-three subjects were randomized and included in the safety analyses. Galcanezumab was well tolerated in single doses (1–600 mg SC and consecutive doses (150 mg SC. There was no dose-dependent difference in type or frequency of treatment-emergent adverse events, and no clinically meaningful difference when compared with placebo. Pharmacokinetics were linear. Galcanezumab induced a robust, dose-dependent, and durable inhibition of capsaicin-induced increase in DBF, supporting the continued clinical development of galcanezumab for prophylaxis in migraine patients.

A phase I trial to evaluate the safety and pharmacokinetics of low-dose methotrexate as an anti-malarial drug in Kenyan adult healthy volunteers

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Oyoo George O

2011-03-01

Full Text Available Abstract Background Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers. Methods Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days. Results The mean age of participants was 23.9 ± 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product were reported. The maximum concentration (Cmax was 160-200 nM and after 6 hours, the effective concentration (Ceff was Conclusion Low-dose methotraxate had an acceptable safety profile. However, methotrexate blood levels did not reach the desirable Ceff of 250-400-nM required to clear malaria infection in vivo. Further dose finding and safety studies are necessary to confirm suitability of this drug as an anti-malarial agent.

Safety of bazedoxifene in a randomized, double-blind, placebo- and active-controlled phase 3 study of postmenopausal women with osteoporosis

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Palacios Santiago

2010-06-01

Full Text Available Abstract Background We report the safety findings from a 3-year phase 3 study (NCT00205777 of bazedoxifene, a novel selective estrogen receptor modulator under development for the prevention and treatment of postmenopausal osteoporosis. Methods Healthy postmenopausal osteoporotic women (N = 7,492; mean age, 66.4 years were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. Safety and tolerability were assessed by adverse event (AE reporting and routine physical, gynecologic, and breast examination. Results Overall, the incidence of AEs, serious AEs, and discontinuations due to AEs in the bazedoxifene groups was not different from that seen in the placebo group. The incidence of hot flushes and leg cramps was higher with bazedoxifene or raloxifene compared with placebo. The rates of cardiac disorders and cerebrovascular events were low and evenly distributed among groups. Venous thromboembolic events, primarily deep vein thromboses, were more frequently reported in the active treatment groups compared with the placebo group; rates were similar with bazedoxifene and raloxifene. Bazedoxifene showed a neutral effect on the breast and an excellent endometrial safety profile. The incidence of fibrocystic breast disease was lower with bazedoxifene 20 and 40 mg versus raloxifene or placebo. Reductions in total and low-density lipoprotein levels and increases in high-density lipoprotein levels were seen with bazedoxifene versus placebo; similar results were seen with raloxifene. Triglyceride levels were similar among groups. Conclusion Bazedoxifene showed a favorable safety and tolerability profile in women with postmenopausal osteoporosis. Trial Registration Trial registration number: NCT00205777; Trial registration date: September 16, 2005

A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Oral ELND005 (scyllo-Inositol) in Young Adults with Down Syndrome without Dementia

Science.gov (United States)

Rafii, Michael S.; Skotko, Brian G.; McDonough, Mary Ellen; Pulsifer, Margaret; Evans, Casey; Doran, Eric; Muranevici, Gabriela; Kesslak, Patrick; Abushakra, Susan; Lott, Ira T.

2018-01-01

Background ELND005 (scyllo-Inositol; cyclohexane-1,2,3,4,5,6-hexol) has been evaluated as a potential disease-modifying treatment for Alzheimer’s disease (AD). Individuals with Down syndrome (DS) have an increased risk for developing AD dementia. Objective To evaluate the safety and tolerability of ELND005 and to determine its pharmacokinetics (PK) and relationship between PK parameters, safety outcome measures, and exploratory efficacy outcome measures in young adults with DS without dementia. Methods This was a prospective, randomized, double-blind, placebo-controlled, parallel-group, three-arm, multicenter Phase 2 study of the safety and pharmacokinetics of ELND005 administered orally for 4 weeks (ClinicalTrials.gov NCT01791725). Participants who met study eligibility criteria were randomly assigned in a 2:1:1 ratio to receive ELND005 at either 250 mg twice daily (BID) or 250 mg once daily (QD) or matching placebo for 4 weeks. Results There were no apparent treatment group-related trends on cognitive or behavioral measures and there were no SAEs and no deaths in the study. Overall, mean changes from baseline in clinical laboratory parameters, vital sign measurements, electrocardiogram (ECG) results, and other physical findings were unremarkable. ELND005 accumulation averaged approximately 2-fold with QD dosing, and 3- to 4-fold with BID dosing. Conclusion Overall, treatment of adults with DS with ELND005 at both doses was well tolerated, achieved measurable blood levels and demonstrated no safety findings. Further studies will be needed to test efficacy. PMID:28453471

First-In-Human, Double-Blind, Placebo-Controlled, Randomized, Dose-Escalation Study of BG00010, a Glial Cell Line-Derived Neurotrophic Factor Family Member, in Subjects with Unilateral Sciatica.

Science.gov (United States)

Rolan, Paul E; O'Neill, Gilmore; Versage, Eve; Rana, Jitesh; Tang, Yongqiang; Galluppi, Gerald; Aycardi, Ernesto

2015-01-01

To evaluate the safety, tolerability, and pharmacokinetics of single doses of BG00010 (neublastin, artemin, enovin) in subjects with unilateral sciatica. This was a single-center, blinded, placebo-controlled, randomized Phase 1 sequential-cohort, dose-escalation study (ClinicalTrials.gov identifier NCT00961766; funded by Biogen Idec). Adults with unilateral sciatica were enrolled at The Royal Adelaide Hospital, Australia. Four subjects were assigned to each of eleven cohorts (intravenous BG00010 0.3, 1, 3, 10, 25, 50, 100, 200, 400, or 800 μg/kg, or subcutaneous BG00010 50 μg/kg) and were randomized 3:1 to receive a single dose of BG00010 or placebo. The primary safety and tolerability assessments were: adverse events; clinical laboratory parameters and vital signs; pain as measured by a Likert rating scale; intra-epidermal nerve fiber density; and longitudinal assessment of quantitative sensory test parameters. Blood, serum, and plasma samples were collected for pharmacokinetic and pharmacodynamic assessments. Subjects were blinded to treatment assignment throughout the study. The investigator was blinded to treatment assignment until the Data Safety Review Committee review of unblinded data, which occurred after day 28. Beyond the planned enrollment of 44 subjects, four additional subjects were enrolled into to the intravenous BG00010 200 μg/kg cohort after one original subject experienced mild generalized pruritus. Therefore, a total of 48 subjects were enrolled between August 2009 and December 2011; all were included in the safety analyses. BG00010 was generally well tolerated: in primary analyses, the most common treatment-emergent adverse events were changes in temperature perception, pruritus, rash, or headache; no trends were observed in clinical laboratory parameters, vital signs, intra-epidermal nerve fiber density, or quantitative sensory testing. BG00010 was not associated with any clear, dose-dependent trends in Likert pain scores. BG00010 was

A Randomized controlled trial on safety and efficacy of single intramuscular versus staggered oral dose of 600 000IU Vitamin D in treatment of nutritional rickets.

Science.gov (United States)

Mondal, Krishanu; Seth, Anju; Marwaha, Raman K; Dhanwal, Dinesh; Aneja, Satinder; Singh, Ritu; Sonkar, Pitambar

2014-06-01

Comparison of efficacy and safety of two different regimens of vitamin D-600 000 IU as a single intramuscular dose, and 60 000IU orally once a week for 10 weeks-in treatment of nutritional rickets. Children with nutritional rickets (age: 0.5-5 years, n = 61) were randomized to receive either 60 000IU vitamin D orally once a week for 10 weeks or 600 000IU single intramuscular injection. Serum calcium, phosphate, alkaline phosphatase, urinary calcium/creatinine ratio, serum 25 hydroxy vitamin D and radiological score were compared at 12-week follow-up. No difference was found in efficacy of the two regimens on comparing biochemical and radiological parameters. Serum 25 hydroxy vitamin D >100 ng/ml was found in two children in the oral group and one child in the intramuscular group. No child developed hypercalcemia or hypercalciuria after starting treatment. Staggered oral and one-time intramuscular administrations of 600 000IU vitamin D are equally effective and safe in treatment of nutritional rickets. © The Author [2014]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Immunogenicity and safety of the new reduced-dose tetanus-diphtheria vaccine in healthy Korean adolescents: A comparative active control, double-blind, randomized, multicenter phase III study.

Science.gov (United States)

Han, Seung Beom; Rhim, Jung-Woo; Shin, Hye Jo; Kim, Sang Yong; Kim, Jong-Hyun; Kim, Hyun-Hee; Lee, Kyung-Yil; Kim, Hwang Min; Choi, Young Youn; Ma, Sang Hyuk; Kim, Chun Soo; Kim, Dong Ho; Ahn, Dong Ho; Kang, Jin Han

2017-04-01

A new reduced-dose tetanus-diphtheria (Td) vaccine was developed in Korea, and phase I and II clinical trials were successfully undertaken. We conducted this double-blind, randomized, multicenter phase III clinical trial to assess the immunogenicity and safety of the new Td vaccine. Healthy adolescents 11-12 years of age were enrolled and randomized to receive the new Td vaccine (study group) or a commercially available Td vaccine (control group). Blood samples were collected prior to and 4 weeks after the vaccination. Between the study and control groups, seroprotection rate, booster response, and geometric mean titer of antibodies against diphtheria and tetanus toxoids were compared after the vaccination. All solicited and unsolicited adverse events and serious adverse events during the 6-week study period were monitored. A total of 164 adolescents received vaccination, and 156 of them were evaluated to assess immunogenicity. The seroprotection rate and geometric mean titer for antibodies against diphtheria were significantly higher in the study group, whereas those against tetanus were significantly higher in the control group. However, all seroprotection rates against diphtheria and tetanus in the study and control groups were high: 100% against diphtheria and tetanus in the study group, and 98.7% against diphtheria and 100% against tetanus in the control group. No significant differences in the frequency of solicited and unsolicited adverse events were observed between the two vaccine groups. The new Td vaccine is highly immunogenic and safe, and this new Td vaccine can be effectively used for preventing diphtheria and tetanus. Copyright © 2015. Published by Elsevier B.V.

Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN.

Science.gov (United States)

Jabbour, Elias; Short, Nicholas J; Montalban-Bravo, Guillermo; Huang, Xuelin; Bueso-Ramos, Carlos; Qiao, Wei; Yang, Hui; Zhao, Chong; Kadia, Tapan; Borthakur, Gautam; Pemmaraju, Naveen; Sasaki, Koji; Estrov, Zeev; Cortes, Jorge; Ravandi, Farhad; Alvarado, Yesid; Komrokji, Rami; Sekeres, Mikkael A; Steensma, David P; DeZern, Amy; Roboz, Gail; Kantarjian, Hagop; Garcia-Manero, Guillermo

2017-09-28

Hypomethylating agents (HMAs) improve survival in patients with higher-risk myelodysplastic syndromes (MDS) but are less well-studied in lower-risk disease. We compared the safety and efficacy of low-dose decitabine vs low-dose azacitidine in this group of patients. Adults with low- or intermediate 1-risk MDS or MDS/myeloproliferative neoplasm (MPN), including chronic myelomonocytic leukemia, according to the International Prognostic Scoring System, were randomly assigned using a Bayesian adaptive design to receive either azacitidine 75 mg/m 2 intravenously/subcutaneously daily or decitabine 20 mg/m 2 intravenously daily for 3 consecutive days on a 28-day cycle. The primary outcome was overall response rate (ORR). Between November 2012 and February 2016, 113 patients were treated: 40 (35%) with azacitidine and 73 (65%) with decitabine. The median age was 70 years; 81% of patients were intermediate 1-risk patients. The median number of cycles received was 9. The ORRs were 70% and 49% ( P = .03) for patients treated with decitabine and azacitidine, respectively. Thirty-two percent of patients treated with decitabine became transfusion independent compared with 16% of patients treated with azacitidine ( P = .2). Cytogenetic response rates were 61% and 25% ( P = .02), respectively. With a median follow-up of 20 months, the overall median event-free survival was 18 months: 20 and 13 months for patients treated with decitabine and azacitidine, respectively ( P = .1). Treatment was well tolerated, with a 6-week mortality rate of 0%. The use of low-dose HMAs is safe and effective in patients with lower-risk MDS and MDS/MPN. Their effect on the natural history of lower-risk disease needs to be further studied. This trial was registered at clinicaltrials.gov (identifier NCT01720225). © 2017 by The American Society of Hematology.

A step-up test procedure to find the minimum effective dose.

Science.gov (United States)

Wang, Weizhen; Peng, Jianan

2015-01-01

It is of great interest to find the minimum effective dose (MED) in dose-response studies. A sequence of decreasing null hypotheses to find the MED is formulated under the assumption of nondecreasing dose response means. A step-up multiple test procedure that controls the familywise error rate (FWER) is constructed based on the maximum likelihood estimators for the monotone normal means. When the MED is equal to one, the proposed test is uniformly more powerful than Hsu and Berger's test (1999). Also, a simulation study shows a substantial power improvement for the proposed test over four competitors. Three R-codes are provided in Supplemental Materials for this article. Go to the publishers online edition of Journal of Biopharmaceutical Statistics to view the files.

Single dose (400 mg) versus 7 day (200 mg) daily dose itraconazole in the treatment of tinea versicolor: a randomized clinical trial.

Science.gov (United States)

Wahab, M A; Ali, M E; Rahman, M H; Chowdhury, S A; Monamie, N S; Sultana, N; Khondoker, L

2010-01-01

Tinea (pityriasis) versicolor is a superficial fungal infection and one of the most commonly found pigmentary disorders of skin caused by the yeast Malassezia. Multiple topical as well as systemic therapies are available for treatment. Systemic therapies are used for extensive disease, frequent relapse or where topical agents have failed. The aim that translates the rationale of the study was to compare the efficacy, safety, tolerability and cost effectiveness of single dose 400mg versus 7 day 200 mg daily dose of itraconazole in the treatment of tinea versicolor. A clinical study was done to compare the efficacy of single dose (400 mg) of itraconazole and 7 day 200 mg daily dose of itraconazole in the treatment of extensive tinea versicolor. Total 60 patients (aged 18-50 years) were selected for the study during the period of June 2007 to May 2008 in the department of Dermatology of three different hospitals in Bangladesh. Cases having with extensive involvement, diagnosed clinically and confirmed by wood's lamp and KOH microscopy were taken. Patients were randomly allocated into equal groups. Group A was given single dose 400 mg itraconazole and Group B was given 7 day 200 mg daily itraconazole. Fifty three (88%) male and 7(12%) female were included in the study. The mean age of group A was 32.37+/-9 years and in group B 33.23+/-8 years. The mean duration of the disease in group A was 2.63+/-2 months and 2.76+/-2 months in group B. In group A clinical responders was found cure 22(73.33%) and improvement 5(16.33%) and in group B it was found cure 24(79.99%) and improvement 4(13.33%). The measure at the End point (EP1) equals to 90% response and in-group B it was found cure 24 (79.99%) and improvement 4(13.33%). (Here the End point EP2) equals to 93.33%. The EP clinical analysis however shows 91.66% response. Both single dose and 7 day daily dose of itraconazole can be effective in the treatment of tinea versicolor with extensive involvement but single dose appears

Immunogenicity and safety of purified chick-embryo cell rabies vaccine under Zagreb 2-1-1 or 5-dose Essen regimen in Chinese children 6 to 17 years old and adults over 50 years: A randomized open-label study

Science.gov (United States)

Li, RongCheng; Li, YanPing; Wen, ShuQing; Wen, HuiChun; Nong, Yi; Mo, Zhaojun; Xie, Fang; Pellegrini, Michele

2015-01-01

The aim of this Phase IIIb, open-label, randomized study was to demonstrate the non-inferiority of immune responses and to assess the safety of a purified chick-embryo cell rabies vaccine (PCECV) in healthy Chinese children (6 to 17 years) and older adults (≥51 years) following 2 alternative intramuscular (IM) simulated post-exposure prophylaxis (PEP) regimens: 4-dose Zagreb or 5-dose Essen regimen. Serum samples were collected prior to vaccination on Days 1 and 15 and on day 43 to assess immune response by rabies virus neutralizing antibody (RVNA) concentrations. Solicited adverse events (AEs) were recorded for up to 7 days following each vaccine dose, and unsolicited AEs throughout the entire study period. PCECV vaccination induced a strong immune response at Day 15, and the non-inferiority in immune response of the Zagreb vs. the Essen regimen was demonstrated in children and older adults. At Day 15,100% of children (N = 224), and 99% of subjects ≥51 years of age (N = 376) developed adequate RVNA concentrations (≥0.5 IU/mL); at Day 43 all subjects achieved RVNA concentrations ≥0.5 IU/mL, for both PEP regimens. The well-known tolerability and safety profile of the PCECV was again observed in this study following either Zagreb or Essen regimens. Rabies PEP vaccination with PCECV following a Zagreb regimen induced immune responses non-inferior to those of the Essen regimen, and had a similar safety and tolerability profile to the Essen regimen in Chinese children, adolescents, and adults over 51 years. ClinicalTrials.gov identifier: NCT01680016. PMID:25692350

Safety evaluation of combination toceranib phosphate (Palladia®) and piroxicam in tumour-bearing dogs (excluding mast cell tumours): a phase I dose-finding study.

Science.gov (United States)

Chon, E; McCartan, L; Kubicek, L N; Vail, D M

2012-09-01

Toceranib phosphate and piroxicam have individually demonstrated antineoplastic activity. Additionally, non-steroidal anti-inflammatory therapy is often warranted in aged cancer-bearing dogs for management of osteoarthritis comorbidity. As concurrent use may be warranted for a given individual and the adverse event (AE) profile for each can be overlapping (gastrointestinal), a phase I trial was performed in tumour-bearing (non-mast cell) dogs to establish the safety of the combination using a standard 3+3 cohort design. Five dose-escalating cohorts, up to and including approved label dosage for toceranib and standard dosage for piroxicam, were completed without observing a frequency of dose-limiting AEs necessitating cohort closure. Therefore, the combination of standard dosages of both drugs (toceranib, 3.25 mg kg(-1), every other day; piroxicam, 0.3 mg kg(-1) daily) is generally safe. Several antitumour responses were observed. As with single-agent toceranib, label-indicated treatment holidays and dose reductions (e.g. 2.5-2.75 mg kg(-1)) may occasionally be required owing to gastrointestinal events. © 2011 Blackwell Publishing Ltd.

Cardiac effects of granisetron in a prospective crossover randomized dose comparison trial.

Science.gov (United States)

Cakir, F B; Yapar, O; Canpolat, C; Akalin, F; Berrak, S G

2012-10-01

Cardiac side effects of granisetron have been studied mostly in adult patients that are using cardiotoxic chemotherapeutics. There is limited evidence in pediatric age group and no information in pediatric oncology patients with non-cardiotoxic chemotherapeutics. In this prospective, crossover randomized study, the cardiac side effects of granisetron are compared in pediatric oncology patients who had carboplatin based chemotherapy. They were randomized to receive either 10 or 40 μg kg(-1) dose(-1) of granisetron before each cycle of chemotherapy. We drew blood for creatine phosphokinase (CPK), CPK-muscle band (MB) and Troponin-T before and 24 h after administering granisetron. Electrocardiography (ECG) tracings were taken at 0, 1, 2, 3, 6 and 24 h of granisetron. Twenty-four hours Holter ECG monitorisation was performed after each granisetron infusion. A total of 16 patients (median 8.7 years of age) were treated with weekly consecutive courses of carboplatin. There was bradycardia (p = 0.000) in patients that had granisetron at 40 μg/kg and PR interval was shortened in patients that had granisetron at 10 μg/kg dose (p = 0.021). At both doses of granisetron, QTc interval and dispersion were found to be similar. CPK, CK-MB and Troponin-T values were found to be normal before and 24 h after granisetron infusion. As the first study that has studied cardiac side effects of granisetron in patients that are not using cardiotoxic chemotherapeutics, we conclude that granisetron at 40 μg kg(-1) dose(-1) causes bradycardia only. We have also demonstrated that granisetron does not cause any clinically cardiac side effects either at 10 or 40 μg kg(-1) dose(-1). However, our results should be supported by prospective randomized studies with larger samples of patient groups.

Randomized clinical trial: pharmacokinetics and safety of multimatrix mesalamine for treatment of pediatric ulcerative colitis

Directory of Open Access Journals (Sweden)

Cuffari C

2016-02-01

Full Text Available Carmen Cuffari,1 David Pierce,2 Bartosz Korczowski,3 Krzysztof Fyderek,4 Heather Van Heusen,5 Stuart Hossack,6 Hong Wan,5 Alena YZ Edwards,7 Patrick Martin5 1Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Shire, Basingstoke, UK; 3Medical College, University of Rzeszów, Rzeszów, Poland; 4University Children’s Hospital of Cracow, Cracow, Poland; 5Shire, Wayne, PA, USA; 6Covance Clinical Research Unit Limited, Leeds, UK; 7ICON Early Phase Services, Marlow, Buckinghamshire, UK Background: Limited data are available on mesalamine (5-aminosalicylic acid; 5-ASA use in pediatric ulcerative colitis (UC.Aim: To evaluate pharmacokinetic and safety profiles of 5-ASA and metabolite acetyl-5-ASA (Ac-5-ASA after once-daily, oral administration of multimatrix mesalamine to children and adolescents with UC.Methods: Participants (5–17 years of age; 18–82 kg, stratified by weight with UC received multimatrix mesalamine 30, 60, or 100 mg/kg/day once daily (to 4,800 mg/day for 7 days. Blood samples were collected pre-dose on days 5 and 6. On days 7 and 8, blood and urine samples were collected and safety was evaluated. 5-ASA and Ac-5-ASA plasma and urine concentrations were analyzed by non-compartmental methods and used to develop a population pharmacokinetic model.Results: Fifty-two subjects (21 [30 mg/kg]; 22 [60 mg/kg]; 9 [100 mg/kg] were randomized. On day 7, systemic exposures of 5-ASA and Ac-5-ASA exhibited a dose-proportional increase between 30 and 60 mg/kg/day cohorts. For 30, 60, and 100 mg/kg/day doses, mean percentages of 5-ASA absorbed were 29.4%, 27.0%, and 22.1%, respectively. Simulated steady-state exposures and variabilities for 5-ASA and Ac-5-ASA (coefficient of variation approximately 50% and 40%–45%, respectively were similar to those observed previously in adults at comparable doses. Treatment-emergent adverse events were

Safety objectives for nuclear power plants in terms of dose-frequency targets; a comparison exercise performed by the Commission of the European Communities on dose assessment within a licencing framework

International Nuclear Information System (INIS)

Lange, F.; Tolley, B.; Kelly, N.; Harbison, S.; Gilby, E.

1987-01-01

The Task Force on Safety Objectives (T.F.S.O.) of the CEC has initiated a benchmark exercise with the purpose to review the methods and data used in dose assessment being adopted in various countries to estimate doses from design basis accidents of nuclear power plants within a regulatory framework. This benchmark exercise forms one of the initiatives of the T.F.S.O. to enable a comprehensive intercomparison of the degree of coherence between the dose-frequency targets used in different Members States for application to design basis accidents. The structure, contents and results of the benchmark exercise in which eight countries/institutions participated are described. Some of the more important findings and conclusions and the relation to a parallel benchmark exercise on source terms for design basis accidents are discussed. (orig.)

Safety aspects of preoperative high-dose glucocorticoid in primary total knee replacement

DEFF Research Database (Denmark)

Jørgensen, C C; Pitter, F T; Kehlet, H

2017-01-01

Background: Preoperative single high-dose glucocorticoid may have early outcome benefits in total hip arthroplasty (THA) and knee arthroplasty (TKA), but long-term safety aspects have not been evaluated. Methods: From October 2013, the departments reporting to the prospective Lundbeck Foundation....... Conclusions: In this detailed prospective cohort study, preoperative high-dose glucocorticoid administration was not associated with LOS >4 days, readmissions or infectious complications in TKA patients without contraindications....

Review of WHC criticality safety audit findings for 1970-1981

International Nuclear Information System (INIS)

Rogers, C.A.; Paglieri, J.N.

1984-01-01

At Westinghouse Hanford Company (WHC) all fissionable material handling must meet DOE requirements for safety. This necessitates a program of regular audits by the Safety group to verify compliance with criticality safety limits and controls and to alert facility management to observed discrepancies and potential problems. Audits of fissionable material facilities by Safety are required at least once every 6 months, but in practice are conducted more frequently. This paper summarizes findings from over 400 criticality safety audits conducted by Safety between July 1970 and July 1981 in seven fissionable material facilities to show their types and frequencies of occurrence. All limit violations occurring during this period are summarized, including those found by the operating group. 1 ref., 1 tab

Efficacy and safety of belimumab in patients with rheumatoid arthritis: a phase II, randomized, double-blind, placebo-controlled, dose-ranging Study.

Science.gov (United States)

Stohl, William; Merrill, Joan T; McKay, James D; Lisse, Jeffrey R; Zhong, Z John; Freimuth, William W; Genovese, Mark C

2013-05-01

To evaluate the efficacy/safety of belimumab in patients with rheumatoid arthritis (RA). Patients fulfilling American College of Rheumatology (ACR) criteria for RA for ≥ 1 year who had at least moderate disease activity while receiving stable disease-modifying antirheumatic drug (DMARD) therapy and failed ≥ 1 DMARD were randomly assigned to placebo or belimumab 1, 4, or 10 mg/kg, administered intravenously on Days 1, 14, and 28, and then every 4 weeks for 24 weeks (n = 283). This was followed by an optional 24-week extension (n = 237) in which all patients received belimumab. Primary efficacy endpoint was the Week 24 ACR20 response. Week 24 ACR20 responses with placebo and belimumab 1, 4, and 10 mg/kg were 15.9%, 34.7% (p = 0.010), 25.4% (p = 0.168), and 28.2% (p = 0.080), respectively. Patients taking any belimumab dose who continued with belimumab in the open-label extension had an ACR20 response of 41% at 48 weeks. A similar ACR20 response (42%) at 48 weeks was seen in patients taking placebo who switched in the extension to belimumab 10 mg/kg. Greater response rates were observed in patients who at baseline were rheumatoid factor-positive, anticitrullinated protein antibody-positive, or tumor necrosis factor inhibitor-naive, or had elevated C-reactive protein levels, Disease Activity Score 28 > 5.1, or low B lymphocyte stimulator levels (< 0.858 ng/ml). Adverse event rates were similar across treatment groups. In this phase II trial, belimumab demonstrated efficacy and was generally well tolerated in patients with RA who had failed previous therapies. [ClinicalTrials.gov identifier NCT00071812].

Evaluation of an ultra-low-dose oral contraceptive for dysmenorrhea: a placebo-controlled, double-blind, randomized trial.

Science.gov (United States)

Harada, Tasuku; Momoeda, Mikio

2016-12-01

To evaluate the efficacy and safety of an ultra-low-dose oral contraceptive (NPC-01; 0.02 mg ethinyl estradiol and 1 mg norethisterone) in subjects with dysmenorrhea. Placebo-controlled, double-blind, randomized trial. Clinical trial sites. Two hundred fifteen subjects with dysmenorrhea. Subjects were randomly assigned to receive NPC-01, placebo, or IKH-01 (0.035 mg ethinyl estradiol and 1 mg norethisterone) for four cycles. Total dysmenorrhea score (verbal rating scale) assessing pain on the basis of limited ability to work and need for analgesics. The reductions of total dysmenorrhea score and visual analog scale score after the treatment were significantly higher in the NPC-01 group than in the placebo group. Furthermore, the efficacy of NPC-01 was comparable to that of IKH-01. The overall incidence of side effects was significantly higher in the NPC-01 group than in the placebo group. All side effects that occurred in the NPC-01 group were previously reported in patients receiving IKH-01. No serious side effects occurred. The ultra-low-dose contraceptive NPC-01 relieved dysmenorrhea as effectively as IKH-01. Thus, NPC-01 could represent a new option for long-term treatment of dysmenorrhea. NCT01129102. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Motivation for Different Types and Doses of Exercise During Breast Cancer Chemotherapy: a Randomized Controlled Trial.

Science.gov (United States)

Courneya, Kerry S; Segal, Roanne J; Vallerand, James R; Forbes, Cynthia C; Crawford, Jennifer J; Dolan, Lianne B; Friedenreich, Christine M; Reid, Robert D; Gelmon, Karen; Mackey, John R; McKenzie, Donald C

2016-08-01

Exercise is beneficial for breast cancer patients during chemotherapy, but their motivation to perform different types and doses of exercise is unknown. The purpose of this study was to examine the anticipated and experienced motivation of breast cancer patients before and after three different exercise programs during chemotherapy. Breast cancer patients initiating chemotherapy (N = 301) were randomized to a standard dose of 25-30 min of aerobic exercise, a higher dose of 50-60 min of aerobic exercise, or a combined dose of 50-60 min of aerobic and resistance exercise. Patient preference and motivational outcomes from the theory of planned behavior (i.e., perceived benefit, enjoyment, support, difficulty, and motivation) were assessed before and after the interventions. At pre-randomization, breast cancer patients were significantly (p types and doses of exercise during chemotherapy varied considerably at pre-randomization, but the motivational outcomes experienced after the three interventions were similar. Clinicians can recommend any of the three exercise interventions to breast cancer patients knowing that positive motivational outcomes will result. Clinicaltrials.gov identifier: NCT00249015 .

Safety of Flibanserin in Women Treated With Antidepressants: A Randomized, Placebo-Controlled Study.

Science.gov (United States)

Clayton, Anita H; Croft, Harry A; Yuan, James; Brown, Louise; Kissling, Robert

2018-01-01

Depression is often associated with sexual dysfunction, and pharmacologic treatment for hypoactive sexual desire disorder can be considered in women receiving treatment for depression. To evaluate the safety of flibanserin in women treated for depression with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors. In this double-blinded, randomized, placebo-controlled trial, women with remitted or mild depression treated with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors who were not postmenopausal and were experiencing symptoms of hypoactive sexual desire disorder (ie, decreased sexual desire and related distress) received flibanserin 50 mg at bedtime (qhs) for 2 weeks and up-titrated to 100 mg qhs, flibanserin 100 mg qhs for the entire treatment period, or placebo for up to 12 weeks. Safety assessment included adverse events and symptoms of depression and anxiety. 73 patients were randomly assigned to flibanserin (both dose groups combined) and 38 to placebo. The sponsor terminated the study early at discontinuation of the development of flibanserin. Treatment duration was at least 8 weeks for 84.9% and 94.7% of patients in the flibanserin and placebo groups, respectively. The most common adverse events (incidence ≥ 2% in the flibanserin group and higher than that in the placebo group) included dry mouth (5.5% for flibanserin vs 2.6% for placebo), insomnia (5.5% vs 2.6%), back pain (4.1% vs 2.6%), and dizziness (4.1% vs 0.0%). There were no serious adverse events and no instances of suicidal ideation or behavior. The proportions of patients with symptom worsening in the flibanserin and placebo groups, respectively, were 6.9% and 21.6% for depression and 1.4% and 2.7% for anxiety. Remission of depression at study end point, as measured by the Quick Inventory of Depressive Symptomatology-Self Report, was experienced by 19.4% of flibanserin-treated patients and 10.8% of patients

A Phase 1 Randomized, Open Label, Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Three Formulations of Tenofovir 1% Gel (the CHARM-01 Study.

Directory of Open Access Journals (Sweden)

Ian Mcgowan

Full Text Available The CHARM-01 study characterized the safety, acceptability, pharmacokinetics (PK, and pharmacodynamics (PD of three tenofovir (TFV gels for rectal application. The vaginal formulation (VF gel was previously used in the CAPRISA 004 and VOICE vaginal microbicide Phase 2B trials and the RMP-02/MTN-006 Phase 1 rectal safety study. The reduced glycerin VF (RGVF gel was used in the MTN-007 Phase 1 rectal microbicide trial and is currently being evaluated in the MTN-017 Phase 2 rectal microbicide trial. A third rectal specific formulation (RF gel was also evaluated in the CHARM-01 study.Participants received 4 mL of the three TFV gels in a blinded, crossover design: seven daily doses of RGVF, seven daily doses of RF, and six daily doses of placebo followed by one dose of VF, in a randomized sequence. Safety, acceptability, compartmental PK, and explant PD were monitored throughout the trial.All three gels were found to be safe and acceptable. RF and RGVF PK were not significantly different. Median mucosal mononuclear cell (MMC TFV-DP trended toward higher values for RF compared to RGVF (1136 and 320 fmol/106 cells respectively. Use of each gel in vivo was associated with significant inhibition of ex vivo colorectal tissue HIV infection. There was also a significant negative correlation between the tissue levels of TFV, tissue TFV-DP, MMC TFV-DP, rectal fluid TFV, and explant HIV-1 infection.All three formulations were found to be safe and acceptable. However, the safety profile of the VF gel was only based on exposure to one dose whereas participants received seven doses of the RGVF and RF gels. There was a trend towards higher tissue MMC levels of TFV-DP associated with use of the RF gel. Use of all gels was associated with significant inhibition of ex vivo tissue HIV infection.ClinicalTrials.gov NCT01575405.

Occupational exposure to ionising radiation 1990-1996. Analysis of doses reported to the Health and Safety Executive's Central Index of Dose Information

International Nuclear Information System (INIS)

1998-01-01

The Central Index of Dose Information (CIDI) is the Health and Safety Executive's (HSE's) national database of occupational exposure to ionising radiation. It is operated under contract by the National Radiological Protection Board (NRPB). CIDI receives annually, from Approved Dosimetry Services (ADS) summaries of radiation doses recorded for employees designated as classified persons in the United Kingdom. This is the second analysis of dose summary information to be published. (author)

Low-Dose versus Standard-Dose Intravenous Immunoglobulin to Prevent Fetal Intracranial Hemorrhage in Fetal and Neonatal Alloimmune Thrombocytopenia: A Randomized Trial.

Science.gov (United States)

Paridaans, Noortje P; Kamphuis, Marije M; Taune Wikman, Agneta; Tiblad, Eleonor; Van den Akker, Eline S; Lopriore, Enrico; Challis, Daniel; Westgren, Magnus; Oepkes, Dick

2015-01-01

Pregnancies at risk of fetal and neonatal alloimmune thrombocytopenia (FNAIT) are commonly treated using weekly intravenous immunoglobulin (IVIG) at 1 g/kg maternal weight. IVIG is an expensive multidonor human blood product with dose-related side effects. Our aim was to evaluate the effectiveness of IVIG at a lower dose, i.e., 0.5 g/kg. This was a randomized controlled multicenter trial conducted in Sweden, the Netherlands and Australia. Pregnant women with human platelet antigen alloantibodies and an affected previous child without intracranial hemorrhage (ICH) were enrolled. The participants were randomized to IVIG at 0.5 or 1 g/kg per week. The analyses were per intention to treat. The primary outcome was fetal or neonatal ICH. Secondary outcomes were platelet count at birth, maternal and neonatal IgG levels, neonatal treatment and bleeding other than ICH. A total of 23 women were randomized into two groups (low dose: n = 12; standard dose: n = 11). The trial was stopped early due to poor recruitment. No ICH occurred. The median newborn platelet count was 81 × 10(9)/l (range 8-269) in the 0.5 g/kg group versus 110 × 10(9)/l (range 11-279) in the 1 g/kg group (p = 0.644). The risk of adverse outcomes in FNAIT pregnancies treated with IVIG at 0.5 g/kg is very low, similar to that using 1 g/kg, although our uncompleted trial lacked the power to conclusively prove the noninferiority of using the low dose.

2-Year Efficacy, Immunogenicity, and Safety of Vigoo Enterovirus 71 Vaccine in Healthy Chinese Children: A Randomized Open-Label Study.

Science.gov (United States)

Wei, Mingwei; Meng, Fanyue; Wang, Shiyuan; Li, Jingxin; Zhang, Yuntao; Mao, Qunying; Hu, Yuemei; Liu, Pei; Shi, Nianmin; Tao, Hong; Chu, Kai; Wang, Yuxiao; Liang, Zhenglun; Li, Xiuling; Zhu, Fengcai

2017-01-01

 This study evaluated the 2-year efficacy, immunogenicity, and safety of the Vigoo enterovirus 71 (EV71) vaccine.  In an initial phase 3 study, we randomly assigned healthy infants and children aged 6-35 months (ratio, 1:1) to receive 2 doses of either EV71 vaccine (5120 participants) or placebo (5125 participants) at days 0 and 28, and followed them for 12 months after vaccination. In this extended follow-up study, we continued to evaluate the efficacy, immunogenicity, and safety of the EV71 vaccine for up to 2 years.  Overall efficacy was 94.84% (95% confidence interval [CI], 83.53%-98.38%) during the 2-year follow-up period (P vaccine efficacy during the second year was 100.00% (95% CI, 84.15%-100.00%) against EV71-associated hand-foot-and-mouth disease (HFMD; P vaccine-related serious adverse events were recorded.  Two doses of Vigoo EV71 vaccine could provide sustained protection against EV71-associated HFMD in healthy Chinese children.  NCT01508247. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Human placenta-derived cells (PDA-001) for the treatment of adults with multiple sclerosis: a randomized, placebo-controlled, multiple-dose study.

Science.gov (United States)

Lublin, Fred D; Bowen, James D; Huddlestone, John; Kremenchutzky, Marcelo; Carpenter, Adam; Corboy, John R; Freedman, Mark S; Krupp, Lauren; Paulo, Corri; Hariri, Robert J; Fischkoff, Steven A

2014-11-01

Infusion of PDA-001, a preparation of mesenchymal-like cells derived from full-term human placenta, is a new approach in the treatment of patients with multiple sclerosis. This safety study aimed to rule out the possibility of paradoxical exacerbation of disease activity by PDA-001 in patients with multiple sclerosis. This was a phase 1b, multicenter, randomized, double-blind, placebo-controlled, 2-dose ranging study including patients with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis. The study was conducted at 6 sites in the United States and 2 sites in Canada. Patients were randomized 3:1 to receive 2 low-dose infusions of PDA-001 (150×10(6) cells) or placebo, given 1 week apart. After completing this cohort, subsequent patients received high-dose PDA-001 (600×10(6) cells) or placebo. Monthly brain magnetic resonance imaging scans were performed. The primary end point was ruling out the possibility of paradoxical worsening of MS disease activity. This was monitored using Cutter׳s rule (≥5 new gadolinium lesions on 2 consecutive scans) by brain magnetic resonance imaging on a monthly basis for six months and also the frequency of multiple sclerosis relapse. Ten patients with relapsing-remitting multiple sclerosis and 6 with secondary progressive multiple sclerosis were randomly assigned to treatment: 6 to low-dose PDA-001, 6 to high-dose PDA-001, and 4 to placebo. No patient met Cutter׳s rule. One patient receiving high-dose PDA-001 had an increase in T2 and gadolinium lesions and in Expanded Disability Status Scale score during a multiple sclerosis flare 5 months after receiving PDA-001. No other patient had an increase in Expanded Disability Status Scale score>0.5, and most had stable or decreasing Expanded Disability Status Scale scores. With high-dose PDA-001, 1 patient experienced a grade 1 anaphylactoid reaction and 1 had grade 2 superficial thrombophlebitis. Other adverse events were mild to moderate and included

Modern dose-finding designs for cancer phase I trials drug combinations and molecularly targeted agents

CERN Document Server

Hirakawa, Akihiro; Daimon, Takashi; Matsui, Shigeyuki

2018-01-01

This book deals with advanced methods for adaptive phase I dose-finding clinical trials for combination of two agents and molecularly targeted agents (MTAs) in oncology. It provides not only methodological aspects of the dose-finding methods, but also software implementations and practical considerations in applying these complex methods to real cancer clinical trials. Thus, the book aims to furnish researchers in biostatistics and statistical science with a good summary of recent developments of adaptive dose-finding methods as well as providing practitioners in biostatistics and clinical investigators with advanced materials for designing, conducting, monitoring, and analyzing adaptive dose-finding trials. The topics in the book are mainly related to cancer clinical trials, but many of those topics are potentially applicable or can be extended to trials for other diseases. The focus is mainly on model-based dose-finding methods for two kinds of phase I trials. One is clinical trials with combinations of tw...

Neurodevelopmental Outcomes of Extremely Preterm Infants Randomized to Stress Dose Hydrocortisone.

Directory of Open Access Journals (Sweden)

Nehal A Parikh

Full Text Available To compare the effects of stress dose hydrocortisone therapy with placebo on survival without neurodevelopmental impairments in high-risk preterm infants.We recruited 64 extremely low birth weight (birth weight ≤1000 g infants between the ages of 10 and 21 postnatal days who were ventilator-dependent and at high-risk for bronchopulmonary dysplasia. Infants were randomized to a tapering 7-day course of stress dose hydrocortisone or saline placebo. The primary outcome at follow-up was a composite of death, cognitive or language delay, cerebral palsy, severe hearing loss, or bilateral blindness at a corrected age of 18-22 months. Secondary outcomes included continued use of respiratory therapies and somatic growth.Fifty-seven infants had adequate data for the primary outcome. Of the 28 infants randomized to hydrocortisone, 19 (68% died or survived with impairment compared with 22 of the 29 infants (76% assigned to placebo (relative risk: 0.83; 95% CI, 0.61 to 1.14. The rates of death for those in the hydrocortisone and placebo groups were 31% and 41%, respectively (P = 0.42. Randomization to hydrocortisone also did not significantly affect the frequency of supplemental oxygen use, positive airway pressure support, or need for respiratory medications.In high-risk extremely low birth weight infants, stress dose hydrocortisone therapy after 10 days of age had no statistically significant effect on the incidence of death or neurodevelopmental impairment at 18-22 months. These results may inform the design and conduct of future clinical trials.ClinicalTrials.gov NCT00167544.

Update on radiation safety and dose reduction in pediatric neuroradiology

International Nuclear Information System (INIS)

Mahesh, Mahadevappa

2015-01-01

The number of medical X-ray imaging procedures is growing exponentially across the globe. Even though the overall benefit from medical X-ray imaging procedures far outweighs any associated risks, it is crucial to take all necessary steps to minimize radiation risks to children without jeopardizing image quality. Among the X-ray imaging studies, except for interventional fluoroscopy procedures, CT studies constitute higher dose and therefore draw considerable scrutiny. A number of technological advances have provided ways for better and safer CT imaging. This article provides an update on the radiation safety of patients and staff and discusses dose optimization in medical X-ray imaging within pediatric neuroradiology. (orig.)

Update on radiation safety and dose reduction in pediatric neuroradiology

Energy Technology Data Exchange (ETDEWEB)

Mahesh, Mahadevappa [Johns Hopkins University School of Medicine, The Russell H. Morgan Department of Radiology and Radiological Science, Baltimore, MD (United States)

2015-09-15

The number of medical X-ray imaging procedures is growing exponentially across the globe. Even though the overall benefit from medical X-ray imaging procedures far outweighs any associated risks, it is crucial to take all necessary steps to minimize radiation risks to children without jeopardizing image quality. Among the X-ray imaging studies, except for interventional fluoroscopy procedures, CT studies constitute higher dose and therefore draw considerable scrutiny. A number of technological advances have provided ways for better and safer CT imaging. This article provides an update on the radiation safety of patients and staff and discusses dose optimization in medical X-ray imaging within pediatric neuroradiology. (orig.)

Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: Long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study.

Science.gov (United States)

Papp, Kim A; Krueger, James G; Feldman, Steven R; Langley, Richard G; Thaci, Diamant; Torii, Hideshi; Tyring, Stephen; Wolk, Robert; Gardner, Annie; Mebus, Charles; Tan, Huaming; Luo, Yingchun; Gupta, Pankaj; Mallbris, Lotus; Tatulych, Svitlana

2016-05-01

Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. We sought to report longer-term tofacitinib efficacy and safety in patients with moderate to severe psoriasis. Data from 2 identical phase-III studies, Oral-treatment Psoriasis Trial Pivotal 1 and 2, were pooled with data from these patients in an ongoing open-label long-term extension study. Patients (n = 1861) were randomized 2:2:1 to tofacitinib 5 mg, 10 mg, or placebo twice daily (BID). At week 16, placebo patients were rerandomized to tofacitinib. Pivotal study participants could enroll into the long-term extension where they received tofacitinib at 10 mg BID for 3 months, after which dosing could be 5 or 10 mg BID. At week 28, the proportions of patients randomized to tofacitinib 5 and 10 mg BID achieving 75% or greater reduction in Psoriasis Area and Severity Index score from baseline were 55.6% and 68.8%, and achieving Physician Global Assessment of clear or almost clear were 54.7% and 65.9%. Efficacy was maintained in most patients through 24 months. Serious adverse events and discontinuations because of adverse events were reported in less than 11% of patients over 33 months of tofacitinib exposure. There was no dose comparison beyond week 52. Oral tofacitinib demonstrated sustained efficacy in patients with psoriasis through 2 years, with 10 mg BID providing greater efficacy than 5 mg BID. No unexpected safety findings were observed. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Multi-isocenter stereotactic radiotherapy: implications for target dose distributions of systematic and random localization errors

International Nuclear Information System (INIS)

Ebert, M.A.; Zavgorodni, S.F.; Kendrick, L.A.; Weston, S.; Harper, C.S.

2001-01-01

Purpose: This investigation examined the effect of alignment and localization errors on dose distributions in stereotactic radiotherapy (SRT) with arced circular fields. In particular, it was desired to determine the effect of systematic and random localization errors on multi-isocenter treatments. Methods and Materials: A research version of the FastPlan system from Surgical Navigation Technologies was used to generate a series of SRT plans of varying complexity. These plans were used to examine the influence of random setup errors by recalculating dose distributions with successive setup errors convolved into the off-axis ratio data tables used in the dose calculation. The influence of systematic errors was investigated by displacing isocenters from their planned positions. Results: For single-isocenter plans, it is found that the influences of setup error are strongly dependent on the size of the target volume, with minimum doses decreasing most significantly with increasing random and systematic alignment error. For multi-isocenter plans, similar variations in target dose are encountered, with this result benefiting from the conventional method of prescribing to a lower isodose value for multi-isocenter treatments relative to single-isocenter treatments. Conclusions: It is recommended that the systematic errors associated with target localization in SRT be tracked via a thorough quality assurance program, and that random setup errors be minimized by use of a sufficiently robust relocation system. These errors should also be accounted for by incorporating corrections into the treatment planning algorithm or, alternatively, by inclusion of sufficient margins in target definition

A randomized, active- and placebo-controlled study of the efficacy and safety of different doses of dutasteride versus placebo and finasteride in the treatment of male subjects with androgenetic alopecia.

Science.gov (United States)

Gubelin Harcha, Walter; Barboza Martínez, Julia; Tsai, Tsen-Fang; Katsuoka, Kensei; Kawashima, Makoto; Tsuboi, Ryoji; Barnes, Allison; Ferron-Brady, Geraldine; Chetty, Dushen

2014-03-01

Dihydrotestosterone is the main androgen causative of androgenetic alopecia, a psychologically and physically harmful condition warranting medical treatment. We sought to compare the efficacy and safety of dutasteride (type 1 and 2 5-alpha reductase inhibitor) with finasteride (type 2 5-alpha reductase inhibitor) and placebo in men with androgenetic alopecia. Men aged 20 to 50 years with androgenetic alopecia were randomized to receive dutasteride (0.02, 0.1, or 0.5 mg/d), finasteride (1 mg/d), or placebo for 24 weeks. The primary end point was hair count (2.54-cm diameter) at week 24. Other assessments included hair count (1.13-cm diameter) and width, photographic assessments (investigators and panel), change in stage, and health outcomes. In total, 917 men were randomized. Hair count and width increased dose dependently with dutasteride. Dutasteride 0.5 mg significantly increased hair count and width in a 2.54-cm diameter and improved hair growth (frontal view; panel photographic assessment) at week 24 compared with finasteride (P = .003, P = .004, and P = .002, respectively) and placebo (all P < .001). The number and severity of adverse events were similar among treatment groups. The study was limited to 24 weeks. Dutasteride increased hair growth and restoration in men with androgenetic alopecia and was relatively well tolerated. Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

The starting dose of levothyroxine in primary hypothyroidism treatment: a prospective, randomized, double-blind trial

NARCIS (Netherlands)

Roos, Annemieke; Linn-Rasker, Suzanne P.; van Domburg, Ron T.; Tijssen, Jan P.; Berghout, Arie

2005-01-01

BACKGROUND: The treatment of hypothyroidism with levothyroxine is effective and simple; however, recommendations for the starting dose vary considerably. To our knowledge, the levothyroxine starting dose has never been studied prospectively. METHODS: We conducted a prospective, randomized,

Efficacy between high and medium doses of glucocorticoid therapy in remission induction of IgG4-related diseases: a preliminary randomized controlled trial.

Science.gov (United States)

Wu, Qingjun; Chang, Jie; Chen, Hua; Chen, Yu; Yang, Hongxian; Fei, Yunyun; Zhang, Panpan; Zeng, Xiaofeng; Zhang, Fengchun; Zhang, Wen

2017-05-01

In order to evaluate the efficacy and safety of high versus medium doses of glucocorticoid therapy in remission induction of immunoglobulin G4-related disease (IgG4-RD), we set up a randomized controlled study. Newly diagnosed IgG4-RD patients were randomly assigned to two groups: high doses of prednisone (0.8-1.0 mg/kg/day) and medium doses (0.5-0.6 mg/kg/day). Patients were assessed at weeks 0, 4, 12 and 24. The primary outcome was the remission rate at week 24. The secondary endpoints included IgG4-RD responder index (IgG4-RD RI), IgG and IgG4 levels. Twenty cases in each group finished the study. At week 24, the total response rates were 95% and 80% in high and medium dose groups, respectively. There was no significant difference between the two groups. IgG4-RD RI reduced from 14.9 to 3.0 in the high dose group, while in the medium dose group it was from 13.1 to 3.2. At week 24, the average level of IgG4 reduced from 1576 to 324 mg/dL and from 1445 to 684 mg/dL in the two groups, respectively. Relapsed patients had higher baseline IgG4-RD RI. There was no severe adverse effect shown in both groups. The effect of remission induction was similar in high and medium glucocorticoid groups. However, patients with more organs involved and higher IgG4-RD RI score at baseline might get more benefit with high dose glucocorticoid for remission induction. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Collection and accumulation of seismic safety research findings, and considerations for information dissemination

International Nuclear Information System (INIS)

2013-01-01

Seismic Safety Division of JNES is collecting and analyzing the findings of seismic safety research, and is developing a system to organize and disseminate the information internally and internationally. These tasks have been conducted in response to the lessons learned from Fukushima Daiichi NPP accident. The overview of the tasks is as follows; 1) Collection of the knowledge and findings from seismic safety research. JNES collects information on seismic safety researches including the 2011 off the Pacific coast of Tohoku Earthquake. The information is analyzed whether it is important for regulation to increase seismic safety of NPP. 2) Constructing database of seismic safety research. JNES collects information based on documents published by committee and constructs database of active faults around NPP sites in order to incorporate in the seismic safety review. 3) Dissemination of information related to seismic safety. JNES disseminates outcomes of own researches internally and internationally. (author)

Collection and accumulation of seismic safety research findings, and considerations for information dissemination

Energy Technology Data Exchange (ETDEWEB)

NONE

2013-08-15

Seismic Safety Division of JNES is collecting and analyzing the findings of seismic safety research, and is developing a system to organize and disseminate the information internally and internationally. These tasks have been conducted in response to the lessons learned from Fukushima Daiichi NPP accident. The overview of the tasks is as follows; 1) Collection of the knowledge and findings from seismic safety research. JNES collects information on seismic safety researches including the 2011 off the Pacific coast of Tohoku Earthquake. The information is analyzed whether it is important for regulation to increase seismic safety of NPP. 2) Constructing database of seismic safety research. JNES collects information based on documents published by committee and constructs database of active faults around NPP sites in order to incorporate in the seismic safety review. 3) Dissemination of information related to seismic safety. JNES disseminates outcomes of own researches internally and internationally. (author)

A randomized trial of the efficacy and safety of quilizumab in adults with inadequately controlled allergic asthma.

Science.gov (United States)

Harris, Jeffrey M; Maciuca, Romeo; Bradley, Mary S; Cabanski, Christopher R; Scheerens, Heleen; Lim, Jeremy; Cai, Fang; Kishnani, Mona; Liao, X Charlene; Samineni, Divya; Zhu, Rui; Cochran, Colette; Soong, Weily; Diaz, Joseph D; Perin, Patrick; Tsukayama, Miguel; Dimov, Dimo; Agache, Ioana; Kelsen, Steven G

2016-03-18

Quilizumab, a humanized IgG1 monoclonal antibody, targets the M1-prime segment of membrane-expressed IgE, leading to depletion of IgE-switched and memory B cells. In patients with mild asthma, quilizumab reduced serum IgE and attenuated the early and late asthmatic reaction following whole lung allergen challenge. This study evaluated the efficacy and safety of quilizumab in adults with allergic asthma, inadequately controlled despite high-dose inhaled corticosteroids (ICS) and a second controller. Five hundred seventy-eight patients were randomized to monthly or quarterly dosing regimens of subcutaneous quilizumab or placebo for 36 weeks, with a 48-week safety follow-up. Quilizumab was evaluated for effects on the rate of asthma exacerbations, lung function, patient symptoms, serum IgE, and pharmacokinetics. Exploratory analyses were conducted on biomarker subgroups (periostin, blood eosinophils, serum IgE, and exhaled nitric oxide). Quilizumab was well tolerated and reduced serum total and allergen-specific IgE by 30-40 %, but had no impact on asthma exacerbations, lung function, or patient-reported symptom measures. At Week 36, the 300 mg monthly quilizumab group showed a 19.6 % reduction (p = 0.38) in the asthma exacerbation rate relative to placebo, but this was neither statistically nor clinically significant. Biomarker subgroups did not reveal meaningful efficacy benefits following quilizumab treatment. Quilizumab had an acceptable safety profile and reduced serum IgE. However, targeting the IgE pathway via depletion of IgE-switched and memory B cells was not sufficient for a clinically meaningful benefit for adults with allergic asthma uncontrolled by standard therapy. ClinicalTrials.gov NCT01582503.

Vitamin D supplementation in nursing home patients: randomized controlled trial of standard daily dose versus individualized loading dose regimen.

Science.gov (United States)

Wijnen, Hugo; Salemink, Dayenne; Roovers, Lian; Taekema, Diana; de Boer, Hans

2015-05-01

Supplementation of cholecalciferol 800 IU daily appears to be insufficient to raise vitamin D levels to >75 nmol/l in nursing home (NH) patients. Our objective was to compare the efficacy of an individualized cholecalciferol loading dose (LD) regimen and a daily dose (DD) regimen of cholecalciferol 800 IU in reaching 25-OH vitamin D (25OHD) levels >75 nmol/l. A total of 30 NH patients with 25OHD levels 50 nmol/l were included. Patients were randomized using the minimization method in the LD or DD group. The cholecalciferol LD, calculated with an algorithm based on serum 25OHD level and body weight, was administered in divided doses of 50,000 IU twice a week, followed by a monthly maintenance dose of either 50,000 or 25,000 IU. The DD regimen consisted of cholecalciferol 800 IU daily for 26 weeks. Serum 25OHD, calcium, creatinine, phosphate, and parathyroid hormone were measured, and 2-minute walking test, handgrip strength, and timed get up and go test were assessed at baseline (T 0), after 5 weeks (T 5), 12 weeks (T 12), and 26 weeks (T 26). The primary endpoint was the percentage of patients with 25OHD levels >75 nmol/l at T 5. Secondary endpoints were the proportion of patients with 25OHD levels >75 nmol/l at T 26, safety of LD regimen, and improvement of performance tests with normalization of vitamin D levels. Median baseline 25OHD levels (interquartile range) were comparable between the 14 DD and 16 LD patients: 20.9 (15.9-29.6) and 21.7 (16.4-32.8) nmol/l, respectively. Levels of 25OHD >75 nmol/l at T 5 were reached in 79 % of the 14 LD patients, but in none of the 13 DD patients (p 75 nmol/l were reached in 83 % of the 12 LD patients and in 30 % of the ten DD patients (p tests was observed. In NH patients with severe 25OHD deficiency, an individualized calculated cholecalciferol LD is likely to be superior to a DD of cholecalciferol 800 IU in terms of the ability to rapidly normalize vitamin D levels.

Efficacy, safety and tolerability of escitalopram in doses up to 50 mg in Major Depressive Disorder (MDD: an open-label, pilot study

Directory of Open Access Journals (Sweden)

Crawford Gordon M

2011-03-01

Full Text Available Abstract Background Escitalopram is licensed for use at doses up to 20 mg but is used clinically at higher doses. There is limited published data at higher doses and none in the treatment of Major Depressive Disorder (MDD. Methods This open-label, pilot study was designed to investigate the efficacy, safety and tolerability of escitalopram in doses up to 50 mg in MDD. It was conducted in 60 primary care patients with MDD who had not responded to adequate treatment with citalopram. Patients were treated with escalating doses of escitalopram up to 50 mg for up to 32 weeks until they achieved remission (Montgomery-Asberg Depression Rating Scale [MADRS] ≤8 or failed to tolerate the dose. Results Forty-two patients (70% completed the study. Twenty-one patients (35% achieved remission with 8 of the 21 patients (38% needing the 50 mg dose to achieve remission. Median time to remission was 24 weeks and median dose in remission was 30 mg. No significant safety issues were identified although tolerability appeared to decline above a dose of 40 mg with 26% of patients unable to tolerate 50 mg. Twelve (20% patients had adverse events leading to discontinuation. The most common adverse events were headache (35%, nausea, diarrhoea and nasopharyngitis (all 25%. Minor mean weight gain was found during the study, which did not appear to be dose-related. Half of the patients who completed the study chose to continue treatment with escitalopram rather than taper down the dose at 32 weeks. Conclusions Dose escalation with escitalopram above 20 mg may have a useful role in the management of patients with MDD, although further studies are needed to confirm this finding. Trial Registration ClinicalTrials.gov: NCT00785434

Efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Asian patients with hypertension: a randomized, double-blind, placebo-controlled study.

Science.gov (United States)

Kario, Kazuomi; Sun, Ningling; Chiang, Fu-Tien; Supasyndh, Ouppatham; Baek, Sang Hong; Inubushi-Molessa, Akiko; Zhang, Ying; Gotou, Hiromi; Lefkowitz, Martin; Zhang, Jack

2014-04-01

LCZ696 (Japanese adopted name: sucabitril valsartan sodium hydrate), a first-in-class angiotensin receptor neprilysin inhibitor, concomitantly inhibits neprilysin and blocks angiotensin type 1 receptor. This randomized, double-blind, placebo-controlled study, the first in Asia for this drug, evaluated the dose-related efficacy and safety of LCZ696 in patients with hypertension using 24-hour ambulatory blood pressure (BP) monitoring. Asian patients aged ≥18 years (n=389) with hypertension were randomized to receive LCZ696 100 mg (n=100), 200 mg (n=101), 400 mg (n=96), or placebo (n=92) for 8 weeks. The primary end point was mean difference across the 3 single-dose pairwise comparisons of LCZ696 versus placebo in clinic diastolic BP after 8-week treatment. Key secondary efficacy variables included changes in clinic systolic BP and pulse pressure and changes in 24-hour, daytime, and nighttime ambulatory BPs and pulse pressure. Safety assessments included recording all adverse events and serious adverse events. A total of 362 patients completed the study. Reductions in clinic systolic BP, diastolic BP (Phypertension in Asian population and, in general, is safe and well tolerated. Clinical Trial Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01193101.

Dose-dependent effects of lesogaberan on reflux measures in patients with refractory gastroesophageal reflux disease: a randomized, placebo-controlled study.

Science.gov (United States)

Miner, Philip B; Silberg, Debra G; Ruth, Magnus; Miller, Frank; Pandolfino, John

2014-11-18

The γ-aminobutyric acid type B-receptor agonist lesogaberan (AZD3355) has been developed for use in patients with gastroesophageal reflux disease (GERD) symptoms despite proton pump inhibitor (PPI) therapy (partial responders). This study aimed to explore the dose-response effect of lesogaberan on reflux episodes in partial responders. In this randomized, single-centre, double-blind, crossover, placebo-controlled study, partial responders taking optimised PPI therapy were given 30, 90, 120 and 240 mg doses of lesogaberan. Each dose was given twice (12 h apart) during a 24-h period, during which impedance-pH measurements were taken. Twenty-five patients were included in the efficacy analysis and 27 in the safety analysis. The effect of lesogaberan on the mean number of reflux episodes was dose-dependent, and all doses significantly reduced the mean number of reflux episodes relative to placebo. Lesogaberan also dose-dependently reduced the mean number of acid reflux episodes (except the 30 mg dose) and weakly acid reflux episodes (all doses) significantly, relative to placebo. Regardless of dose, lesogaberan had a similar effect on the percentage of time with esophageal pH < 4 [mean reduction: 68.5% (30 mg), 54.2% (90 mg), 65.9% (120 mg), 72.1% (240 mg); p < 0.05 except 90 mg dose]. No adverse events led to discontinuation and no serious adverse events occurred during active treatment. Lesogaberan inhibited reflux in a dose-dependent manner in partial responders taking optimised PPI therapy, and these effects were significant versus placebo. All lesogaberan doses were well tolerated and were not associated with clinically relevant adverse events. ClinicalTrials.gov identifier: NCT01043185.

Review of proton pump inhibitors for the initial treatment of heartburn: is there a dose ceiling effect?

Science.gov (United States)

Kushner, Pamela R; Peura, David A

2011-05-01

Proton pump inhibitors (PPIs) are widely used in clinical practice. However, concerns have been expressed about their long-term use, particularly with regard to bone health, Clostridium difficile infections, and drug interactions with platelet aggregation inhibitors. There has been limited guidance for clinicians concerning appropriate dose selection of PPIs for the initial treatment of heartburn. This review explored whether published clinical trials provide evidence of a ceiling above which higher PPI doses do not provide additional clinical benefit over the lowest approved dose. All articles of randomized, controlled clinical trials in nonerosive gastroesophageal reflux disease (GERD) in which the effects of two or more doses of the same PPI on symptomatic relief of heartburn were quantified as a study endpoint were identified and analyzed through PubMed searches up to the end of September 2010. The majority of trials evaluated provided no evidence that higher PPI doses were superior to the lowest approved dose for the initial treatment of heartburn. There were no clinically relevant findings with respect to dose dependence and safety outcomes in these studies. Efficacy outcomes from the trials suggest there may be a dose ceiling effect and highlight the need for further research on the use of the lowest effective PPI doses as an appropriate strategy in the initial treatment of uncomplicated heartburn. Observational studies and some meta-analyses have suggested that long-term PPI pharmacotherapy might be associated with safety concerns, which necessitate the periodic evaluation of therapeutic benefit in terms of symptom resolution and regimen tolerability. However, evidence to date suggests that use of the lowest effective dose for the indication is not associated with significant adverse events, particularly in the short term. Clinical practice suggests that patients requiring long-term treatment should be maintained on the lowest dose necessary to control

Topical administration of regorafenib eye drops: phase I dose-escalation study in healthy volunteers.

Science.gov (United States)

Zimmermann, Torsten; Höchel, Joachim; Becka, Michael; Boettger, Michael K; Rohde, Beate; Schug, Barbara; Kunert, Kathleen S; Donath, Frank

2018-05-01

Regorafenib is a multikinase inhibitor under investigation for use in neovascular age-related macular degeneration. In this phase I study, regorafenib eye drops were administered to healthy volunteers to provide information on safety, tolerability and systemic exposure. This was a single-centre, randomized, double-masked, parallel-group, dose-escalation, placebo-controlled study. Subjects received regorafenib eye drops (30 mg ml -1 , 25 μl) as a 0.75 mg single dose (Cohort 1), 0.75 mg twice daily (bid) or thrice daily (tid) over 14 days (Cohorts 2 and 3, respectively), 1.5 mg tid unilaterally for 3 days, then bilaterally for up to 14 days (Cohort 4), or placebo. Plasma samples were taken to estimate systemic exposure. Safety and functional assessments were performed throughout the study. Thirty-six subjects received regorafenib and 12 received placebo. Regorafenib was safe and well tolerated over the dose range. No pathological changes occurred in the anterior, vitreous or posterior eye compartments. Mild eyelid redness, oedema and conjunctival hyperaemia were observed across all regorafenib cohorts; these were comparable with the effects seen with placebo. Predominant symptoms were blurred vision in the active and placebo groups. Systemic safety evaluations showed no clinically relevant findings. Absolute systemic exposure after multiple administrations of regorafenib eye drops at a dose of 0.75 mg was 600-700-fold lower than after multiple oral administration of 160 mg day -1 , the dose approved in cancer indications. These results indicate a favourable safety and tolerability profile of regorafenib eye drops up to 30 mg ml -1 tid for use in clinical studies. © 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Robust EM Continual Reassessment Method in Oncology Dose Finding

Science.gov (United States)

Yuan, Ying; Yin, Guosheng

2012-01-01

The continual reassessment method (CRM) is a commonly used dose-finding design for phase I clinical trials. Practical applications of this method have been restricted by two limitations: (1) the requirement that the toxicity outcome needs to be observed shortly after the initiation of the treatment; and (2) the potential sensitivity to the prespecified toxicity probability at each dose. To overcome these limitations, we naturally treat the unobserved toxicity outcomes as missing data, and use the expectation-maximization (EM) algorithm to estimate the dose toxicity probabilities based on the incomplete data to direct dose assignment. To enhance the robustness of the design, we propose prespecifying multiple sets of toxicity probabilities, each set corresponding to an individual CRM model. We carry out these multiple CRMs in parallel, across which model selection and model averaging procedures are used to make more robust inference. We evaluate the operating characteristics of the proposed robust EM-CRM designs through simulation studies and show that the proposed methods satisfactorily resolve both limitations of the CRM. Besides improving the MTD selection percentage, the new designs dramatically shorten the duration of the trial, and are robust to the prespecification of the toxicity probabilities. PMID:22375092

Control of moderate-to-severe asthma with randomized ciclesonide doses of 160, 320 and 640 μg/day

Directory of Open Access Journals (Sweden)

Pedersen SE

2017-03-01

Full Text Available Søren E Pedersen,1 Niyati Prasad,2 Udo-Michael Goehring,3 Henrik Andersson,4 Dirkje S Postma5 1Pediatric Research Unit, Kolding Hospital, University of Southern Denmark, Kolding, Denmark; 2Vertex, Phase IV & Global Strategy, London, UK; 3Vifor Pharma Ltd, Clinical Research & Biometrics, Glattbrugg, Switzerland; 4Swedish Social Insurance Agency, Government Offices of Sweden, Stockholm, Sweden; 5Department of Pulmonology, Griac Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands Background: The inhaled corticosteroid (ICS ciclesonide (Cic, controls asthma symptoms in the majority of patients at the recommended dose of 160 µg/day. However, the relationship between the level of asthma control and increasing doses of Cic is unknown. This study investigated whether long-term treatment with higher doses of Cic would further improve asthma symptoms in patients with uncontrolled asthma despite ICS use. Patients and methods: In a double-blind, randomized, parallel-group study, 367 patients were allocated to one of three treatment arms (Cic 160, 320 and 640 μg/day. After a single-blind, 3-week baseline period with Cic 160 µg/day, eligible patients were randomized to receive 52 weeks of treatment with Cic 160, 320 or 640 μg/day (double-blind period during which forced expiratory volume in 1 second (FEV1, exacerbations and Asthma Control Questionnaire (ACQ scores were measured. Results: Treatment with all the three doses was associated with significant improvements in ACQ scores, FEV1 and asthma symptoms (P<0.01. There were no statistically significant differences between the three doses. The results of the primary end point analysis showed a numerical improvement in the ACQ score with Cic 640 μg/day compared with Cic 160 μg/day (least square [LS] mean: -0.122; two-sided P-value: 0.30. Post hoc subgroup analyses showed that the improvement in the ACQ score with Cic 640 μg/day compared

Immunogenicity and safety of a novel monovalent high-dose inactivated poliovirus type 2 vaccine in infants: a comparative, observer-blind, randomised, controlled trial.

Science.gov (United States)

Sáez-Llorens, Xavier; Clemens, Ralf; Leroux-Roels, Geert; Jimeno, José; Clemens, Sue Ann Costa; Weldon, William C; Oberste, M Steven; Molina, Natanael; Bandyopadhyay, Ananda S

2016-03-01

Following the proposed worldwide switch from trivalent oral poliovirus vaccine (tOPV) to bivalent types 1 and 3 OPV (bOPV) in 2016, inactivated poliovirus vaccine (IPV) will be the only source of protection against poliovirus type 2. With most countries opting for one dose of IPV in routine immunisation schedules during this transition because of cost and manufacturing constraints, optimisation of protection against all poliovirus types will be a priority of the global eradication programme. We assessed the immunogenicity and safety of a novel monovalent high-dose inactivated poliovirus type 2 vaccine (mIPV2HD) in infants. This observer-blind, comparative, randomised controlled trial was done in a single centre in Panama. We enrolled healthy infants who had not received any previous vaccination against poliovirus. Infants were randomly assigned (1:1) by computer-generated randomisation sequence to receive a single dose of either mIPV2HD or standard trivalent IPV given concurrently with a third dose of bOPV at 14 weeks of age. At 18 weeks, all infants were challenged with one dose of monovalent type 2 OPV (mOPV2). Primary endpoints were seroconversion and median antibody titres to type 2 poliovirus 4 weeks after vaccination with mIPV2HD or IPV; and safety (as determined by the proportion and nature of serious adverse events and important medical events for 8 weeks after vaccination). The primary immunogenicity analyses included all participants for whom a post-vaccination blood sample was available. All randomised participants were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02111135. Between April 14 and May 9, 2014, 233 children were enrolled and randomly assigned to receive mIPV2HD (117 infants) or IPV (116 infants). 4 weeks after vaccination with mIPV2HD or IPV, seroconversion to poliovirus type 2 was recorded in 107 (93·0%, 95% CI 86·8-96·9) of 115 infants in the mIPV2HD group compared with 86 (74·8%, 65·8

A randomized dose-response trial of aerobic exercise and health-related quality of life in colon cancer survivors.

Science.gov (United States)

Brown, Justin C; Damjanov, Nevena; Courneya, Kerry S; Troxel, Andrea B; Zemel, Babette S; Rickels, Michael R; Ky, Bonnie; Rhim, Andrew D; Rustgi, Anil K; Schmitz, Kathryn H

2018-04-01

To examine the dose-response effects of aerobic exercise on health-related quality of life (HRQoL) among colon cancer survivors. Thirty-nine stage I to III colon cancer survivors were randomized to 1 of 3 groups: usual-care control, 150 min·wk -1 of aerobic exercise (low-dose) and 300 min·wk -1 of aerobic exercise (high-dose) for 6 months. HRQoL outcomes included the Short Form (SF)-36 physical and mental component summary, Functional Assessment of Cancer Therapy-Colorectal, Pittsburgh Sleep Quality Index, Fear of Cancer Recurrence Inventory, Fatigue Symptom Inventory, and North Central Cancer Treatment Group bowel function questionnaire, assessed at baseline and post intervention. The primary hypothesis was that exercise would improve HRQoL outcomes in a dose-response fashion, such that high-dose aerobic exercise would yield the largest improvements in HRQoL outcomes. Over 6 months, the low-dose group completed 141 ± 10 min·wk -1 of aerobic exercise, and the high-dose group completed 247 ± 11 min·wk -1 of aerobic exercise. Over 6 months, exercise improved the physical component summary score of the SF-36 (P trend  = 0.002), the Functional Assessment of Cancer Therapy-Colorectal (P trend  = 0.025), the Pittsburgh Sleep Quality Index (P trend  = 0.049), and the Fatigue Symptom Inventory (P trend  = 0.045) in a dose-response fashion. Between-group standardized mean difference effects sizes for the above-described findings were small to moderate in magnitude (0.35-0.75). No dose-response effects were observed for the mental component summary score of the SF-36, the Fear of Cancer Recurrence Inventory, or bowel function. Higher doses of aerobic exercise, up to 300 min·wk -1 , improve multiple HRQoL outcomes among stage I to III colon cancer survivors. These findings provide evidence that aerobic exercise may provide multiple health benefits for colon cancer survivors. Copyright © 2018 John Wiley & Sons, Ltd.

Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: results of a Phase III randomized study (MIRROR)

NARCIS (Netherlands)

Rubbert-Roth, Andrea; Tak, Paul P.; Zerbini, Cristiano; Tremblay, Jean-Luc; Carreño, Luis; Armstrong, Gillian; Collinson, Neil; Shaw, Tim M.

2010-01-01

Methods. Patients with active RA despite stable MTX (10-25 mg/week) were randomly assigned to one of the three treatment regimens comprising two courses of RTX given 24 weeks apart: 2 x 500 and 2 x 500 mg; 2 x 500 and 2 x 1000 mg (dose escalation); and 2 x 1000 and 2 x 1000 mg. The primary endpoint

Effect of fixed-dose combinations of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS-ROZE (Multicenter Randomized Study of ROsuvastatin and eZEtimibe).

Science.gov (United States)

Kim, Kyung-Jin; Kim, Sang-Hyun; Yoon, Young Won; Rha, Seung-Woon; Hong, Soon-Jun; Kwak, Choong-Hwan; Kim, Weon; Nam, Chang-Wook; Rhee, Moo-Yong; Park, Tae-Ho; Hong, Taek-Jong; Park, Sungha; Ahn, Youngkeun; Lee, Namho; Jeon, Hui-Kyung; Jeon, Dong-Woon; Han, Kyoo-Rok; Moon, Keon-Woong; Chae, In-Ho; Kim, Hyo-Soo

2016-10-01

We aimed to compare the effects of fixed-dose combinations of ezetimibe plus rosuvastatin to rosuvastatin alone in patients with primary hypercholesterolemia, including a subgroup analysis of patients with diabetes mellitus (DM) or metabolic syndrome (MetS). This multicenter eight-week randomized double-blind phase III study evaluated the safety and efficacy of fixed-dose combinations of ezetimibe 10 mg plus rosuvastatin, compared with rosuvastatin alone in patients with primary hypercholesterolemia. Four hundred and seven patients with primary hypercholesterolemia who required lipid-lowering treatment according to the ATP III guideline were randomized to one of the following six treatments for 8 weeks: fixed-dose combinations with ezetimibe 10 mg daily plus rosuvastatin (5, 10, or 20 mg daily) or rosuvastatin alone (5, 10, or 20 mg daily). Fixed-dose combination of ezetimibe plus rosuvastatin significantly reduced LDL cholesterol, total cholesterol, and triglyceride levels compared with rosuvastatin alone. Depending on the rosuvastatin dose, these fixed-dose combinations of ezetimibe plus rosuvastatin provided LDL cholesterol, total cholesterol, and triglyceride reductions of 56%-63%, 37%-43%, and 19%-24%, respectively. Moreover, the effect of combination treatment on cholesterol levels was more pronounced in patients with DM or MetS than in non-DM or non-MetS patients, respectively, whereas the effect of rosuvastatin alone did not differ between DM vs non-DM or MetS vs non-MetS patients. Fixed-dose combinations of ezetimibe and rosuvastatin provided significantly superior efficacy to rosuvastatin alone in lowering LDL cholesterol, total cholesterol, and triglyceride levels. Moreover, the reduction rate was greater in patients with DM or MetS. © 2016 The Authors Cardiovascular Therapeutics Published by John Wiley & Sons Ltd.

Exposing exposure: enhancing patient safety through automated data mining of nuclear medicine reports for quality assurance and organ dose monitoring.

Science.gov (United States)

Ikuta, Ichiro; Sodickson, Aaron; Wasser, Elliot J; Warden, Graham I; Gerbaudo, Victor H; Khorasani, Ramin

2012-08-01

To develop and validate an open-source informatics toolkit capable of creating a radiation exposure data repository from existing nuclear medicine report archives and to demonstrate potential applications of such data for quality assurance and longitudinal patient-specific radiation dose monitoring. This study was institutional review board approved and HIPAA compliant. Informed consent was waived. An open-source toolkit designed to automate the extraction of data on radiopharmaceuticals and administered activities from nuclear medicine reports was developed. After iterative code training, manual validation was performed on 2359 nuclear medicine reports randomly selected from September 17, 1985, to February 28, 2011. Recall (sensitivity) and precision (positive predictive value) were calculated with 95% binomial confidence intervals. From the resultant institutional data repository, examples of usage in quality assurance efforts and patient-specific longitudinal radiation dose monitoring obtained by calculating organ doses from the administered activity and radiopharmaceutical of each examination were provided. Validation statistics yielded a combined recall of 97.6% ± 0.7 (95% confidence interval) and precision of 98.7% ± 0.5. Histograms of administered activity for fluorine 18 fluorodeoxyglucose and iodine 131 sodium iodide were generated. An organ dose heatmap which displays a sample patient's dose accumulation from multiple nuclear medicine examinations was created. Large-scale repositories of radiation exposure data can be extracted from institutional nuclear medicine report archives with high recall and precision. Such repositories enable new approaches in radiation exposure patient safety initiatives and patient-specific radiation dose monitoring.

Safety handling manual for high dose rate remote afterloading system

International Nuclear Information System (INIS)

1999-01-01

This manual is mainly for safety handling of 192 Ir-RALS (remote afterloading system) of high dose rate and followings were presented: Procedure and document format for the RALS therapy and for handling of its radiation source with the purpose of prevention of human errors and unexpected accidents, Procedure for preventing errors occurring in the treatment schedule and operation, and Procedure and format necessary for newly introducing the system into a facility. Consistency was intended in the description with the quality assurance guideline for therapy with small sealed radiation sources made by JASTRO (Japan Society for Therapeutic Radiology and Oncology). Use of the old type 60 Co-RALS was pointed out to be a serious problem remained and its safety handling procedure was also presented. (K.H.)

A cluster randomized non-inferiority field trial on the immunogenicity and safety of tetanus toxoid vaccine kept in controlled temperature chain compared to cold chain.

Science.gov (United States)

Juan-Giner, Aitana; Domicent, Camille; Langendorf, Céline; Roper, Martha H; Baoundoh, Paul; Fermon, Florence; Gakima, Primitive; Zipursky, Simona; Tamadji, Mbaihol; Grais, Rebecca F

2014-10-29

In resource-poor settings, cold chain requirements present barriers for vaccine delivery. We evaluated the immunogenicity and safety of tetanus toxoid (TT) vaccine in "Controlled Temperature Chain" (CTC; up to 40 °C for cold chain (SCC; 2-8 °C). Prior to the study, stability parameters of TT-CTC were shown to meet international requirements. A cluster randomized, non-inferiority trial was conducted in Moïssala district, Chad, December 2012-March 2013. Thirty-four included clusters were randomized to CTC or SCC. Women aged 14-49 years, eligible for TT vaccination and with a history of ≤1 TT dose, received two TT doses 4 weeks apart. Participants were blinded to allocation strategy. Tetanus antibody titers were measured using standard ELISA at inclusion and 4 weeks post-TT2. Primary outcome measures were post-vaccination seroconversion and fold-increase in geometric mean concentrations (GMC). Non-inferiority was by seroconversion difference (TTSCC-TTCTC) 95% of participants; upper 95%CI of the difference was 5.6%. Increases in GMC were over 4-fold; upper 95%CI of GMC ratio was 1.36 in the adjusted analysis. Few adverse events were recorded. This study demonstrates the immunogenicity and safety of TT in CTC at cold chain cannot be maintained. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Screening of repeated dose toxicity data present in SCC(NF)P/SCCS safety evaluations of cosmetic ingredients.

Science.gov (United States)

Vinken, Mathieu; Pauwels, Marleen; Ates, Gamze; Vivier, Manon; Vanhaecke, Tamara; Rogiers, Vera

2012-03-01

Alternative methods, replacing animal testing, are urgently needed in view of the European regulatory changes in the field of cosmetic products and their ingredients. In this context, a joint research initiative called SEURAT was recently raised by the European Commission and COLIPA, representing the European cosmetics industry, with the overall goal of developing an animal-free repeated dose toxicity testing strategy for human safety assessment purposes. Although cosmetic ingredients are usually harmless for the consumer, one of the initial tasks of this research consortium included the identification of organs that could potentially be affected by cosmetic ingredients upon systemic exposure. The strategy that was followed hereof is described in the present paper and relies on the systematic evaluation, by using a self-generated electronic databank, of published reports issued by the scientific committee of DG SANCO responsible for the safety of cosmetic ingredients. By screening of the repeated dose toxicity studies present in these reports, it was found that the liver is potentially the most frequently targeted organ by cosmetic ingredients when orally administered to experimental animals, followed by the kidney and the spleen. Combined listing of altered morphological, histopathological, and biochemical parameters subsequently indicated the possible occurrence of hepatotoxicity, including steatosis and cholestasis, triggered by a limited number of cosmetic compounds. These findings are not only of relevance for the in vitro modeling efforts and choice of compounds to be tested in the SEURAT project cluster, but also demonstrate the importance of using previously generated toxicological data through an electronic databank for addressing specific questions regarding the safety evaluation of cosmetic ingredients.

Safety and effectiveness evaluation of a domestic peritoneal dialysis fluid packed in non-PVC bags: study protocol for a randomized controlled trial.

Science.gov (United States)

Zhou, Jianhui; Cao, Xueying; Lin, Hongli; Ni, Zhaohui; He, Yani; Chen, Menghua; Zheng, Hongguang; Chen, Xiangmei

2015-12-29

Peritoneal dialysis is an important type of renal replacement therapy for uremic patients. In peritoneal dialysis, fluids fill in and flow out of the abdominal cavity three to five times per day. Usually, the fluid is packed in a polyvinyl chloride (PVC) bag. Safety concerns have arisen over di-(2-ethylhexyl) phthalate, which is essential in the formation of PVC materials. In 2011, the National Development and Reform Commission of China released a catalog of industrial structural adjustments, mandating the elimination of PVC bags for intravenous infusion and food containers. Although bags for peritoneal dialysis fluid were not included in the elimination list, several manufacturers began to develop new materials for fluid bags. HUAREN peritoneal dialysis fluid consists of the same electrolytes and buffer agent as in Baxter fluid, but is packed in bags that do not contain PVC. This multicenter randomized controlled trial was designed to compare peritoneal dialysis fluid packed in non-PVC-containing and PVC-containing bags. Further, the study sought to determine the proper dose of peritoneal dialysis fluid and the actual survival rates of Chinese patients undergoing peritoneal dialysis. The study participants are adults undergoing continuous ambulatory peritoneal dialysis for 30 days to 6 months. All eligible patients are randomized (1:1) to peritoneal dialysis with Baxter and HUAREN dialysis fluids (initial dose, 6 l/day), with dosages adjusted according to a unified protocol. The primary outcomes are the 1-, 2-, 3-, 4-, and 5-year overall survival rates. Secondary outcome measures include technique survival rates, reductions in estimated glomerular filtration rate, nutritional status, quality of life, cardiovascular events, medical costs and drop-out rates. Safety outcome measures include adverse events, changes in vital signs and laboratory parameters, peritonitis, allergies, and quality of products. This study is the first to evaluate the long-term safety and

Containment-emergency-sump performance. Technical findings related to Unresolved Safety Issue A-43

International Nuclear Information System (INIS)

1983-04-01

This report summarizes key technical findings related to the Unresolved Safety Issue A-43, Containment Emergency Sump Performance, and provides recommendations for resolution of attendant safety issues. The key safety questions relate to: (a) effects of insulation debris on sump performance; (b) sump hydraulic performance as determined by design features, submergence, and plant induced effects, and (c) recirculation pump performance wherein air and/or particulate ingestion can occur. The technical findings presented in this report provide information relevant to the design and performance evaluation of the containment emergency sump

Effect of vaccine dose on the safety and immunogenicity of a candidate TB vaccine, MVA85A, in BCG vaccinated UK adults.

Science.gov (United States)

Pathan, Ansar A; Minassian, Angela M; Sander, Clare R; Rowland, Rosalind; Porter, David W; Poulton, Ian D; Hill, Adrian V S; Fletcher, Helen A; McShane, Helen

2012-08-17

A non-randomised, open-label, Phase I safety and immunogenicity dose-finding study to assess the safety and immunogenicity of the candidate TB vaccine Modified Vaccinia virus Ankara expressing Antigen 85A (MVA85A) from Mycobacterium tuberculosis (MTB) in healthy adult volunteers previously vaccinated with BCG. Healthy BCG-vaccinated volunteers were vaccinated with either 1×10(7) or 1×10(8)PFU of MVA85A. All adverse events were documented and antigen specific T cell responses were measured using an ex vivo IFN-γ ELISPOT assay. Safety and immunogenicity were compared between the 2 dose groups and with a previous trial in which a dose of 5×10(7)PFU MVA85A had been administered. There were no serious adverse events recorded following administration of either 1×10(7) or 1×10(8)PFU of MVA85A. Systemic adverse events were more frequently reported following administration of 1×10(8)PFU of MVA85A when compared to either 5×10(7) or 1×10(7)PFU of MVA85A but were mild or moderate in severity and resolved completely within 7 days of immunisation. Antigen specific T cell responses as measured by the IFN-γ ELISPOT were significantly higher following immunisation in adults receiving 1×10(8)PFU compared to the 5×10(7) and 1×10(7) doses. Additionally, a broader range of Ag85A epitopes are detected following 1×10(8)PFU of MVA85A. A higher dose of 1×10(8)PFU of MVA85A is well-tolerated, increases the frequency of IFN-γ secreting T cells detected following immunisation and broadens the range of Ag85A epitopes detected. Copyright © 2012 Elsevier Ltd. All rights reserved.

[Safety and immunogenicity of a 7-valent pneumococcal conjugate vaccine (Prevenar) booster dose in healthy Chinese toddlers].

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Li, Rong-cheng; Li, Feng-xiang; Li, Yan-ping

2009-06-01

To evaluate the safety and immunogenicity of the booster dose of 7 valent pneumococcal conjugate vaccine (PCV7) to the healthy Chinese toddlers who had received 3 primary doses. Four hundred and eighty-eight Chinese toddlers received a booster dose of PCV7 at age of 12-15 months following a primary series of the vaccine given at ages 3, 4, 5 months separately with Diphtheria Tetanus Acellular Pertussis Combined Vaccine (DTaP) in Group 1 or concurrently with DTaP in Group 2. Following the booster dose immunization, each subject was followed up for 30 days to observe the safety of the vaccine. Blood samples were taken from a subset of subjects prior and post 30 days the booster dose immunization to evaluate immunogenicity. A high proportion of subjects in Group 1 (89%) and Group 2 (91%) remained afebrile after the booster dose. Local reactions to the PCV7 booster dose were generally mild. For each serotype, the rise in GMC (post-/pre-vaccination) showed a statistically significant difference (P<0.0001) between both groups. PCV7 administered as a booster dose is generally safe, well tolerate, and immunogenic in healthy Chinese toddlers.

The impact of low-dose aspirin on preterm birth: secondary analysis of a randomized controlled trial.

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Allshouse, A A; Jessel, R H; Heyborne, K D

2016-06-01

The objective of this study is to determine whether low-dose aspirin (LDA) reduced the rate of preterm birth (PTB) in a cohort of women at high risk for preeclampsia. Secondary analysis of the Maternal-Fetal Medicine Units High-Risk Aspirin trial. Preterm births were categorized by phenotype: indicated, spontaneous or due to preterm premature rupture of membranes (PPROMs). Of 1789 randomized women, 30.5% delivered before 37 weeks (18.5% indicated, 5.8% spontaneous and 6.2% following preterm PPROMs). Among women randomized to LDA, we observed a trend favoring fewer PTBs due to spontaneous preterm labor and preterm PPROMs, odds ratio (OR: 0.826 (0.620, 1.099)); the incidence of indicated PTBs appeared unchanged, OR: 0.999 (0.787, 1.268). Although not reaching significance, we observed an effect size similar to other studies of both low- and high-risk women. These results support findings from other studies assessing LDA as a PTB prevention strategy.

The Safety and Efficacy of Low-Dose Naltrexone in the Management of Chronic Pain and Inflammation in Multiple Sclerosis, Fibromyalgia, Crohn's Disease, and Other Chronic Pain Disorders.

Science.gov (United States)

Patten, Denise K; Schultz, Bob G; Berlau, Daniel J

2018-03-01

Chronic inflammatory diseases are complex to treat and have an impact on a large number of patients. Due to the difficulty of treating these diseases and the great impact on quality of life, patients often seek off-label, complimentary, or alternative medicines to gain relief from symptoms. Low-dose naltrexone has been used off-label for treatment of pain and inflammation in multiple sclerosis, Crohn's disease, fibromyalgia, and other diseases. Naltrexone is a mu-opioid receptor antagonist indicated by the U.S. Food and Drug Administration for opioid and alcohol dependence. It is hypothesized that lower than standard doses of naltrexone inhibit cellular proliferation of T and B cells and block Toll-like receptor 4, resulting in an analgesic and antiinflammatory effect. It is the purpose of this review to examine the evidence of the safety, tolerability, and efficacy of low-dose naltrexone for use in chronic pain and inflammatory conditions. Currently, evidence supports the safety and tolerability of low-dose naltrexone in multiple sclerosis, fibromyalgia, and Crohn's disease. Fewer studies support the efficacy of low-dose naltrexone, with most of these focusing on subjective measures such as quality of life or self-reported pain. These studies do demonstrate that low-dose naltrexone has subjective benefits over placebo, but evidence for more objective measures is limited. However, further randomized controlled trials are needed to determine the efficacy of low-dose naltrexone due to insufficient evidence supporting its use in these disease states. This review provides practitioners with the extent of low-dose naltrexone evidence so that they can be cognizant of situations where it may not be the most appropriate therapy. © 2018 Pharmacotherapy Publications, Inc.

Cluster Randomized Trail of the uptake of a take-home Infant dose ...

African Journals Online (AJOL)

Objective: To test whether a single take home dose of infant nevirapine increased infant uptake without decreasing institutional deliveries. Design: Cluster randomized post-test only study with control group. Setting: Ten hospitals in urban areas of Coast, Rift Valley, and Western provinces, Kenya. Participants: Pregnant ...

Safety and efficacy of low-dose isotretinoin in the treatment of moderate to severe acne vulgaris

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Parinitha K Rao

2014-01-01

Full Text Available Background: Isotretinoin is indicated for moderate to severe cases of acne which are unresponsive to conventional therapy. The classical recommended dose is 0.5 to 1.0 mg/kg/day. As the side effects are dose related, low-dose isotretinoin therapy for acne is an attractive option; however, but little data exists on the safety and efficacy of this strategy. Materials and Methods: In this prospective, non-comparative study, 50 participants, both male and female, having moderate to severe acne vulgaris were enrolled and treated with isotretinoin at a dose of 20 mg/day (approximately 0.3-0.4 mg/kg/day, for a period of 3 months. Participants were evaluated by means of clinical and laboratory investigations before starting isotretinoin. Investigations were repeated at the end of the first and third months following completion of treatment, and participants were followed up for 6 months to look for any relapse. Results: At the end of the treatment, very good results were observed in 90% of participants. Cheilitis was the most common among the side effects observed and was seen in 98% of the participants. One participant developed vitiligo as a side effect, which is a new finding, and has not reported in literature before. Elevated serum lipid levels were observed in 6% of the participants, and relapse occurred in 4% of the participants over a 6 month follow up period. Conclusion: Three months of treatment with low-dose isotretinoin (20 mg/day was found to be effective in the treatment of moderate to severe acne vulgaris, with a low incidence of serious side effects. This dose also was more economical than the higher doses.

Single-dose intra-articular bupivacaine plus morphine versus bupivacaine alone after arthroscopic knee surgery: a meta-analysis of randomized controlled trials.

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Yang, Ye; Zeng, Chao; Wei, Jie; Li, Hui; Yang, Tuo; Deng, Zhen-Han; Li, Yu-Sheng; Yang, Tu-Bao; Lei, Guang-Hua

2017-03-01

The purpose of this meta-analysis was to compare the efficacy and safety of single-dose intra-articular bupivacaine plus morphine versus bupivacaine alone for pain management following arthroscopic knee surgery. A comprehensive literature search was conducted to identify randomized controlled trials that used single-dose intra-articular bupivacaine plus morphine and bupivacaine alone for post-operative pain, using MEDLINE (1966-2014), Cochrane Library and EMBASE databases. The weighted mean difference (WMD), relative risk (RR) and their corresponding 95 % confidence intervals (CIs) were calculated using RevMan statistical software. A total of twenty-nine trials (n = 1167) were included. The post-operative visual analog scale (VAS) pain score of the bupivacaine plus morphine group compared with the bupivacaine alone group was significantly lower (WMD -1.15, 95 % CI -1.67 to -0.63, p bupivacaine plus morphine was shown to be significantly better than bupivacaine alone at relieving post-operative pain after arthroscopic knee surgery without increasing the short-term side effects. Routine use of single-dose intra-articular bupivacaine plus morphine is an effective way for pain management after arthroscopic knee surgery. II.

A double-blind, randomized, placebo-controlled, fixed-dose phase III study of vilazodone in patients with generalized anxiety disorder.

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Gommoll, Carl; Durgam, Suresh; Mathews, Maju; Forero, Giovanna; Nunez, Rene; Tang, Xiongwen; Thase, Michael E

2015-06-01

Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist, is approved for treating major depressive disorder in adults. This study (NCT01629966 ClinicalTrials.gov) evaluated the efficacy and safety of vilazodone in adults with generalized anxiety disorder (GAD). A multicenter, double-blind, parallel-group, placebo-controlled, fixed-dose study in patients with GAD randomized (1:1:1) to placebo (n = 223), or vilazodone 20 mg/day (n = 230) or 40 mg/day (n = 227). Primary and secondary efficacy parameters were total score change from baseline to week 8 on the Hamilton Rating Scale for Anxiety (HAMA) and Sheehan Disability Scale (SDS), respectively, analyzed using a predefined mixed-effect model for repeated measures (MMRM). Safety outcomes were presented by descriptive statistics. The least squares mean difference (95% confidence interval) in HAMA total score change from baseline (MMRM) was statistically significant for vilazodone 40 mg/day versus placebo (-1.80 [-3.26, -0.34]; P = .0312 [adjusted for multiple comparisons]), but not for vilazodone 20 mg/day versus placebo. Mean change from baseline in SDS total score was not significantly different for either dose of vilazodone versus placebo when adjusted for multiplicity; significant improvement versus placebo was noted for vilazodone 40 mg/day without adjustment for multiplicity (P = .0349). The incidence of adverse events was similar for vilazodone 20 and 40 mg/day (∼71%) and slightly lower for placebo (62%). Nausea, diarrhea, dizziness, vomiting, and fatigue were reported in ≥5% of patients in either vilazodone group and at least twice the rate of placebo. Vilazodone was effective in treating anxiety symptoms of GAD. No new safety concerns were identified. © 2015 The Authors. Depression and Anxiety published by Wiley Periodicals, Inc.

Efficacy and safety of oxcarbazepine in the treatment of children with epilepsy: a meta-analysis of randomized controlled trials.

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Geng, Hua; Wang, Chengzhong

2017-01-01

To assess the efficacy and safety of oxcarbazepine (OXC) in the treatment of children with epilepsy. Randomized controlled trials (RCTs) published in PubMed, Embase, Web of Science, Cochrane Library, Scopus, SinoMed (Chinese BioMedical Literature Service System, China), and Chinese National Knowledge Infrastructure (China) database were systematically reviewed. Eligible studies were those that compared the efficacy and safety of OXC with other antiepileptic drugs in epilepsy. Risk ratio (RR) with 95% confidence intervals (95% CIs) was calculated using fixed-effects or random-effects model. Eleven RCTs with a total of 1,241 patients met the inclusion criteria and were included in this meta-analysis. Compared with other antiepileptic drugs (sodium valproate, levetiracetam, phenytoin, and placebo), OXC was associated with similar seizure-free rate (RR =1.06, 95% CI: 0.94, 1.20; P =0.366) and percentage reduction from baseline in seizure frequency (for ≥75% reduction: RR =1.15, 95% CI: 0.88, 1.49; P =0.310; for 50%-75% reduction: RR =1.12, 95% CI: 0.90, 1.39; P =0.301; for effects and safety as other antiepileptic drugs in the treatment of children with epilepsy. Further well-conducted, large-scale RCTs are needed to validate these findings.

Immunogenicity and safety of high-dose hepatitis B vaccine among drug users: A randomized, open-labeled, blank-controlled trial.

Science.gov (United States)

Feng, Yongliang; Shi, Jing; Gao, Linying; Yao, Tian; Feng, Dan; Luo, Dan; Li, Zhansheng; Zhang, Yawei; Wang, Fuzhen; Cui, Fuqiang; Li, Li; Liang, Xiaofeng; Wang, Suping

2017-06-03

Due to the low uptake, adherence, and completion of vaccination among drug users, and their compromised immune responses to hepatitis B vaccination, the current practice of hepatitis B vaccination may not provide optimal protection. The aim of this study was to evaluate the immunogenicity and safety of 60 µg and 20 µg hepatitis B vaccines among drug users. A randomized, open-labeled, blank-controlled trial was conducted among drug users at 2 drug rehabilitation centers in China. The eligible participants were drug users who were serologically negative for the hepatitis B surface antigen (HBsAg) and the hepatitis B surface antibody (anti-HBs). Participants were randomized in a ratio of 1:1:1 to receive 20 µg (IM20 group) or 60 µg (IM60 group) of hepatitis B vaccine or blank control at months 0, 1, and 6, and followed at months 6, 7, and 12. Seroconversion rates of 94.7% and 92.6% were observed in IM20 and IM60 groups at month 7, and correspondingly decreased to 89.5% and 91.7% respectively at month 12. The IM60 group showed significantly higher geometric mean concentrations (GMCs) of anti-HBs (2022.5 and 676.7 mIU mL-1) than the IM20 group did (909.6 and 470.5 mIU mL-1) at months 7 and 12 (P B vaccines showed good immunogenicity among the drug users.

Low-dose ketamine infusion for labor analgesia: A double-blind, randomized, placebo controlled clinical trial

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Sam Joel

2014-01-01

Full Text Available Background: Most primary and secondary level hospitals in developing countries provide inadequate labor analgesia due to various medical, technical and economic reasons. This clinical trial was an effort to study the efficacy, safety and feasibility of intravenous (IV ketamine to provide labor analgesia. Materials and Methods: A total of 70 parturients were consented and randomly assigned to receive either IV ketamine or 0.9% saline. A loading dose of ketamine (0.2 mg/kg was followed-by an infusion (0.2 mg/kg/h until the delivery of the neonate. Similar volume of saline was infused in the placebo-group. Intramuscular meperidine was the rescue analgesic in both groups. The pain score, hemodynamic parameters of mother and fetus and the anticipated side-effects of ketamine were observed for. The newborn was assessed by the Neonatologist. Results: The pain score showed a decreasing trend in the ketamine group and after the 1 st h more than 60% of women in the ketamine group had pain relief, which was statistically significant. There was no significant clinical change in the maternal hemodynamics and fetal heart rate. However, 17 (48.5% of them had transient light headedness in the ketamine group. All the neonates were breast fed and the umbilical cord blood pH was between 7.1 and 7.2. The overall satisfaction was significantly high in the intervention group (P = 0.028. Conclusion: A low-dose ketamine infusion (loading dose of 0.2 mg/kg delivered over 30 min, followed-by an infusion at 0.2 mg/kg/h could provide acceptable analgesia during labor and delivery.

Dose-Dependent Effects of the Cimicifuga racemosa Extract Ze 450 in the Treatment of Climacteric Complaints: A Randomized, Placebo-Controlled Study

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Ruediger Schellenberg

2012-01-01

Full Text Available Extracts from Cimicifuga racemosa (CR, synonym Actaea racemosa have shown efficacy in trials in women with menopausal symptoms. Yet, dose dependency remains unclear. Therefore, 180 female outpatients with climacteric complaints were treated for 12 weeks in a randomized, double-blind, placebo-controlled, 3-armed trial (CR extract Ze 450 in 6.5 mg or 13.0 mg, or placebo. Primary outcome was the difference in menopausal symptoms (vasomotor, psychological, and somatic, assessed by the Kupperman Menopausal Index between baseline and week 12. Secondary efficacy variables were patients’ self-assessments of general quality of life (QoL, responder rates, and safety. Compared to placebo, patients receiving Ze 450 showed a significant reduction in the severity of menopausal symptoms in a dose-dependent manner from baseline to endpoint (mean absolute differences 17.0 (95% CI 14.65–19.35 score points, P<0.0001 for 13.0 mg; mean absolute differences 8.47 (95% CI 5.55–11.39 score points, P=0.0003 for 6.5 mg. QoL and responder rates corresponded with the main endpoint. Changes in menopausal symptoms and QoL were inversely correlated. Reported adverse events and clinical laboratory testing did not raise safety concerns. The CR extract Ze 450 is an effective and well-tolerated nonhormonal alternative to hormone treatment for symptom relief in menopausal women.

Efficacy and Safety of a Colistin Loading Dose, High-Dose Maintenance Regimen in Critically Ill Patients With Multidrug-Resistant Gram-Negative Pneumonia.

Science.gov (United States)

Elefritz, Jessica L; Bauer, Karri A; Jones, Christian; Mangino, Julie E; Porter, Kyle; Murphy, Claire V

2017-09-01

Emergence of multidrug-resistant (MDR) gram-negative (GN) pathogens and lack of novel antibiotics have increased the use of colistin, despite unknown optimal dosing. This study aimed to evaluate the safety and efficacy of a colistin loading dose, high-dose (LDHD) maintenance regimen in patients with MDR-GN pneumonia. A retrospective cohort analysis was performed comparing critically ill patients with MDR-GN pneumonia pre- and postimplementation of a colistin LDHD guideline with a primary outcome of clinical cure. Safety was assessed using incidence of acute kidney injury (AKI) based on RIFLE (risk, injury, failure, loss, end-stage renal disease) criteria. Seventy-two patients met the inclusion criteria (42 preimplementation and 30 postimplementation). Clinical cure was achieved in 23 (55%) patients in the preimplementation group and 20 (67%) patients in the postimplementation group ( P = .31). AKI occurred in 50% of the patients during the preimplementation period and 58% during the postimplementation period ( P = .59) with no difference in initiation rates of renal replacement therapy. The increased clinical cure rate after implementation of the colistin LDHD guideline did not reach statistical significance. The LDHD guideline, however, was not associated with an increased incidence of AKI, despite higher intravenous colistin doses. Opportunity exists to optimize colistin dosage while balancing toxicity, but larger studies are warranted.

Pharmacokinetics After Single Ascending Dose, Food Effect, and Safety of Sacubitril/Valsartan (LCZ696), an Angiotensin Receptor and Neprilysin Inhibitor, in Healthy Japanese Subjects.

Science.gov (United States)

Akahori, Mizuki; Ayalasomayajula, Surya; Langenickel, Thomas; Pal, Parasar; Zhou, Wei; Sunkara, Gangadhar

2017-06-01

LCZ696 (sacubitril/valsartan) is a novel angiotensin receptor neprilysin inhibitor (ARNI) that has been developed for treatment of heart failure patients with reduced ejection fraction and approved in the US, Europe, and many other countries. This randomized, placebo-controlled study was conducted in healthy Japanese male subjects (N = 50) to assess the pharmacokinetics and safety of single ascending oral doses (20-600 mg) of LCZ696. Food effect was also evaluated following administration of 200 mg dose. Plasma and urine samples from 40 subjects receiving LCZ696 were collected to assess pharmacokinetics of LCZ696 analytes (sacubitril, sacubitrilat, and valsartan). Following single oral dose administration of LCZ696, sacubitril and valsartan rapidly appeared in systemic circulation with a dose-linear increase in the exposure to the LCZ696 analytes. Of the administered dose, approximately 0.85 %, 54.0 %, and 8.19 % of sacubitril, sacubitrilat, and valsartan, respectively, were recovered in urine. Food reduced AUC of sacubitril, sacubitrilat, and valsartan by 21, 8, and 40 %, respectively, and C max by 72, 27, and 51 %, respectively. Single oral doses of up to 600 mg of LCZ696 were safe and generally well tolerated in healthy Japanese male subjects.

Epidural Labor Analgesia-Fentanyl Dose and Breastfeeding Success: A Randomized Clinical Trial.

Science.gov (United States)

Lee, Amy I; McCarthy, Robert J; Toledo, Paloma; Jones, Mary Jane; White, Nancy; Wong, Cynthia A

2017-10-01

Breastfeeding is an important public health concern. High cumulative doses of epidural fentanyl administered for labor analgesia have been reported to be associated with early termination of breastfeeding. We tested the hypothesis that breastfeeding success is adversely influenced by the cumulative epidural fentanyl dose administered for labor analgesia. The study was a randomized, double-blind, controlled trial of parous women at greater than 38 weeks gestation who planned to breastfeed, had successfully breastfed a prior infant, and who received neuraxial labor analgesia. Participants were randomized to receive one of three epidural maintenance solutions for labor analgesia (bupivacaine 1 mg/ml, bupivacaine 0.8 mg/ml with fentanyl 1 μg/ml, or bupivacaine 0.625 mg/ml with fentanyl 2 μg/ml). The primary outcome was the proportion of women breastfeeding at 6 weeks postpartum. Maternal and umbilical venous blood fentanyl and bupivacaine concentration at delivery were measured. A total of 345 women were randomized and 305 had complete data for analysis. The frequency of breastfeeding at 6 weeks was 97, 98, and 94% in the groups receiving epidural fentanyl 0, 1, and 2 μg/ml, respectively (P = 0.34). The cumulative fentanyl dose (difference: 37 μg [95% CI of the difference, -58 to 79 μg], P = 0.28) and maternal and umbilical cord venous fentanyl and bupivacaine concentrations did not differ between women who discontinued breastfeeding and those who were still breastfeeding at 6 weeks postpartum. Labor epidural solutions containing fentanyl concentrations as high as 2 μg/ml do not appear to influence breastfeeding rates at 6 weeks postpartum.

Comparison of the Efficacy and Safety of 2 Acetaminophen Dosing Regimens in Febrile Infants and Children: A Report on 3 Legacy Studies.

Science.gov (United States)

Temple, Anthony R; Zimmerman, Brenda; Gelotte, Cathy; Kuffner, Edwin K

2017-01-01

Compare efficacy and safety of 10 to 15 mg/kg with 20 to 30 mg/kg acetaminophen in febrile children 6 months to ≤ 11 years from 3 double-blind, randomized, single or multiple dose studies. Doses were compared on sum of the temperature differences (SUMDIFF), maximum temperature difference (MAXDIFF), temperature differences at each time point, and dose by time interactions. Alanine aminotransferase (ALT) was evaluated in the 72-hour duration study. A single dose of acetaminophen 20 to 30 mg/kg produced a greater effect on temperature decrement and duration of antipyretic effect over 8 hours than a single dose of 10 to 15 mg/kg. When equivalent total doses (i.e., 2 doses of 10 to 15 mg/kg given at 4-hour intervals and 1 dose of 20 to 30 mg/kg) were given over the initial 8-hour period, there were no significant temperature differences. Over a 72-hour period, 10 to 15 mg/kg acetaminophen administered every 4 hours maintained a more consistent temperature decrement than 20 to 30 mg/kg acetaminophen administered every 8 hours. Following doses of 60 to 90 mg/kg/day for up to 72 hours, no child had a clinically important increase in ALT from baseline. The number of children with reported adverse events was similar between doses. Data demonstrate the antipyretic effect of acetaminophen is dependent on total dose over a given time interval. These 3 studies provide clinical evidence that the recommended standard acetaminophen dose of 10 to 15 mg/kg is a safe and effective dose for treating fever in pediatric patients when administered as a single dose or as multiple doses for up to 72 hours.

Safety of allergen immunotherapy: a review of premedication and dose adjustment.

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Morris, A Erika; Marshall, Gailen D

2012-03-01

From the first allergen immunotherapy proposed in the early 1900s to the present day, numerous studies have proven the efficacy of allergen immunotherapy for the treatment of allergic rhinitis, allergic conjunctivitis, allergic asthma and stinging insect hypersensitivity. The major risk, however small, with allergen immunotherapy is anaphylaxis. There has been considerable interest and debate regarding risk factors for immunotherapy reactions (local and systemic) and interventions to reduce the occurrence of these reactions. One of these interventions that is especially debated regards dose adjustment for various reasons, but in particular for local reactions. In this review, we discuss the safety of immunotherapy and provide a comprehensive review of the literature regarding immunotherapy schedules and doses.

Comparison of antiplatelet activity of garlic tablets with cardio-protective dose of aspirin in healthy volunteers: a randomized clinical trial

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Mojtaba Shafiekhani

2016-08-01

Full Text Available Objective: Some of the adverse effects of aspirin including peptic ulcers, gastrointestinal bleeding and aspirin resistance compelled researchers to find a suitable alternative with fewer adverse effects. In this clinical trial, we aimed to find the effective antiplatelet dose of garlic. Materials and Methods: This randomized controlled clinical trial (RCT was conducted on 62 healthy volunteers of 20-50 years old. All volunteers used 80 mg aspirin per day for 1 week and at the end of this time, platelet aggregation (PA induced by 4 agonists acting in aggregation pathway including adenosinediphosphate (20 μmol/l, epinephrine (20 μmol/l, collagen(0.19 mg/ ml and arachidonic acid (0.5mg/ ml was measured by Light Transmittance Aggregometry (LTA in all participants. After one month washout period, volunteers were randomized into 3 groups and each received 1, 2 or 3 garlic tablets (1250 mg a day for 1 month. After one month, PA was examined in all groups. Results: The mean ±SD of the age of all volunteers was 28.60 ± 9.00 years. In addition, 52.00 % of our volunteers were male and 48.00% of them were female. Garlic tablet didnot have significant effect on PA at any dose. However, 30% of volunteers in the group that used 3 garlic tablets/day reported adverse effect (i.e. bleeding. No significant association between sex, age and PA was observed. Conclusion:  In this study, we were unable to determine the effective anti-platelet dose of garlic which that could be equal to that of aspirin anti-platelet activity, as assessed LTA method.

Single Ascending Dose Safety and Pharmacokinetics of CDRI-97/78: First-in-Human Study of a Novel Antimalarial Drug

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N. Shafiq

2014-01-01

Full Text Available Background. CDRI 97/78 has shown efficacy in animal models of falciparum malaria. The present study is the first in-human phase I trial in healthy volunteers. Methods. The study was conducted in 50 healthy volunteers in a single, ascending dose, randomized, placebo-controlled, double blind design. The dose ranges evaluated were from 80 mg to 700 mg. Volunteers were assessed for clinical, biochemical, haematological, radiographic, and electrocardiographic parameters for any adverse events in an in-house facility. After evaluation of safety study results, another cohort of 16 participants were administered a single oral dose of 200 mg of the drug and a detailed pharmacokinetic analysis was undertaken. Results. The compound was found to be well tolerated. MTD was not reached. The few adverse events noted were of grade 2 severity, not requiring intervention and not showing any dose response relationship. The laboratory and electrocardiographic parameters showed statistically significant differences, but all were within the predefined normal range. These parameters were not associated with symptoms/signs and hence regarded as clinically irrelevant. Mean values of T1/2, MRT, and AUC0-∞ of the active metabolite 97/63 were 11.85±1.94 h, 13.77±2.05 h, and 878.74±133.15 ng·h/mL, respectively Conclusion. The novel 1,2,4 trioxane CDRI 97/78 is safe and will be an asset in malarial therapy if results are replicated in multiple dose studies and benefit is shown in confirmatory trials.

An extended car-following model considering random safety distance with different probabilities

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Wang, Jufeng; Sun, Fengxin; Cheng, Rongjun; Ge, Hongxia; Wei, Qi

2018-02-01

Because of the difference in vehicle type or driving skill, the driving strategy is not exactly the same. The driving speeds of the different vehicles may be different for the same headway. Since the optimal velocity function is just determined by the safety distance besides the maximum velocity and headway, an extended car-following model accounting for random safety distance with different probabilities is proposed in this paper. The linear stable condition for this extended traffic model is obtained by using linear stability theory. Numerical simulations are carried out to explore the complex phenomenon resulting from multiple safety distance in the optimal velocity function. The cases of multiple types of safety distances selected with different probabilities are presented. Numerical results show that the traffic flow with multiple safety distances with different probabilities will be more unstable than that with single type of safety distance, and will result in more stop-and-go phenomena.

Safety and persistence of the humoral and cellular immune responses induced by 2 doses of an AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine administered to infants, children and adolescents: Two open, uncontrolled studies.

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Garcia-Sicilia, José; Arístegui, Javier; Omeñaca, Félix; Carmona, Alfonso; Tejedor, Juan C; Merino, José M; García-Corbeira, Pilar; Walravens, Karl; Bambure, Vinod; Moris, Philippe; Caplanusi, Adrian; Gillard, Paul; Dieussaert, Ilse

2015-01-01

In children, 2 AS03-adjuvanted A(H1N1)pdm09 vaccine doses given 21 days apart were previously shown to induce a high humoral immune response and to have an acceptable safety profile up to 42 days following the first vaccination. Here, we analyzed the persistence data from 2 open-label studies, which assessed the safety, and humoral and cell-mediated immune responses induced by 2 doses of this vaccine. The first study was a phase II, randomized trial conducted in 104 children aged 6-35 months vaccinated with the A(H1N1)pdm09 vaccine containing 1.9 µg haemagglutinin antigen (HA) and AS03B (5.93 mg tocopherol) and the second study, a phase III, non-randomized trial conducted in 210 children and adolescents aged 3-17 years vaccinated with the A(H1N1)pdm09 vaccine containing 3.75 µg HA and AS03A (11.86 mg tocopherol). Approximately one year after the first dose, all children with available data were seropositive for haemagglutinin inhibition and neutralising antibody titres, but a decline in geometric mean antibody titres was noted. The vaccine induced a cell-mediated immune response in terms of antigen-specific CD4(+) T-cells, which persisted up to one year post-vaccination. The vaccine did not raise any safety concern, though these trials were not designed to detect rare events. In conclusion, 2 doses of the AS03-adjuvanted A(H1N1)pdm09 vaccine at 2 different dosages had a clinically acceptable safety profile, and induced high and persistent humoral and cell-mediated immune responses in children aged 6-35 months and 3-17 years. These studies have been registered at www.clinicaltrials.gov NCT00971321 and NCT00964158.

Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II).

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Lamo-Espinosa, José M; Mora, Gonzalo; Blanco, Juan F; Granero-Moltó, Froilán; Nuñez-Córdoba, Jorge M; Sánchez-Echenique, Carmen; Bondía, José M; Aquerreta, Jesús Dámaso; Andreu, Enrique J; Ornilla, Enrique; Villarón, Eva M; Valentí-Azcárate, Andrés; Sánchez-Guijo, Fermín; Del Cañizo, María Consuelo; Valentí-Nin, Juan Ramón; Prósper, Felipe

2016-08-26

Mesenchymal stromal cells are a promising option to treat knee osteoarthritis. Their safety and usefulness must be confirmed and the optimal dose established. We tested increasing doses of bone marrow mesenchymal stromal cells (BM-MSCs) in combination with hyaluronic acid in a randomized clinical trial. A phase I/II multicenter randomized clinical trial with active control was conducted. Thirty patients diagnosed with knee OA were randomly assigned to intraarticularly administered hyaluronic acid alone (control), or together with 10 × 10(6) or 100 × 10(6) cultured autologous BM-MSCs, and followed up for 12 months. Pain and function were assessed using VAS and WOMAC and by measuring the knee motion range. X-ray and magnetic resonance imaging analyses were performed to analyze joint damage. No adverse effects were reported after BM-MSC administration or during follow-up. BM-MSC-administered patients improved according to VAS during all follow-up evaluations and median value (IQR) for control, low-dose and high-dose groups change from 5 (3, 7), 7 (5, 8) and 6 (4, 8) to 4 (3, 5), 2 (1, 3) and 2 (0,4) respectively at 12 months (low-dose vs control group p = 0.005 and high-dose vs control group p injection of in vitro expanded autologous BM-MSCs together with HA is a safe and feasible procedure that results in a clinical and functional improvement of knee OA, especially when 100 × 10(6) cells are administered. These results pave the way for a future phase III clinical trial. gov identifier NCT02123368. Nº EudraCT: 2009-017624-72.

Optimizing adaptive design for Phase 2 dose-finding trials incorporating long-term success and financial considerations: A case study for neuropathic pain.

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Gao, Jingjing; Nangia, Narinder; Jia, Jia; Bolognese, James; Bhattacharyya, Jaydeep; Patel, Nitin

2017-06-01

In this paper, we propose an adaptive randomization design for Phase 2 dose-finding trials to optimize Net Present Value (NPV) for an experimental drug. We replace the traditional fixed sample size design (Patel, et al., 2012) by this new design to see if NPV from the original paper can be improved. Comparison of the proposed design to the previous design is made via simulations using a hypothetical example based on a Diabetic Neuropathic Pain Study. Copyright © 2017 Elsevier Inc. All rights reserved.

Immunogenicity of fractional doses of tetravalent a/c/y/w135 meningococcal polysaccharide vaccine: results from a randomized non-inferiority controlled trial in Uganda.

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Philippe J Guerin

Full Text Available Neisseria meningitidis serogroup A is the main causative pathogen of meningitis epidemics in sub-Saharan Africa. In recent years, serogroup W135 has also been the cause of epidemics. Mass vaccination campaigns with polysaccharide vaccines are key elements in controlling these epidemics. Facing global vaccine shortage, we explored the use of fractional doses of a licensed A/C/Y/W135 polysaccharide meningococcal vaccine.We conducted a randomized, non-inferiority trial in 750 healthy volunteers 2-19 years old in Mbarara, Uganda, to compare the immune response of the full dose of the vaccine versus fractional doses (1/5 or 1/10. Safety and tolerability data were collected for all subjects during the 4 weeks following the injection. Pre- and post-vaccination sera were analyzed by measuring serum bactericidal activity (SBA with baby rabbit complement. A responder was defined as a subject with a > or =4-fold increase in SBA against a target strain from each serogroup and SBA titer > or =128. For serogroup W135, 94% and 97% of the vaccinees in the 1/5- and 1/10-dose arms, respectively, were responders, versus 94% in the full-dose arm; for serogroup A, 92% and 88% were responders, respectively, versus 95%. Non-inferiority was demonstrated between the full dose and both fractional doses in SBA seroresponse against serogroups W135 and Y, in total population analysis. Non-inferiority was shown between the full and 1/5 doses for serogroup A in the population non-immune prior to vaccination. Non-inferiority was not shown for any of the fractionate doses for serogroup C. Safety and tolerability data were favourable, as observed in other studies.While the advent of conjugate A vaccine is anticipated to largely contribute to control serogroup A outbreaks in Africa, the scale-up of its production will not cover the entire "Meningitis Belt" target population for at least the next 3 to 5 years. In view of the current shortage of meningococcal vaccines for Africa

Some effects of random dose measurement errors on analysis of atomic bomb survivor data

International Nuclear Information System (INIS)

Gilbert, E.S.

1985-01-01

The effects of random dose measurement errors on analyses of atomic bomb survivor data are described and quantified for several procedures. It is found that the ways in which measurement error is most likely to mislead are through downward bias in the estimated regression coefficients and through distortion of the shape of the dose-response curve. The magnitude of the bias with simple linear regression is evaluated for several dose treatments including the use of grouped and ungrouped data, analyses with and without truncation at 600 rad, and analyses which exclude doses exceeding 200 rad. Limited calculations have also been made for maximum likelihood estimation based on Poisson regression. 16 refs., 6 tabs

Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers.

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Jose Muñoz

2018-01-01

associated with BMI or weight in our study. These findings contribute to further understand the pharmacokinetic characteristics of ivermectin, highlighting its safety across different dosing regimens. They also correlate with known pharmacokinetic parameters showing stable levels of AUC and Cmax across a wide range of body weights, which justifies the strategy of fix dosing from a pharmacokinetic perspective.ClinicalTrials.gov NCT03173742.

A 12-week DBPC dose-finding study with sublingual monomeric allergoid tablets in house dust mite-allergic patients.

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Hüser, C; Dieterich, P; Singh, J; Shah-Hosseini, K; Allekotte, S; Lehmacher, W; Compalati, E; Mösges, R

2017-01-01

In sublingual immunotherapy, optimal doses are a key factor for therapeutic outcomes. The aim of this study with tablets containing carbamylated monomeric house dust mite allergoids was to determine the most effective and safe dose. In this double-blind, placebo-controlled dose-finding study, 131 patients with house dust mite-induced allergic rhinoconjunctivitis were randomized to 12-week treatments with 300 UA/day, 1000 UA/day, 2000 UA/day, 3000 UA/day or placebo. Conjunctival provocation tests (CPT) were performed before, during and after treatment. The change in mean allergic severity (primary endpoint), calculated from the severity of the CPT reaction, and the proportion of patients with an improved CPT threshold (secondary endpoint) determined the treatment effect. The mean allergic severity decreased in all groups, including the placebo group. It was lower in all active treatment groups (300 UA/day: 0.14, 1000 UA/day: 0.15, 2000 UA/day: 0.10, 3000 UA/day: 0.15) than in the placebo group (0.30). However, this difference was not statistically significant (P allergoid sublingual tablets is well tolerated and reduces the CPT reaction in house dust mite-allergic patients. © 2016 The Authors. Allergy Published by John Wiley & Sons Ltd.

GOLIMUMAB SAFETY ACCORDING TO CLINICAL FINDINGS

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G. V. Lukina

2015-01-01

Full Text Available                                                      The review analyzes trials dealing with the safety of golimumab (GLM  used in rheumatology.  This drug was the latest Contact: Galina Lukina;gvl3@yandex.ru Поступила 12.05.14tumor necrosis factor α (TNF-α inhibitor introduced  into clinical practice and therefore the estimation of its tolerability is particularly relevant. The data obtained in large-scale clinical trials suggest that GLM has a good safety profile. The most common  adverse events (AE were infections, more often mild. The rate of infections was higher with the use of GLM 100 mg than with that of 50 mg. The overall cancer rate did not increase during a follow-up of less than 160 weeks. However, the rate of lymphomas in patients receiving GLM 100 mg proved to be higher than in those taking GLM 50 mg, in the general population, and in the placebo group in particular. AE were evenly distributed among patients with rheumatoid  arthritis, psoriatic arthritis, or ankylosing spondylitis. Overall, the findings are in agreement with the data on the safety of previously used TNF-α inhibitors. No fundamentally new AE have been encountered. It is necessary to accumulate  data on the use of GLM in real clinical practice, which will be able to more objectively define its place in the current therapy of rheumatic diseases.

Erlotinib 150 mg daily plus chemotherapy in advanced pancreatic cancer: an interim safety analysis of a multicenter, randomized, cross-over phase III trial of the 'Arbeitsgemeinschaft Internistische Onkologie'.

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Boeck, Stefan; Vehling-Kaiser, Ursula; Waldschmidt, Dirk; Kettner, Erika; Märten, Angela; Winkelmann, Cornelia; Klein, Stefan; Kojouharoff, Georgi; Gauler, Thomas; Fischer von Weikersthal, Ludwig; Clemens, Michael R; Geissler, Michael; Greten, Tim F; Hegewisch-Becker, Susanna; Neugebauer, Sascha; Heinemann, Volker

2010-01-01

To date, only limited toxicity data are available for the combination of erlotinib with either capecitabine or gemcitabine as front-line therapy for advanced pancreatic cancer. Within a randomized phase III trial, 281 treatment-naive patients were randomly assigned between capecitabine (2000 mg/m/day, for 14 days, once every 3 weeks) plus erlotinib (150 mg/day, arm A) and gemcitabine (1000 mg/m as a 30-min infusion) plus erlotinib (150 mg/day, arm B). In case of treatment failure, patients were crossed over to a second-line treatment with the comparator cytostatic drug without erlotinib. The primary study endpoint was the time to treatment failure of second-line therapy (TTF2). This interim analysis of toxicity contains safety data from the first 127 randomized patients. During first-line therapy, patients received a median number of three treatment cycles (range 0-13) in both the arms. Regarding chemotherapy, a treatment delay was observed in 12% of the cycles in arm A and in 22% of the cycles in arm B. Dose reductions of the cytostatic drug were performed in 18 and 27% of treatment cycles, respectively. Erlotinib dose reductions were performed in 6 and 11% of all cycles. Grade 3/4 hematological toxicity was arms; major grade 3/4 toxicities in arms A and B were diarrhea (9 vs. 7%), skin rash (4 vs. 12%), and hand-foot syndrome (7 vs. 0%). No treatment-related death was observed. In conclusion, this interim safety analysis suggests that treatment with erlotinib 150 mg/day is feasible in combination with capecitabine or gemcitabine.

Single Dose Versus 3 Doses of Intramuscular Benzathine Penicillin for Early Syphilis in HIV: A Randomized Clinical Trial.

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Andrade, Roberto; Rodriguez-Barradas, Maria C; Yasukawa, Kosuke; Villarreal, Erick; Ross, Michael; Serpa, Jose A

2017-03-15

Patients coinfected with syphilis and human immunodeficiency virus (HIV) may have a slower decrease in rapid plasma reagin (RPR) titers. Currently a single dose of 2.4 million units of intramuscular benzathine penicillin G (BPG) is recommended for the treatment of early syphilis. Some observational studies have suggested that this regimen may lead to high failure rates in coinfected patients. We conducted an open-label randomized clinical trial to compare the efficacy of single-dose and 3-dose regimens of BPG for the treatment of early syphilis in HIV-infected individuals. RPR titers were monitored every 3 months. Treatment success was defined as a decrease in RPR titers of ≥2 dilutions (4-fold) during a 12-month follow-up period. Sixty-four patients were included. In the intention-to-treat analysis, treatment success rates were 80% (28 of 35 subjects) and 93% (27 of 29 subjects) in the single-dose and 3-dose regimens, respectively (absolute difference, 13% [95% confidence interval {CI}, -5% to 30%; P = .17). In the per-protocol analysis, success rates were 93% (27 of 29) and 100% in the single-dose and 3-dose regimens, respectively (absolute difference, 7% [95% CI, -7% to 22%]; P = .49). CD4 T-cell count, RPR titer and syphilis stage did not affect treatment results. When compared with a single dose of BPG, a 3-dose regimen did not improve syphilis serological outcomes. Our results support the Centers for Disease Control and Prevention recommendation of a single dose of BPG in HIV-infected patients with early syphilis. NCT02611765. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Comparison of the safety and immunogenicity of live attenuated and inactivated hepatitis A vaccine in healthy Chinese children aged 18 months to 16 years: results from a randomized, parallel controlled, phase IV study.

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Ma, F; Yang, J; Kang, G; Sun, Q; Lu, P; Zhao, Y; Wang, Z; Luo, J; Wang, Z

2016-09-01

For large-scale immunization of children with hepatitis A (HA) vaccines in China, accurately designed studies comparing the safety and immunogenicity of the live attenuated HA vaccine (HA-L) and inactivated HA vaccine (HA-I) are necessary. A randomized, parallel controlled, phase IV clinical trial was conducted with 6000 healthy children aged 18 months to 16 years. HA-L or HA-I was administered at a ratio of 1: 1 to randomized selected participants. The safety and immunogenicity were evaluated. Both HA-L and HA-I were well tolerated by all participants. The immunogenicity results showed that the seroconversion rates (HA-L versus HA-I: 98.0% versus 100%, respectively, p >0.05), and geometric mean concentrations in participants negative for antibodies against HA virus IgG (anti-HAV IgG) before vaccination did not differ significantly between the two types of vaccines (HA-L versus HA-I first dose: 898.9 versus 886.2 mIU/mL, respectively, p >0.05). After administration of the booster dose of HA-I, the geometric mean concentrations of anti-HAV IgG (HA-I booster dose: 2591.2 mIU/mL) was higher than that after the first dose (p children. The effects of long-term immunogenicity after natural exposure to wild-type HA virus and the possibility of mutational shifts of the live vaccine virus in the field need to be studied in more detail. Copyright © 2016. Published by Elsevier Ltd.

The efficacy and safety of multiple doses of vortioxetine for generalized anxiety disorder: a meta-analysis

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Fu J

2016-04-01

Full Text Available Jie Fu,1 Lilei Peng,2 Xiaogang Li1 1Department of Neurology, 2Department of Neurosurgery, The Affiliated Hospital of Luzhou Medical College, Luzhou, People’s Republic of China Objective: Vortioxetine is a novel antidepressant approved for the treatment of major depressive disorder by the US Food and Drug Administration in September 2013. This meta-analysis assessed the efficacy and safety of different doses of vortioxetine for generalized anxiety disorder of adults.Methods: PubMed, Cochrane Library, PsycINFO, and Clinical Trials databases were searched from 2000 through 2015. The abstracts of the annual meetings of the American Psychiatric Association and previous reviews were searched to identify additional studies. The search was limited to individual randomized controlled trials (RCTs, and there was no language restriction. Four RCTs met the selection criteria. These studies included 1,843 adult patients. Results were expressed as odds ratios (ORs and 95% confidence intervals (CIs. The data were pooled with a random-effects or fixed-effects model.Results: The results showed that multiple doses (2.5, 5, and 10 mg/d of vortioxetine did not significantly improve the generalized anxiety disorder symptoms compared to placebo (OR=1.16, 95% CI=0.84–1.60, Z=0.89, P=0.38; OR=1.41, 95% CI=0.82–2.41, Z=1.25, P=0.21; OR=1.05, 95% CI=0.76–1.46, Z=0.32, P=0.75, respectively. We measured the efficacy of 2.5 mg/d vortioxetine compared to 10 mg/d, and no significant differences were observed. The common adverse effects included nausea and headache. With increased dose, nausea was found to be more frequent in the vortioxetine (5 and 10 mg/d group (OR=2.99, 95% CI=1.31–6.84, Z=2.60, P=0.009; OR=2.80, 95% CI=1.85–4.25, Z=4.85, P<0.00001, respectively, but no significant differences were observed for headache.Conclusion: The results showed no significant improvement in the treatment of generalized anxiety disorder for vortioxetine compared to placebo

Low-Dose Daily Intake of Vitamin K(2) (Menaquinone-7) Improves Osteocalcin γ-Carboxylation: A Double-Blind, Randomized Controlled Trials.

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Inaba, Naoko; Sato, Toshiro; Yamashita, Takatoshi

2015-01-01

Vitamin K is essential for bone health, but the effects of low-dose vitamin K intake in Japanese subjects remain unclear. We investigated the effective minimum daily menaquinone-7 dose for improving osteocalcin γ-carboxylation. Study 1 was a double-blind, randomized controlled dose-finding trial; 60 postmenopausal women aged 50-69 y were allocated to one of four dosage group and consumed 0, 50, 100, or 200 μg menaquinone-7 daily for 4 wk, respectively, with a controlled diet in accordance with recommended daily intakes for 2010 in Japan. Study 2 was a double-blind, randomized placebo-controlled trial based on the results of Study 1; 120 subjects aged 20-69 y were allocated to the placebo or MK-7 group and consumed 0 or 100 μg menaquinone-7 daily for 12 wk, respectively. In both studies, circulating carboxylated osteocalcin and undercarboxylated osteocalcin were measured. The carboxylated osteocalcin/undercarboxylated osteocalcin ratio decreased significantly from baseline in the 0 μg menaquinone-7 group, in which subjects consumed the recommended daily intake of vitamin K with vitamin K1 and menaquinone-4 (Study 1). Menaquinone-7 increased the carboxylated osteocalcin/undercarboxylated osteocalcin ratio dose dependently, and significant effects were observed in both the 100 and 200 μg groups compared with the 0 μg group. Undercarboxylated osteocalcin concentrations decreased significantly, and the carboxylated osteocalcin/undercarboxylated osteocalcin ratio increased significantly in the 100 μg menaquinone-7 group compared with the placebo group (Study 2). Daily menaquinone-7 intake ≥100 μg was suggested to improve osteocalcin γ-carboxylation.

Efficacy and Safety of a Fixed-Dose Combination Therapy of Tamsulosin and Tadalafil for Patients With Lower Urinary Tract Symptoms and Erectile Dysfunction: Results of a Randomized, Double-Blinded, Active-Controlled Trial.

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Kim, Sae Woong; Park, Nam Cheol; Lee, Seung Wook; Yang, Dae Yul; Park, Jong Kwan; Moon, Du Geon; Yang, Sang-Kuk; Lee, Sung Won; Moon, Ki Hak; Ahn, Tai Young; Kim, Soo Woong; Park, Kwangsung; Min, Kweon Sik; Ryu, Ji-Kan; Son, Hankil; Jung, Jina; Hyun, Jae Seog

2017-08-01

Phosphodiesterase type 5 inhibitors and α-adrenergic blocking agents (α-blockers) are widely used for the treatment of erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). To assess the efficacy and safety of fixed-dose combinations (FDCs) of tamsulosin and tadalafil compared with tadalafil monotherapy in patients with comorbid BPH-associated LUTS and ED. A randomized, double-blinded, active-controlled trial was conducted of 510 men with BPH-associated LUTS and ED. Patients were treated with FDCs of tamsulosin 0.4 mg plus tadalafil 5 mg (FDC 0.4/5 mg), tamsulosin 0.2 mg plus tadalafil 5 mg (FDC 0.2/5 mg), or tadalafil 5 mg for a 12-week treatment period. For a subsequent 12-week extension period, the patients were administered FDC 0.4/5 mg. The primary outcomes were changes from baseline in total International Prostate Symptom Score (IPSS) and International Index of Erectile Function erectile function domain (IIEF-EF) score at week 12 to prove superiority and non-inferiority of FDCs compared with tadalafil 5 mg. The safety assessments were adverse reactions, laboratory test results, and vital signs at week 24. The mean changes in total IPSS and IIEF-EF scores were -9.46 and 9.17 for FDC 0.4/5 mg and -8.14 and 9.49 for tadalafil 5 mg, respectively, which indicated superiority in LUTS improvement (P = .0320) and non-inferiority in ED treatment with FDC 0.4/5 mg compared with tadalafil 5 mg. However, the results from FDC 0.2/5 mg failed to demonstrate superiority in LUTS improvement. No clinically significant adverse events regarding the investigational products were observed during the 24-week period. The FDC 0.4/5 mg is the first combined formulation of an α-blocker and a phosphodiesterase type 5 inhibitor that offers benefits in patient compliance and as add-on therapy in patients with comorbid BPH-associated LUTS and ED. The study clearly demonstrated the advantage of FDC 0.4/5 mg. The main

Safety and tolerability of a cell culture derived trivalent subunit inactivated influenza vaccine administered to healthy children and adolescents: A Phase III, randomized, multicenter, observer-blind study.

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Nolan, Terry; Chotpitayasunondh, Tawee; Capeding, Maria Rosario; Carson, Simon; Senders, Shelly David; Jaehnig, Peter; de Rooij, Richard; Chandra, Richa

2016-01-04

Cell culture-derived inactivated influenza vaccines (TIVc) are necessary for scale and predictability of production to meet global demand. This study compared the safety and tolerability of TIVc with an egg-derived trivalent influenza vaccine (TIVf) in 4-17 yearolds. A Phase 3 observer blind, multicenter study enrolled 2055 healthy participants randomized 2:1 to receive either TIVc or TIVf, respectively (1372 TIVc and 683 TIVf evaluable subjects). Participants received one dose each on Days 1 and 28 (4-8 year-olds not previously vaccinated [NPV]) or one dose on Day 1 (4-8 and 9-17 yearolds previously vaccinated [PV]). Solicited adverse events (AEs) occurring within 7 days after each vaccination were assessed; participants were followed up for 6 months after their last dose for safety. Most solicited and unsolicited AEs were mild to moderate with vaccine-related SAEs were reported. TIVc and TIVf were similar in percentages of participants reporting solicited reactions in 4-8 years NPV group after the 1st dose: local reactions, TIVc: 48%, TIVf: 43%; systemic reactions, TIVc: 34%, TIVf: 32%; percentages were lower following the 2nd dose in TIVc; local reactions: TIVc: 40%; TIVf: 43%; systemic reactions: TIVc: 21%; TIVf: 22%. In 4-17 years PV group, solicited reactions were lower following TIVf, local reactions: TIVc: 53%; TIVf: 43%; systemic reactions: TIVc: 37%, TIVf: 30%. Injection-site pain was the most common solicited reaction, and was similar following TIVc and TIVf in 4-8 yearolds (TIVc: 56%; TIVf: 55%), and lower following TIVf in 9-17 years group (TIVc: 52%; TIVf: 42%). Reporting of unsolicited AEs was similar for TIVc and TIVf across the two age groups. TIVc was well tolerated and had a safety and reactogenicity profile similar to that of TIVf in healthy 4-17 yearolds (NCT01857206). Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Intranasal administration of a therapeutic HIV vaccine (Vacc-4x induces dose-dependent systemic and mucosal immune responses in a randomized controlled trial.

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Kristin Brekke

Full Text Available Vacc-4x, a Gag p24-based therapeutic HIV vaccine, has been shown to reduce viral load set-points after intradermal administration. In this randomized controlled pilot study we investigate intranasal administration of Vacc-4x with Endocine as adjuvant.Safety and immunogenicity were tested in patients on effective ART. They were randomized to low, medium or high dose Vacc-4x or adjuvant alone, administered four times at weekly intervals with no booster. Vacc-4x-specific T cell responses were measured in vitro by proliferation and in vivo by a single DTH skin test at the end of study. Nasal and rectal mucosal secretions were analyzed for Vacc-4x-specific antibodies by ELISA. Immune regulation induced by Vacc-4x was assessed by functional blockade of the regulatory cytokines IL-10 and TGF-β.Vacc-4x proliferative T cell responses increased only among the vaccinated (p ≤ 0.031. The low dose group showed the greatest increase in Vacc-4x CD8+T cell responses (p = 0.037 and developed larger DTH (p = 0.005 than the adjuvant group. Rectal (distal Vacc-4x IgA and IgG antibodies also increased (p = 0.043 in this group. In contrast, the high dose generated higher nasal (local Vacc-4x IgA (p = 0.028 and serum IgG (p = 0.030 antibodies than the adjuvant. Irrespective of dose, increased Vacc-4x CD4+T cell responses were associated with low proliferation (r = -0.82, p < 0.001 and high regulation (r = 0.61, p = 0.010 at baseline.Intranasal administration of Vacc-4x with Endocine was safe and induced dose-dependent vaccine-specific T cell responses and both mucosal and systemic humoral responses. The clinical significance of dose, immune regulation and mucosal immunity warrants further investigation.ClinicalTrials.gov NCT01473810.

Subgroup analysis of patients with localized prostate cancer treated within the Dutch-randomized dose escalation trial

International Nuclear Information System (INIS)

Al-Mamgani, Abrahim; Heemsbergen, Wilma D.; Levendag, Peter C.; Lebesque, Joos V.

2010-01-01

Purpose: To investigate the effect of dose escalation within prognostic risk groups in prostate cancer. Patients and methods: Between 1997 and 2003, 664 patients with localized prostate cancer were randomly assigned to receive 68- or 78-Gy of radiotherapy. Two prognostic models were examined: a risk group model (low-, intermediate-, and high-risk) and PSA-level groupings. High-risk patients with hormonal therapy (HT) were analyzed separately. Outcome variable was freedom from failure (FFF) (clinical failure or PSA nadir + 2 μg/L). Results: In relation to the advantage of high-dose radiotherapy, intermediate-risk patients benefited most from dose escalation. However no significant heterogeneity could be demonstrated between the risk groups. For two types of PSA-level groupings: PSA 8 μg/L, the test for heterogeneity was significant (p = 0.03 and 0.05, respectively). Patients with PSA 8-18 μg/L (n = 297, HR = 0.59) derived the greatest benefit from dose escalation. No heterogeneity could be demonstrated for high-risk patients with and without HT. Conclusion: Intermediate-risk group derived the greatest benefit for dose escalation. However, from this trial no indication was found to exclude low-risk or high-risk patients from high-dose radiotherapy. Patients could be selected for high-dose radiotherapy based on PSA-level groupings: for patients with a PSA < 8 μg/L high-dose radiotherapy is probably not indicated, but should be confirmed in other randomized studies.

Randomized clinical trial to comparing efficacy of daily, weekly and monthly administration of vitamin D3.

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Takács, István; Tóth, Béla E; Szekeres, László; Szabó, Boglárka; Bakos, Bence; Lakatos, Péter

2017-01-01

The comparative efficacy and safety profiles of selected daily 1000 IU, weekly 7000 IU and monthly 30,000 IU vitamin D 3 -not previously investigated-will be evaluated. Here, a prospective, randomized clinical trial, comparing efficacy and safety of a daily single dose of 1000 IU (group A) to a once-weekly 7000 IU dose (group B), or monthly 30,000 IU dose (group C) of vitamin D 3 . The present study is a controlled, randomized, open-label, multicenter clinical trial, 3  months in duration. Sixty-four adult subjects with vitamin D deficiency (25OHD<20 ng/ml), were included according to the inclusion and exclusion criteria. Dose-responses for increases in serum vitamin 25OHD were statistically equivalent for each of the three groups: A, B and C. Outcomes were 13.0 ± 1.5; 12.6 ± 1.1 and 12.9 ± 0.9 ng/ml increases in serum 25OHD per 1000 IU, daily, weekly and monthly, respectively. The treatment of subjects with selected doses restored 25OHD values to levels above 20 ng/ml in all groups. Treatment with distinct administration frequency of vitamin D 3 did not exhibit any differences in safety parameters. The daily, weekly and monthly administrations of daily equivalent of 1000 IU of vitamin D 3 provide equal efficacy and safety profiles.

Dose assessment and approach to the safety for the public in the emergency. Proceedings

International Nuclear Information System (INIS)

Nakajima, Toshiyuki

1994-03-01

This issue is the collection of the papers presented at the 21st NIRS seminar on Dose Assessment and Approach to the Safety for the Public in the Emergency. The 16 of the presented papers are indexed individually. (J.P.N.)

BAYESIAN DATA AUGMENTATION DOSE FINDING WITH CONTINUAL REASSESSMENT METHOD AND DELAYED TOXICITY

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Liu, Suyu; Yin, Guosheng; Yuan, Ying

2014-01-01

A major practical impediment when implementing adaptive dose-finding designs is that the toxicity outcome used by the decision rules may not be observed shortly after the initiation of the treatment. To address this issue, we propose the data augmentation continual re-assessment method (DA-CRM) for dose finding. By naturally treating the unobserved toxicities as missing data, we show that such missing data are nonignorable in the sense that the missingness depends on the unobserved outcomes. The Bayesian data augmentation approach is used to sample both the missing data and model parameters from their posterior full conditional distributions. We evaluate the performance of the DA-CRM through extensive simulation studies, and also compare it with other existing methods. The results show that the proposed design satisfactorily resolves the issues related to late-onset toxicities and possesses desirable operating characteristics: treating patients more safely, and also selecting the maximum tolerated dose with a higher probability. The new DA-CRM is illustrated with two phase I cancer clinical trials. PMID:24707327

Findings from a Randomized Controlled Trial of Fecal Transplantation for Patients with Ulcerative Colitis

NARCIS (Netherlands)

Rossen, N.G.; Fuentes Enriquez de Salamanca, S.; Spek, van der M.J.; Tijssen, J.; Hartman, J.H.A.; Duflou, A.; Löwenberg, M.; Brink, van den G.R.; Mathus-Vliegen, E.M.; Vos, de W.M.; Zoetendal, E.G.; Haens, D' G.R.; Ponsioen, C.Y.

2015-01-01

BACKGROUND: & Aims: Several case series have reported the effects of fecal microbiota transplantation (FMT) for ulcerative colitis (UC). We assessed the efficacy and safety of FMT for patients with UC in a double-blind randomized trial. METHODS: Patients with mild to moderately active UC (n=50)

Long-Term Effectiveness and Safety of Dexmethylphenidate Extended-Release Capsules in Adult ADHD

Science.gov (United States)

Adler, Lenard A.; Spencer, Thomas; McGough, James J.; Jiang, Hai; Muniz, Rafael

2009-01-01

Objective: This study evaluates dexmethylphenidate extended release (d-MPH-ER) in adults with ADHD. Method: Following a 5-week, randomized, controlled, fixed-dose study of d-MPH-ER 20 to 40 mg/d, 170 adults entered a 6-month open-label extension (OLE) to assess long-term safety, with flexible dosing of 20 to 40 mg/d. Exploratory effectiveness…

To evaluate efficacy and safety of amphotericin B in two different doses in the treatment of post kala-azar dermal leishmaniasis (PKDL.

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Vidya Nand Rabi Das

Full Text Available Post kala-azar dermal leishmaniasis (PKDL is a skin disorder that usually occurs among patients with a past history of visceral leishmaniasis (VL. Cases are also reported without a history of VL. There is no satisfactory treatment regimen available at present. We aimed to compare the efficacy and safety of amphotericin B in two different doses (0.5mg/kg vs 1mg/kg in a prospective randomized trial in 50 PKDL patients.In this open label study 50 patients with PKDL, aged between 5-60 years were randomized in two groups. Group A received amphotericin B in the dose of 0.5 mg/kg in 5% dextrose, daily for 20 infusions for 3 courses at an interval of 15 days between each course and Group B received amphotericin B in the dose of 1mg/kg in 5% dextrose on alternate days, 20 infusions for 3 courses an interval of 15 days between each course and followed up for one year.A total of 50 patients were enrolled, 25 in each of group A and group B. Two patients lost to follow up and three patients withdrew consent due to adverse events. The initial cure rate was 92% in group A and 88% in group B by intention to treat analysis and final cure rate by per protocol analysis was 95.65% and 95.45% in group A and group B respectively. Two patients each from either group relapsed. Nephrotoxicity was the most common adverse event occurring in both the groups.The lower dose appears to have fewer adverse events however, nephrotoxicity remains a problem in both regimens. The 0.5mg/kg regimen may be considered instead of the higher dosage however safer treatments remain critical for PKDL treatment.

Tailored Rabbit Antithymocyte Globulin Induction Dosing for Kidney Transplantation

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Namita Singh, MD

2018-02-01

Conclusions. The novel findings of the current study include peripheral administration, reduced dosing, favorable safety, excellent allograft outcomes, and clear associative data regarding reduced costs and length of stay.

Preliminary clinical findings on NEUMUNE as a potential treatment for acute radiation syndrome

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Stickney, Dwight R; Groothuis, Jessie R; Ahlem, Clarence; Kennedy, Mike; Miller, Barry S; Onizuka-Handa, Nanette; Schlangen, Karen M; Destiche, Daniel; Reading, Chris; Garsd, Armando; Frincke, James M [Harbor Biosciences, 9171 Towne Centre Drive, Suite 180, San Diego, CA 92122 (United States)

2010-12-01

5-androstenediol (5-AED) has been advanced as a possible countermeasure for treating the haematological component of acute radiation syndrome (ARS). It has been used in animal models to stimulate both innate and adaptive immunity and treat infection and radiation-induced immune suppression. We here report on the safety, tolerability and haematologic activity of 5-AED in four double-blinded, randomized, placebo-controlled studies on healthy adults including elderly subjects. A 5-AED injectable suspension formulation (NEUMUNE) or placebo was administered intramuscularly as either a single injection, or once daily for five consecutive days at doses of 50, 100, 200 or 400 mg. Subjects (n = 129) were randomized to receive NEUMUNE (n = 95) or the placebo (n = 34). NEUMUNE was generally well-tolerated; the most frequent adverse events were local injection site reactions (n = 104, 81%) that were transient, dose-volume dependent, mild to moderate in severity, and that resolved over the course of the study. Blood chemistries revealed a transient increase (up to 28%) in creatine phosphokinase and C-reactive protein levels consistent with intramuscular injection and injection site irritation. The blood concentration profile of 5-AED is consistent with a depot formulation that increases in disproportionate increments following each dose. NEUMUNE significantly increased circulating neutrophils (p < 0.001) and platelets (p < 0.001) in the peripheral blood of adult and elderly subjects. A dose-response relationship was identified. Findings suggest that parenteral administration of 5-AED in aqueous suspension may be a safe and effective means to stimulate innate immunity and alleviate neutropenia and thrombocytopenia associated with ARS.

Preliminary clinical findings on NEUMUNE as a potential treatment for acute radiation syndrome

International Nuclear Information System (INIS)

Stickney, Dwight R; Groothuis, Jessie R; Ahlem, Clarence; Kennedy, Mike; Miller, Barry S; Onizuka-Handa, Nanette; Schlangen, Karen M; Destiche, Daniel; Reading, Chris; Garsd, Armando; Frincke, James M

2010-01-01

5-androstenediol (5-AED) has been advanced as a possible countermeasure for treating the haematological component of acute radiation syndrome (ARS). It has been used in animal models to stimulate both innate and adaptive immunity and treat infection and radiation-induced immune suppression. We here report on the safety, tolerability and haematologic activity of 5-AED in four double-blinded, randomized, placebo-controlled studies on healthy adults including elderly subjects. A 5-AED injectable suspension formulation (NEUMUNE) or placebo was administered intramuscularly as either a single injection, or once daily for five consecutive days at doses of 50, 100, 200 or 400 mg. Subjects (n = 129) were randomized to receive NEUMUNE (n = 95) or the placebo (n = 34). NEUMUNE was generally well-tolerated; the most frequent adverse events were local injection site reactions (n = 104, 81%) that were transient, dose-volume dependent, mild to moderate in severity, and that resolved over the course of the study. Blood chemistries revealed a transient increase (up to 28%) in creatine phosphokinase and C-reactive protein levels consistent with intramuscular injection and injection site irritation. The blood concentration profile of 5-AED is consistent with a depot formulation that increases in disproportionate increments following each dose. NEUMUNE significantly increased circulating neutrophils (p < 0.001) and platelets (p < 0.001) in the peripheral blood of adult and elderly subjects. A dose-response relationship was identified. Findings suggest that parenteral administration of 5-AED in aqueous suspension may be a safe and effective means to stimulate innate immunity and alleviate neutropenia and thrombocytopenia associated with ARS.

Safety analysis of holmium-166 microsphere scout dose imaging during radioembolisation work-up. A cohort study

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Braat, Arthur J.A.T.; Prince, Jip F.; Rooij, Rob van; Bruijnen, Rutger C.G.; Bosch, Maurice A.A.J. van den; Lam, Marnix G.E.H. [University Medical Center Utrecht, Department of Radiology and Nuclear Medicine, Utrecht (Netherlands)

2018-03-15

Radioembolisation is generally preceded by a scout dose of technetium-99m-macroaggregated albumin to estimate extrahepatic shunting of activity. Holmium-166 microspheres can be used as a scout dose (±250 MBq) and as a therapeutic dose. The general toxicity of a holmium-166 scout dose ({sup 166}Ho-SD) and safety concerns of an accidental extrahepatic deposition of {sup 166}Ho-SD were investigated. All patients who received a {sup 166}Ho-SD in our institute were reviewed for general toxicity and extrahepatic depositions. The absorbed dose in extrahepatic tissue was calculated on SPECT/CT and correlated to clinical toxicities. In total, 82 patients were included. No relevant clinical toxicity occurred. Six patients had an extrahepatic deposition of {sup 166}Ho-SD (median administered activity 270 MBq). The extrahepatic depositions (median activity 3.7 MBq) were located in the duodenum (3x), gastric fundus, falciform ligament and the lesser curvature of the stomach, and were deposited in a median volume of 15.3 ml, which resulted in an estimated median absorbed dose of 3.6 Gy (range 0.3-13.8 Gy). No adverse events related to the extrahepatic deposition of the {sup 166}Ho-SD occurred after a median follow-up of 4 months (range 1-12 months). These results support the safety of 250 MBq {sup 166}Ho-SD in a clinical setting. (orig.)

Therapeutic Vaccine for Genital Herpes Simplex Virus-2 Infection: Findings From a Randomized Trial.

Science.gov (United States)

Bernstein, David I; Wald, Anna; Warren, Terri; Fife, Kenneth; Tyring, Stephen; Lee, Patricia; Van Wagoner, Nick; Magaret, Amalia; Flechtner, Jessica B; Tasker, Sybil; Chan, Jason; Morris, Amy; Hetherington, Seth

2017-03-15

Genital herpes simplex virus type 2 (HSV-2) infection causes recurrent lesions and frequent viral shedding. GEN-003 is a candidate therapeutic vaccine containing HSV-2 gD2∆TMR and ICP4.2, and Matrix-M2 adjuvant. Persons with genital herpes were randomized into 3 dose cohorts to receive 3 intramuscular doses 21 days apart of 10 µg, 30 µg, or 100 µg of GEN-003, antigens without adjuvant, or placebo. Participants obtained genital swab specimens twice daily for HSV-2 detection and monitored genital lesions for 28-day periods at baseline and at intervals after the last dose. One hundred and thirty-four persons received all 3 doses. Reactogenicity was associated with adjuvant but not with antigen dose or dose number. No serious adverse events were attributed to GEN-003. Compared with baseline, genital HSV-2 shedding rates immediately after dosing were reduced with GEN-003 (from 13.4% to 6.4% for 30 μg [P genital HSV shedding and lesion rates. NCT01667341 (funded by Genocea). © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Randomized multicenter trial on the effect of radiotherapy for plantar Fasciitis (painful heel spur) using very low doses – a study protocol

International Nuclear Information System (INIS)

Niewald, Marcus; Seegenschmiedt, M Heinrich; Micke, Oliver; Gräber, Stefan

2008-01-01

A lot of retrospective data concerning the effect of radiotherapy on the painful heel spur (plantar fasciitis) is available in the literature. Nevertheless, a randomized proof of this effect is still missing. Thus, the GCGBD (German cooperative group on radiotherapy for benign diseases) of the DEGRO (German Society for Radiation Oncology) decided to start a randomized multicenter trial in order to find out if the effect of a conventional total dose is superior compared to that of a very low dose. In a prospective, controlled and randomized phase III trial two radiotherapy schedules are to be compared: standard arm: total dose 6.0 Gy in single fractions of 1.0 Gy applied twice a week experimental arm: total dose 0.6 Gy in single fractions of 0.1 Gy applied twice a week (acting as a placebo) Patients aged over 40 years who have been diagnosed clinically and radiologically to be suffering from a painful heel spur for at least six months can be included. Former trauma, surgery or radiotherapy to the heel are not allowed nor are patients with a severe psychiatric disease or women during pregnancy and breastfeeding. According to the statistical power calculation 100 patients have to be enrolled into each arm. After having obtaining a written informed consent a patient is randomized by the statistician to one of the arms mentioned above. After radiotherapy, the patients are seen first every six weeks, then regularly up to 48 months after therapy, they additionally receive a questionnaire every six weeks after the follow-up examinations. The effect is measured using several target variables (scores): Calcaneodynia-score according to Rowe et al., SF-12 score, and visual analogue scale of pain. The most important endpoint is the pain relief three months after therapy. Patients with an inadequate result are offered a second radiotherapy series applying the standard dose (equally in both arms). This trial protocol has been approved by the expert panel of the DEGRO as well as

Randomized multicenter trial on the effect of radiotherapy for plantar Fasciitis (painful heel spur using very low doses – a study protocol

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Micke Oliver

2008-09-01

Full Text Available Abstract Background A lot of retrospective data concerning the effect of radiotherapy on the painful heel spur (plantar fasciitis is available in the literature. Nevertheless, a randomized proof of this effect is still missing. Thus, the GCGBD (German cooperative group on radiotherapy for benign diseases of the DEGRO (German Society for Radiation Oncology decided to start a randomized multicenter trial in order to find out if the effect of a conventional total dose is superior compared to that of a very low dose. Methods/Design In a prospective, controlled and randomized phase III trial two radiotherapy schedules are to be compared: standard arm: total dose 6.0 Gy in single fractions of 1.0 Gy applied twice a week experimental arm: total dose 0.6 Gy in single fractions of 0.1 Gy applied twice a week (acting as a placebo Patients aged over 40 years who have been diagnosed clinically and radiologically to be suffering from a painful heel spur for at least six months can be included. Former trauma, surgery or radiotherapy to the heel are not allowed nor are patients with a severe psychiatric disease or women during pregnancy and breastfeeding. According to the statistical power calculation 100 patients have to be enrolled into each arm. After having obtaining a written informed consent a patient is randomized by the statistician to one of the arms mentioned above. After radiotherapy, the patients are seen first every six weeks, then regularly up to 48 months after therapy, they additionally receive a questionnaire every six weeks after the follow-up examinations. The effect is measured using several target variables (scores: Calcaneodynia-score according to Rowe et al., SF-12 score, and visual analogue scale of pain. The most important endpoint is the pain relief three months after therapy. Patients with an inadequate result are offered a second radiotherapy series applying the standard dose (equally in both arms. This trial protocol has been

Safety and pharmacodynamics of dalazatide, a Kv1.3 channel inhibitor, in the treatment of plaque psoriasis: A randomized phase 1b trial.

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Eric J Tarcha

Full Text Available Dalazatide is a specific inhibitor of the Kv1.3 potassium channel. The expression and function of Kv1.3 channels are required for the function of chronically activated memory T cells, which have been shown to be key mediators of autoimmune diseases, including psoriasis.The primary objective was to evaluate the safety of repeat doses of dalazatide in adult patients with mild-to-moderate plaque psoriasis. Secondary objectives were to evaluate clinical proof of concept and the effects of dalazatide on mediators of inflammation in the blood and on chronically activated memory T cell populations.Patients (n = 24 were randomized 5:5:2 to receive dalazatide at 30 mcg/dose, 60 mcg/dose, or placebo twice weekly by subcutaneous injection (9 doses total. Safety was assessed on the basis of physical and neurological examination and laboratory testing. Clinical assessments included body-surface area affected, Psoriasis Area and Severity Index (PASI, and investigator and patient questionnaires.The most common adverse events were temporary mild (Grade 1 hypoesthesia (n = 20; 75% placebo, 85% dalazatide and paresthesia (n = 15; 25% placebo, 70% dalazatide involving the hands, feet, or perioral area. Nine of 10 patients in the 60 mcg/dose group had a reduction in their PASI score between baseline and Day 32, and the mean reduction in PASI score was significant in this group (P < 0.01. Dalazatide treatment reduced the plasma levels of multiple inflammation markers and reduced the expression of T cell activation markers on peripheral blood memory T cells.The study was small and drug treatment was for a short duration (4 weeks.This study indicates that dalazatide is generally well tolerated and can improve psoriatic skin lesions by modulating T cell surface and activation marker expression and inhibiting mediators of inflammation in the blood. Larger studies of longer duration are warranted.

Personalized versus standardized dosing strategies for the treatment of childhood amblyopia: study protocol for a randomized controlled trial.

Science.gov (United States)

Moseley, Merrick J; Wallace, Michael P; Stephens, David A; Fielder, Alistair R; Smith, Laura C; Stewart, Catherine E

2015-04-25

Amblyopia is the commonest visual disorder of childhood in Western societies, affecting, predominantly, spatial visual function. Treatment typically requires a period of refractive correction ('optical treatment') followed by occlusion: covering the nonamblyopic eye with a fabric patch for varying daily durations. Recent studies have provided insight into the optimal amount of patching ('dose'), leading to the adoption of standardized dosing strategies, which, though an advance on previous ad-hoc regimens, take little account of individual patient characteristics. This trial compares the effectiveness of a standardized dosing strategy (that is, a fixed daily occlusion dose based on disease severity) with a personalized dosing strategy (derived from known treatment dose-response functions), in which an initially prescribed occlusion dose is modulated, in a systematic manner, dependent on treatment compliance. A total of 120 children aged between 3 and 8 years of age diagnosed with amblyopia in association with either anisometropia or strabismus, or both, will be randomized to receive either a standardized or a personalized occlusion dose regimen. To avoid confounding by the known benefits of refractive correction, participants will not be randomized until they have completed an optical treatment phase. The primary study objective is to determine whether, at trial endpoint, participants receiving a personalized dosing strategy require fewer hours of occlusion than those in receipt of a standardized dosing strategy. Secondary objectives are to quantify the relationship between observed changes in visual acuity (logMAR, logarithm of the Minimum Angle of Resolution) with age, amblyopia type, and severity of amblyopic visual acuity deficit. This is the first randomized controlled trial of occlusion therapy for amblyopia to compare a treatment arm representative of current best practice with an arm representative of an entirely novel treatment regimen based on statistical

Safety, tolerability, pharmacokinetics, and pharmacodynamics of novel glucokinase activator HMS5552: results from a first-in-human single ascending dose study

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Xu HR

2016-05-01

Full Text Available Hongrong Xu,1,* Lei Sheng,1,* Weili Chen,1 Fei Yuan,1 Mengjie Yang,1 Hui Li,1 Xuening Li,1 John Choi,2 Guiyu Zhao,2 Tianxin Hu,2 Yongguo Li,2 Yi Zhang,2 Li Chen2 1Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, 2Department of Clinical Research & Development, Hua Medicine, Shanghai, People’s Republic of China *These authors have contributed equally to this work Background: HMS5552, a novel fourth-generation glucokinase (GK activator, has demonstrated promising effects on glycemic control in preclinical models of type 2 diabetes. This single ascending dose study was conducted to investigate the safety, tolerability, pharmacokinetics (PK, and pharmacodynamics (PD of HMS5552 during its first-in-human exposure.Methods: Sixty healthy subjects were enrolled. In each of six dose-cohorts (5, 10, 15, 25, 35, and 50 mg, ten subjects were randomized with eight subjects receiving the same cohort-dose of HMS5552 and two receiving placebo. Plasma HMS5552 exposure, glucose, and insulin were measured repeatedly during fasting and after a standardized meal. Assessment included safety, PK, and PD endpoints.Results: HMS5552 showed dose-proportional increases in area under the curve 0 to the last quantifiable concentration (AUC0–t and maximum plasma concentration (Cmax. Slopes estimated by linear regression for AUC0–t and Cmax were ~1.0 (0.932 and 0.933, respectively. Geometric mean elimination half-life ranged from 4.48 to 7.51 hours and apparent clearance ranged from 11.5 to 13.1 L/h across all doses. No significant sex effect was observed in PK parameters. HMS5552 also demonstrated dose-related PD responses in terms of maximum glucose change from baseline (% and mean glucose area under effect curve 0–4 hours change from baseline (% (P<0.001. Fifteen adverse events were reported by nine subjects (ten with HMS5552 and five with the placebo. All adverse events were mild in intensity and resolved without any treatment

Findings From a Randomized Controlled Trial of Fecal Transplantation for Patients With Ulcerative Colitis

NARCIS (Netherlands)

Rossen, Noortje G.; Fuentes, Susana; van der Spek, Mirjam J.; Tijssen, Jan G.; Hartman, Jorn H. A.; Duflou, Ann; Löwenberg, Mark; van den Brink, Gijs R.; Mathus-Vliegen, Elisabeth M. H.; de Vos, Willem M.; Zoetendal, Erwin G.; D'Haens, Geert R.; Ponsioen, Cyriel Y.

2015-01-01

Several case series have reported the effects of fecal microbiota transplantation (FMT) for ulcerative colitis (UC). We assessed the efficacy and safety of FMT for patients with UC in a double-blind randomized trial. Patients with mild to moderately active UC (n = 50) were assigned to groups that

Medium doses of daily vitamin D decrease falls and higher doses of daily vitamin D3 increase falls: A randomized clinical trial.

Science.gov (United States)

Smith, Lynette M; Gallagher, J Christopher; Suiter, Corinna

2017-10-01

Falls are a serious health problem in the aging population. Because low levels of vitamin D have been associated with increased fall rates, many trials have been performed with vitamin D; two meta-analyses showed either a small effect or no effect of vitamin D on falls. We conducted a study of the effect of vitamin D on serum 25 hydroxyvitamin D (25OHD) and data on falls was collected as a secondary outcome. In a 12-month double blind randomized placebo trial, elderly women, mean age 66 years, were randomized to one of seven daily oral doses of vitamin D or placebo. The main inclusion criterion for study was a baseline serum 25OHDvitamin D on falls followed a U-shaped curve whether analyzed by dose or serum 25OHD levels. There was no decrease in falls on low vitamin D doses 400, 800 IU, a significant decrease on medium doses 1600, 2400,3200 IU (p=0.020) and no decrease on high doses 4000, 4800 IU compared to placebo (p=0.55). When compared to 12-month serum 25OHD quintiles, the faller rate was 60% in the lowest quintile <25ng/ml (<50nmol/L), 21% in the low middle quintile 32-38ng/ml (80-95nmo/L), 72% in the high middle quintile 38-46ng/ml (95-115nmo/L) and 45% in the highest quintile 46-66ng/ml (115-165nmol/L). In the subgroup with a fall history, fall rates were 68% on low dose, 27% on medium doses and 100% on higher doses. Fall rates on high doses were increased compared to medium doses (Odds Ratio 5.6.95% CI: 2.1-14.8). In summary, the maximum decrease in falls corresponds to a 12- month serum 25OHD of 32-38ng/ml (80-95nmol/L) and faller rates increase as serum 25OHD exceed 40-45ng/ml (100-112.5nmol/L). The Tolerable upper limit (TUL) recently increased in 2010 from 2000 to 4000 IU/day may need to be reduced in elderly women especially in those with a fall history. Copyright © 2017 Elsevier Ltd. All rights reserved.

Early Caffeine and Weaning from Mechanical Ventilation in Preterm Infants: A Randomized, Placebo-Controlled Trial.

Science.gov (United States)

Amaro, Cynthia M; Bello, Jose A; Jain, Deepak; Ramnath, Alexandra; D'Ugard, Carmen; Vanbuskirk, Silvia; Bancalari, Eduardo; Claure, Nelson

2018-05-01

To evaluate in a randomized, double-blind, placebo-controlled trial the effect of early caffeine on the age of first successful extubation in preterm infants. Preterm infants born at 23-30 weeks of gestation requiring mechanical ventilation in the first 5 postnatal days were randomized to receive a 20 mg/kg loading dose followed by 5 mg/kg/day of caffeine or placebo until considered ready for extubation. The placebo group received a blinded loading dose of caffeine before extubation. Infants were randomized to receive caffeine (n = 41) or placebo (n = 42). Age at first successful extubation did not differ between early caffeine (median, 24 days; IQR, 10-41 days) and control groups (median, 20 days; IQR, 9-43 days; P = .7). An interim analysis at 75% enrollment showed a trend toward higher mortality in 1 of the groups and the data safety and monitoring board recommended stopping the trial. Unblinded analysis revealed mortality did not differ significantly between the early caffeine (9 [22%]) and control groups (5 [12%]; P = .22). Early initiation of caffeine in this group of premature infants did not reduce the age of first successful extubation. A nonsignificant trend toward higher mortality in the early caffeine group led to a cautious decision to stop the trial. These findings suggest caution with early use of caffeine in mechanically ventilated preterm infants until more efficacy and safety data become available. ClinicalTrials.gov: NCT01751724. Copyright © 2018 Elsevier Inc. All rights reserved.

Efficacy of praziquantel against Schistosoma mekongi and Opisthorchis viverrini: a randomized, single-blinded dose-comparison trial.

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Leonore Lovis

Full Text Available BACKGROUND: Schistosomiasis and opisthorchiasis are of public health importance in Southeast Asia. Praziquantel (PZQ is the drug of choice for morbidity control but few dose comparisons have been made. METHODOLOGY: Ninety-three schoolchildren were enrolled in an area of Lao PDR where Schistosoma mekongi and Opisthorchis viverrini coexist for a PZQ dose-comparison trial. Prevalence and intensity of infections were determined by a rigorous diagnostic effort (3 stool specimens, each examined with triplicate Kato-Katz before and 28-30 days after treatment. Ninety children with full baseline data were randomized to receive PZQ: the 40 mg/kg standard single dose (n = 45 or a 75 mg/kg total dose (50 mg/kg+25 mg/kg, 4 hours apart; n = 45. Adverse events were assessed at 3 and 24 hours posttreatment. PRINCIPAL FINDINGS: Baseline infection prevalence of S. mekongi and O. viverrini were 87.8% and 98.9%, respectively. S. mekongi cure rates were 75.0% (95% confidence interval (CI: 56.6-88.5% and 80.8% (95% CI: 60.6-93.4% for 40 mg/kg and 75 mg/kg PZQ, respectively (P = 0.60. O. viverrini cure rates were significantly different at 71.4% (95% CI: 53.4-84.4% and 96.6% (95% CI: not defined, respectively (P = 0.009. Egg reduction rates (ERRs against O. viverrini were very high for both doses (>99%, but slightly lower for S. mekongi at 40 mg/kg (96.4% vs. 98.1% and not influenced by increasing diagnostic effort. O. viverrini cure rates would have been overestimated and no statistical difference between doses found if efficacy was based on a minimum sampling effort (single Kato-Katz before and after treatment. Adverse events were common (96%, mainly mild with no significant differences between the two treatment groups. CONCLUSIONS/SIGNIFICANCE: Cure rate from the 75 mg/kg PZQ dose was more efficacious than 40 mg/kg against O. viverrini but not against S. mekongi infections, while ERRs were similar for both doses. TRIAL REGISTRATION: Controlled

Evaluating a Website to Teach Children Safety with Dogs: A Randomized Controlled Trial

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David C. Schwebel

2016-12-01

Full Text Available Dog bites represent a significant threat to child health. Theory-driven interventions scalable for broad dissemination are sparse. A website was developed to teach children dog safety via increased knowledge, improved cognitive skills in relevant domains, and increased perception of vulnerability to bites. A randomized controlled trial was conducted with 69 children aged 4–5 randomly assigned to use the dog safety website or a control transportation safety website for ~3 weeks. Assessment of dog safety knowledge and behavior plus skill in three relevant cognitive constructs (impulse control, noticing details, and perspective-taking was conducted both at baseline and following website use. The dog safety website incorporated interactive games, instructional videos including testimonials, a motivational rewards system, and messaging to parents concerning child lessons. Our results showed that about two-thirds of the intervention sample was not adherent to website use at home, so both intent-to-treat and per-protocol analyses were conducted. Intent-to-treat analyses yielded mostly null results. Per-protocol analyses suggested children compliant to the intervention protocol scored higher on knowledge and recognition of safe behavior with dogs following the intervention compared to the control group. Adherent children also had improved scores post-intervention on the cognitive skill of noticing details compared to the control group. We concluded that young children’s immature cognition can lead to dog bites. Interactive eHealth training on websites shows potential to teach children relevant cognitive and safety skills to reduce risk. Compliance to website use is a challenge, and some relevant cognitive skills (e.g., noticing details may be more amenable to computer-based training than others (e.g., impulse control.

Comparison of image quality and visibility of normal and abnormal findings at submillisievert chest CT using filtered back projection, iterative model reconstruction (IMR) and iDose{sup 4}™

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Laqmani, Azien, E-mail: a.laqmani@uke.de [Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg (Germany); Avanesov, Maxim; Butscheidt, Sebastian; Kurfürst, Maximilian [Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg (Germany); Sehner, Susanne [Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg (Germany); Schmidt-Holtz, Jakob; Derlin, Thorsten; Behzadi, Cyrus [Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg (Germany); Nagel, Hans D. [Science & Technology for Radiology, Fritz-Reuter-Weg 5f, 21244 Buchholz, Germany, (Germany); Adam, Gerhard; Regier, Marc [Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg (Germany)

2016-11-15

Objective: To compare both image quality and visibility of normal and abnormal findings at submillisievert chest CT (smSv-CT) using filtered back projection (FBP) and the two different iterative reconstruction (IR) techniques iterative model reconstruction (IMR) and iDose{sup 4}™. Materials and methods: This institutional review board approved study was based on retrospective interpretation of clinically indicated acquired data. The requirement to obtain informed consent was waived. 81 patients with suspected pneumonia underwent smSv-CT (Brilliance iCT, Philips Healthcare; mean effective dose: 0.86 ± 0.2 mSv). Data were reconstructed using FBP and two different IR techniques iDose{sup 4}™ and IMR (Philips Healthcare) at various iteration levels. Objective image noise (OIN) was measured. Two experienced readers independently assessed all images for image noise, image appearance and visibility of normal anatomic and abnormal findings. A random intercept model was used for statistical analysis. Results: Compared to FBP and iDose{sup 4}™, IMR reduced OIN up to 88% and 72%, respectively (p < 0.001). A mild blotchy image appearance was seen in IMR images, affecting diagnostic confidence. iDose{sup 4}™ images provided satisfactory to good image quality for visibility of normal and abnormal findings and were superior to FBP (p < 0.001). IMR images were significantly inferior for visibility of normal structures compared to iDose{sup 4}™, while being superior for visibility of abnormal findings except for reticular pattern (p < 0.001). Conclusion: IMR results for visibility of normal and abnormal lung findings are heterogeneous, indicating that IMR may not represent a priority technique for clinical routine. iDose{sup 4}™ represents a suitable method for evaluation of lung tissue at submillisievert chest CT.

Study on transport safety of refresh MOX fuel. Radiation dose from package hypothetically submerged into sea

International Nuclear Information System (INIS)

Tsumune, Daisuke; Suzuki; Hiroshi; Saegusa, Toshiari; Maruyama, Koki; Ito, Chihiro; Watabe, Naoto

1999-01-01

The sea transport of fresh MOX fuel from Europe to Japan is under planning. For the structure and equipment of transport ships for fresh MOX fuels, there is a special safety standard called the INF Code of IMO (International Maritime Organization). For transport of radioactive materials, there is a safety standard stipulated in Regulations for the Safe Transport of Radioactive Material issued by IAEA (International Atomic Energy Agency). Under those code and standard, fresh MOX fuel will be transported safely on the sea. However, a dose assessment has been made by assuming that a fresh MOX fuel package might be sunk into the sea by unexpected reasons. In the both cases for a package sunk at the coastal region and for that sunk at the ocean, the evaluated result of the dose equivalent by radiation exposure to the public are far below the dose equivalent limit of the ICRP recommendation (1 mSv/year). (author)

Effect of reduced dose schedules and intramuscular injection of anthrax vaccine adsorbed on immunological response and safety profile: a randomized trial.

Science.gov (United States)

Wright, Jennifer G; Plikaytis, Brian D; Rose, Charles E; Parker, Scott D; Babcock, Janiine; Keitel, Wendy; El Sahly, Hana; Poland, Gregory A; Jacobson, Robert M; Keyserling, Harry L; Semenova, Vera A; Li, Han; Schiffer, Jarad; Dababneh, Hanan; Martin, Sandra K; Martin, Stacey W; Marano, Nina; Messonnier, Nancy E; Quinn, Conrad P

2014-02-12

We evaluated an alternative administration route, reduced schedule priming series, and increased intervals between booster doses for anthrax vaccine adsorbed (AVA). AVA's originally licensed schedule was 6 subcutaneous (SQ) priming injections administered at months (m) 0, 0.5, 1, 6, 12 and 18 with annual boosters; a simpler schedule is desired. Through a multicenter randomized, double blind, non-inferiority Phase IV human clinical trial, the originally licensed schedule was compared to four alternative and two placebo schedules. 8-SQ group participants received 6 SQ injections with m30 and m42 "annual" boosters; participants in the 8-IM group received intramuscular (IM) injections according to the same schedule. Reduced schedule groups (7-IM, 5-IM, 4-IM) received IM injections at m0, m1, m6; at least one of the m0.5, m12, m18, m30 vaccine doses were replaced with saline. All reduced schedule groups received a m42 booster. Post-injection blood draws were taken two to four weeks following injection. Non-inferiority of the alternative schedules was compared to the 8-SQ group at m2, m7, and m43. Reactogenicity outcomes were proportions of injection site and systemic adverse events (AEs). The 8-IM group's m2 response was non-inferior to the 8-SQ group for the three primary endpoints of anti-protective antigen IgG geometric mean concentration (GMC), geometric mean titer, and proportion of responders with a 4-fold rise in titer. At m7 anti-PA IgG GMCs for the three reduced dosage groups were non-inferior to the 8-SQ group GMCs. At m43, 8-IM, 5-IM, and 4-IM group GMCs were superior to the 8-SQ group. Solicited injection site AEs occurred at lower proportions in the IM group compared to SQ. Route of administration did not influence the occurrence of systemic AEs. A 3 dose IM priming schedule with doses administered at m0, m1, and m6 elicited long term immunological responses and robust immunological memory that was efficiently stimulated by a single booster vaccination at

SU-F-BRD-09: A Random Walk Model Algorithm for Proton Dose Calculation

International Nuclear Information System (INIS)

Yao, W; Farr, J

2015-01-01

Purpose: To develop a random walk model algorithm for calculating proton dose with balanced computation burden and accuracy. Methods: Random walk (RW) model is sometimes referred to as a density Monte Carlo (MC) simulation. In MC proton dose calculation, the use of Gaussian angular distribution of protons due to multiple Coulomb scatter (MCS) is convenient, but in RW the use of Gaussian angular distribution requires an extremely large computation and memory. Thus, our RW model adopts spatial distribution from the angular one to accelerate the computation and to decrease the memory usage. From the physics and comparison with the MC simulations, we have determined and analytically expressed those critical variables affecting the dose accuracy in our RW model. Results: Besides those variables such as MCS, stopping power, energy spectrum after energy absorption etc., which have been extensively discussed in literature, the following variables were found to be critical in our RW model: (1) inverse squared law that can significantly reduce the computation burden and memory, (2) non-Gaussian spatial distribution after MCS, and (3) the mean direction of scatters at each voxel. In comparison to MC results, taken as reference, for a water phantom irradiated by mono-energetic proton beams from 75 MeV to 221.28 MeV, the gamma test pass rate was 100% for the 2%/2mm/10% criterion. For a highly heterogeneous phantom consisting of water embedded by a 10 cm cortical bone and a 10 cm lung in the Bragg peak region of the proton beam, the gamma test pass rate was greater than 98% for the 3%/3mm/10% criterion. Conclusion: We have determined key variables in our RW model for proton dose calculation. Compared with commercial pencil beam algorithms, our RW model much improves the dose accuracy in heterogeneous regions, and is about 10 times faster than MC simulations

Immunogenicity and Safety of a Booster Injection of DTap-IPV//Hib (Pentaxim) Administered Concomitantly With Tetravalent Dengue Vaccine in Healthy Toddlers 15-18 Months of Age in Mexico: A Randomized Trial.

Science.gov (United States)

Melo, Flor Irene Rodriguez; Morales, José Juan Renteria; De Los Santos, Abiel Homero Mascareñas; Rivas, Enrique; Vigne, Claire; Noriega, Fernando

2017-06-01

The live, attenuated, tetravalent dengue vaccine (CYD-TDV) is licensed in a number of dengue endemic countries for individuals ≥9 years of age. Before the integration of any vaccine into childhood vaccination schedules, a lack of immune interference and acceptable safety when coadministered with other recommended vaccines should be demonstrated. This randomized, multi-center phase III trial was conducted in Mexico. Healthy toddlers (n = 732) received a booster dose of a licensed pentavalent combination vaccine [diphtheria, tetanus, acellular pertussis, inactivated polio vaccine and Haemophilus influenzae type b (DTaP-IPV//Hib)] either concomitantly or sequentially, with the second dose of CYD-TDV administered as a 3-dose schedule. Antibody titers against diphtheria toxoid, tetanus toxoid and pertussis antigens were measured by enzyme-linked immunosorbent assay. Antibodies against poliovirus and dengue serotypes were measured using a plaque reduction neutralization test. Noninferiority was demonstrated for each of the DTaP-IPV//Hib antigens if the lower limit of the 2-sided 95% confidence interval of the difference in seroconversion rates between the 2 groups (CYD-TDV and placebo) was ≥10%. Safety of both vaccines was assessed. Noninferiority in immune response was demonstrated for all DTaP-IPV//Hib antigens. After 3 doses of CYD-TDV, no difference was observed in the immune response for CYD-TDV between groups. There were no safety concerns during the study. Coadministration of the DTaP-IPV//Hib booster vaccine with CYD-TDV has no observed impact on the immunogenicity or safety profile of the DTaP-IPV//Hib booster vaccine. No difference was observed on the CYD-TDV profile when administered concomitantly or sequentially with the DTaP-IPV//Hib booster vaccine.

The efficacy and safety of 10 mg vortioxetine in the treatment of major depressive disorder: a meta-analysis of randomized controlled trials

Directory of Open Access Journals (Sweden)

Li G

2016-02-01

Full Text Available Guangjian Li, Xu Wang, Dihui Ma Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Changchun, People’s Republic of China Background: Vortioxetine is an investigational multimodal antidepressant. We conducted this meta-analysis to assess the efficacy and safety of 10 mg vortioxetine in the treatment of major depressive disorder (MDD. Methods: Randomized controlled trials (RCTs published in PubMed, Web of Science, Embase, and ClinicalTrials.gov were systematically reviewed to assess the treatment effects and safety profiles of patients with MDD who were treated with 10 mg vortioxetine. The outcome measures included response rate, remission rate, changes from baseline in Montgomery–Asberg Depression Rating Scale (MADRS, Hamilton Rating Scale for Depression (24-items (HAM-D24, Clinical Global Impression-Severity (CGI-S, and Clinical Global Impression-Improvement (CGI-I scores. Results were expressed with risk ratio or weighted mean difference with 95% confidence intervals. Pooled results were calculated using a fixed-effects model or a random-effects model according to the heterogeneity among included trials. Results: Six RCTs with a total of 1,801 patients met the inclusion criteria and were included in this meta-analysis. The 10 mg vortioxetine dose significantly increased the response rate and remission rate in the treatment of MDD compared with placebo. Moreover, there was a statistically significant reduction from baseline in the MADRS, HAM-D24, CGI-S, and CGI-I scores with 10 mg vortioxetine vs placebo. The incidence of treatment-emergent adverse events such as nausea, vomiting, constipation, and hyperhidrosis was higher in the 10 mg vortioxetine group than in the placebo group. Conclusion: Vortioxetine 10 mg can significantly increase the response rate and remission rate, and reduce the MADRS, HAM-D24, CGI-S, and CGI-I scores in patients with MDD with an acceptable risk of treatment-emergent adverse

Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial

DEFF Research Database (Denmark)

Nyboe Andersen, Anders; Nelson, Scott M; Fauser, Bart C J M

2017-01-01

OBJECTIVE: To compare the efficacy and safety of follitropin delta, a new human recombinant FSH with individualized dosing based on serum antimüllerian hormone (AMH) and body weight, with conventional follitropin alfa dosing for ovarian stimulation in women undergoing IVF. DESIGN: Randomized, mul...

A blinded, randomized, controlled trial of three doses of high-dose insulin in poison-induced cardiogenic shock.

Science.gov (United States)

Cole, J B; Stellpflug, S J; Ellsworth, H; Anderson, C P; Adams, A B; Engebretsen, K M; Holger, J S

2013-05-01

High dose insulin (HDI) has proven superior to glucagon and catecholamines in the treatment of poison-induced cardiogenic shock (PICS) in previous animal studies. Standard recommendations for dosing of insulin vary and the optimal dose of HDI in PICS has not been established. Our hypothesis was a dose of 10 U/kg/hr of HDI would be superior to 1 U/kg/hr with cardiac output (CO) as our primary outcome measure in pigs with propranolol-induced PICS. This was a blinded, prospective, randomized trial with 4 arms consisting of 4 pigs in each arm. The arms were as follows: placebo (P), 1 U/kg/hr (HDI-1), 5 U/kg/hr (HDI-5), and 10 U/kg/hr (HDI-10). Cardiogenic shock was induced with a bolus of 0.5 mg/kg of propranolol followed by an infusion of 0.25 mg/kg/min until the point of toxicity, defined as 0.75 x (HR x MAP) was reached. At this point the propranolol infusion was decreased to 0.125 mg/kg/min and a 20 mL/kg bolus of normal saline (NS) was administered. The protocol was continued for 6 hours or until the animals died. 2 pigs died in the P arm, 1 pig died each in the HDI-1 and HDI-5 arms, and all pigs lived in the HDI-10 arm. There was a statistically significant difference in dose by time interaction on CO of 1.13 L/min over the 6 hr study period (p = < 0.001). There was also a statistically significant difference in dose by time interaction on MAP, HR, and systemic vascular resistance (SVR). No statistically significant difference was found between any of the arms regarding glucose utilization. HDI was statistically and clinically significantly superior to placebo in this propranolol model of PICS. Furthermore a dose response over time was found where CO increased corresponding to increases in doses of HDI.

A study to evaluate safety and tolerability of repeated doses of tirasemtiv in patients with amyotrophic lateral sclerosis.

Science.gov (United States)

Shefner, Jeremy M; Watson, Mary Lou; Meng, Lisa; Wolff, Andrew A

2013-12-01

Abstract Tirasemtiv is a fast skeletal muscle activator that increases the sensitivity of the sarcomere to calcium, increasing the efficiency of muscle contraction when the muscle is stimulated at submaximal contraction frequencies. A previous study showed single doses of tirasemtiv to be well tolerated and associated with potentially important improvements in a variety of functional outcomes. This study determined safety of tirasemtiv when given at doses up to 500 mg daily for three weeks. Tirasemtiv was given as a single daily dose up to 375 mg for two weeks, with and without concomitant riluzole. In a separate cohort, an ascending dose protocol evaluated a total dose of 500 mg daily given in two divided doses. Safety and tolerability were assessed, as well as measures of function, muscle strength and endurance. Results showed that tirasemtiv was well tolerated, with dizziness the most common adverse event. Tirasemtiv approximately doubled the serum concentration of riluzole. Trends were noted for improvement in ALSFRS-R, Maximum Minute Ventilation, and Nasal Inspiratory Pressure. In conclusion, tirasemtiv is well tolerated and can be given safely with a reduced dose of riluzole. Positive trends in multiple exploratory outcome measures support the further study of this agent in ALS.

A randomized controlled trial to evaluate the Make Safe Happen® app-a mobile technology-based safety behavior change intervention for increasing parents' safety knowledge and actions.

Science.gov (United States)

McKenzie, Lara B; Roberts, Kristin J; Clark, Roxanne; McAdams, Rebecca; Abdel-Rasoul, Mahmoud; Klein, Elizabeth G; Keim, Sarah A; Kristel, Orie; Szymanski, Alison; Cotton, Christopher G; Shields, Wendy C

2018-03-12

Many unintentional injuries that occur in and around the home can be prevented through the use of safety equipment and by consistently following existing safety recommendations. Unfortunately, uptake of these safety behaviors is unacceptably low. This paper describes the design of the Make Safe Happen® smartphone application evaluation study, which aims to evaluate a mobile technology-based safety behavior change intervention on parents' safety knowledge and actions. Make Safe Happen® app evaluation study is a randomized controlled trial. Participants will be parents of children aged 0-12 years who are recruited from national consumer online survey panels. Parents will complete a pretest survey, and will be randomized to receive the Make Safe Happen® app or a non-injury-related app, and then complete a posttest follow-up survey after 1 week. Primary outcomes are: (1) safety knowledge; (2) safety behaviors; (3) safety device acquisition and use, and (4) behavioral intention to take safety actions. Anticipated study results are presented. Wide-reaching interventions, to reach substantial parent and caregiver audiences, to effectively reduce childhood injuries are needed. This study will contribute to the evidence-base about how to increase safety knowledge and actions to prevent home-related injuries in children. NCT02751203 ; Pre-results.

Predicting safety culture: the roles of employer, operations manager and safety professional.

Science.gov (United States)

Wu, Tsung-Chih; Lin, Chia-Hung; Shiau, Sen-Yu

2010-10-01

This study explores predictive factors in safety culture. In 2008, a sample 939 employees was drawn from 22 departments of a telecoms firm in five regions in central Taiwan. The sample completed a questionnaire containing four scales: the employer safety leadership scale, the operations manager safety leadership scale, the safety professional safety leadership scale, and the safety culture scale. The sample was then randomly split into two subsamples. One subsample was used for measures development, one for the empirical study. A stepwise regression analysis found four factors with a significant impact on safety culture (R²=0.337): safety informing by operations managers; safety caring by employers; and safety coordination and safety regulation by safety professionals. Safety informing by operations managers (ß=0.213) was by far the most significant predictive factor. The findings of this study provide a framework for promoting a positive safety culture at the group level. Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.

Pharmacokinetics of a telmisartan/rosuvastatin fixed-dose combination: a single-dose, randomized, open-label, 2-period crossover study in healthy Korean subjects.

Science.gov (United States)

Chae, Dong Woo; Son, Mijeong; Kim, Yukyung; Son, Hankil; Jang, Seong Bok; Seo, Jeong Min; Nam, Su Youn; Park, Kyungsoo

2015-10-01

As hypertension and dyslipidemia are frequent comorbidities, antihypertensive drugs and lipid-lowering agents are often prescribed together for their treatment. Telmisartan and rosuvastatin are widely used together to treat hypertension and dyslipidemia. A combination formulation of these two drugs would improve patient compliance due to ease of dosing. The purpose of this study was to assess bioequivalence of single-dose administration of a newly-developed fixed-dose combination (FDC) tablet containing telmisartan/rosuvastatin 80/20 mg (test treatment) and coadministration of a telmisartan 80-mg tablet and a rosuvastatin 20-mg tablet (reference treatment) in healthy Korean male volunteers. This was a single-dose, randomized, open-label, 2-period crossover study enrolling healthy males aged 20 - 50 years with BMI between 18.5 and 25 kg/m2. Each subject received a single dose of the reference and test treatments with a 14-day washout period. Blood sampling was performed at prespecified intervals for up to 72 hours after dosing. Primary pharmacokinetic parameters were Cmax, AUClast, and AUC0-∞ of telmisartan, rosuvastatin, and N-desmethyl rosuvastatin. Bioequivalence was assessed by determining whether the 90% confidence intervals (CIs) of the geometric mean ratios (test treatment/reference treatment) of these parameters were within the standard range of 80% to 125%. Adverse events were monitored via regular interviews with the subjects and by physical examinations. 60 subjects were enrolled and 55 completed the study. The 90% CIs of the geometric mean ratios of Cmax, AUClast, and AUC00-∞ were 0.9262-1.1498, 0.9294-1.0313, and 0.9312-1.0320 for telmisartan, 0.9041-1.0428, 0.9262-1.0085, and 0.9307-1.0094 for rosuvastatin, and 0.8718-1.0022, 0.8901-0.9904, and 0.8872-0.9767 for N-desmethyl rosuvastatin, respectively. There was no statistical difference in the incidence of adverse events (AEs) (all of which were mild or moderate) between the reference and test

Randomized Phase I: Safety, Immunogenicity and Mucosal Antiviral Activity in Young Healthy Women Vaccinated with HIV-1 Gp41 P1 Peptide on Virosomes.

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Geert Leroux-Roels

Full Text Available Mucosal antibodies harboring various antiviral activities may best protect mucosal surfaces against early HIV-1 entry at mucosal sites and they should be ideally induced by prophylactic HIV-1 vaccines for optimal prevention of sexually transmitted HIV-1. A phase I, double-blind, randomized, placebo-controlled trial was conducted in twenty-four healthy HIV-uninfected young women. The study objectives were to assess the safety, tolerability and immunogenicity of virosomes harboring surface HIV-1 gp41-derived P1 lipidated peptides (MYM-V101. Participants received placebo or MYM-V101 vaccine at 10 μg/dose or 50 μg/dose intramuscularly at week 0 and 8, and intranasally at week 16 and 24. MYM-V101 was safe and well-tolerated at both doses administered by the intramuscular and intranasal routes, with the majority of subjects remaining free of local and general symptoms. P1-specific serum IgGs and IgAs were induced in all high dose recipients after the first injection. After the last vaccination, vaginal and rectal P1-specific IgGs could be detected in all high dose recipients. Approximately 63% and 43% of the low and high dose recipients were respectively tested positive for vaginal P1-IgAs, while 29% of the subjects from the high dose group tested positive for rectal IgAs. Serum samples had total specific IgG and IgA antibody concentrations ≥ 0.4 μg/mL, while mucosal samples were usually below 0.01 μg/mL. Vaginal secretions from MYM-V101 vaccinated subjects were inhibiting HIV-1 transcytosis but had no detectable neutralizing activity. P1-specific Th1 responses could not be detected on PBMC. This study demonstrates the excellent safety and tolerability of MYM-V101, eliciting systemic and mucosal antibodies in the majority of subjects. Vaccine-induced mucosal anti-gp41 antibodies toward conserved gp41 motifs were harboring HIV-1 transcytosis inhibition activity and may contribute to reduce sexually-transmitted HIV-1.ClinicalTrials.gov NCT01084343.

Safety and immunogenicity of one versus two doses of Takeda's tetravalent dengue vaccine in children in Asia and Latin America: interim results from a phase 2, randomised, placebo-controlled study.

Science.gov (United States)

Sáez-Llorens, Xavier; Tricou, Vianney; Yu, Delia; Rivera, Luis; Tuboi, Suely; Garbes, Pedro; Borkowski, Astrid; Wallace, Derek

2017-06-01

02302066. 1800 participants were enrolled between Dec 5, 2014, and Feb 13, 2015. 1794 participants were given study injection as follows: 200 participants were given two-dose regimen at 0 and 3 months (group 1), 398 were given one dose at 0 months (group 2), 998 were given one dose at 0 months and will be given (trial ongoing) a booster at 12 months (group 3), and 198 were given placebo (group 4). These 1794 participants were included in the safety set; 562 participants were randomly assigned to the immunogenicity subset, of which 503 were included in the per-protocol set. TDV elicited neutralising antibodies against all DENV serotypes, which peaked at 1 month and remained elevated above baseline at 6 months. At 6 months, GMTs of neutralising antibodies against DENV-1 were 489 (95% CI 321-746) for group 1, 434 (306-615) for group 2, 532 (384-738) for group 3, and 62 (32-120) for group 4; GMTs of neutralising antibodies against DENV-2 were 1565 (1145-2140) for group 1, 1639 (1286-2088) for group 2, 1288 (1031-1610) for group 3, and 86 (44-169) for group 4; GMTs of neutralising antibodies against DENV-3 were 160 (104-248) for group 1, 151 (106-214) for group 2, 173 (124-240) for group 3, and 40 (23-71) for group 4; and GMTs of neutralising antibodies against DENV-4 were 117 (79-175) for group 1, 110 (80-149) for group 2, 93 (69-125) for group 3, and 24 (15-38) for group 4. No vaccine-related serious adverse events occurred; 15 (3%) of 562 participants in the immunogenicity subset reported vaccine-related unsolicited adverse events. The reactogenicity profile of TDV was acceptable, and similar to previous findings with TDV. TDV is safe and immunogenic in individuals aged 2-17 years, irrespective of previous dengue exposure. A second TDV dose induced enhanced immunogenicity against DENV-3 and DENV-4 in children who were seronegative before vaccination. These data supported the initiation of phase 3 evaluation of the efficacy and safety of TDV given in a two-dose schedule 3

Evaluating higher doses of Shunthi - Guduchi formulations for safety in treatment of osteoarthritis knees: A Government of India NMITLI arthritis project.

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Chopra, Arvind; Saluja, Manjit; Tillu, Girish; Venugopalan, Anuradha; Narsimulu, Gumdal; Sarmukaddam, Sanjeev; Patwardhan, Bhushan

2012-01-01

Results of an exploratory trial suggested activity trends of Zingiber officinale-Tinopsora cordifolia (platform combination)-based formulations in the treatment of Osteoarthritis (OA) Knees. These formulations were "platform combination+Withania somnifera+Tribulus terrestris" (formulation B) and "platform combination+Emblica officinale" (formulation C). This paper reports safety of these formulations when used in higher doses (1.5-2 times) along with Sallaki Guggul and Bhallataka Parpati (a Semecarpus anacardium preparation). Ninety-two patients with symptomatic OA knees were enrolled in a 6 weeks investigator blind, randomized parallel efficacy 4-arm multicenter drug trial. The 4 arms were (I) formulation B, 2 t.i.d.; (II) formulation B, 2 q.i.d.; (III) platform combination+Sallaki Guggul; (IV) Bhallataka Parpati+formulation C. A detailed enquiry was carried out for adverse events (AE) and drug toxicity as per a priori check list and volunteered information. Laboratory evaluation included detailed hematology and metabolic parameters. Patients were examined at baseline, first and fourth weeks, and on completion. Standard statistical program (SPSS version 12.5) was used for analysis. None of the patients reported serious AE or withdrew due to any drug-related toxicity. Mild gut-related (mostly epigastric burning) AE was reported. A mild increase in liver enzymes [serum glutamic pyruvate transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT)] without any other hepatic abnormality was reported in 2 patients (group IV). Other laboratory parameters remained normal. The mean improvement in active pain visual analog scale (1.4, CI 0.5-2.22), WOMAC (functional activity questionnaire) pain score (1.37, CI 0.22-2.5), and urinary C-TAX (cartilage collagen breakdown product) assay was maximum (NS) in group IV. Lower dose group I showed numerically superior improvement compared with higher dose group II. The results suggested that despite higher doses, standardized

Design of a multicentre randomized controlled trial to assess the safety and efficacy of dose titration by specialized nurses in patients with heart failure. ETIFIC study protocol.

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Oyanguren, Juana; García-Garrido, LLuisa; Nebot Margalef, Magdalena; Lekuona, Iñaki; Comin-Colet, Josep; Manito, Nicolás; Roure, Julia; Ruiz Rodriguez, Pilar; Enjuanes, Cristina; Latorre, Pedro; Torcal Laguna, Jesús; García-Gutiérrez, Susana

2017-11-01

Heart failure (HF) is associated with many hospital admissions and relatively high mortality, rates decreasing with administration of beta-blockers (BBs), angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists. The effect is dose dependent, suboptimal doses being common in clinical practice. The 2012 European guidelines recommend close monitoring and dose titration by HF nurses. Our main aim is to compare BB doses achieved by patients after 4 months in intervention (HF nurse-managed) and control (cardiologist-managed) groups. Secondary aims include comparing doses of the other aforementioned drugs achieved after 4 months, adverse events, and outcomes at 6 months in the two groups. We have designed a multicentre (20 hospitals) non-inferiority randomized controlled trial, including patients with new-onset HF, left ventricular ejection fraction ≤40%, and New York Heart Association class II-III, with no contraindications to BBs. We will also conduct qualitative analysis to explore potential barriers to and facilitators of dose titration by HF nurses. In the intervention group, HF nurses will implement titration as prescribed by cardiologists, following a protocol. In controls, cardiologists will both prescribe and titrate doses. The study variables are doses of each of the drugs after 4 months relative to the target dose (%), New York Heart Association class, left ventricular ejection fraction, N-terminal pro B-type natriuretic peptide levels, 6 min walk distance, comorbidities, renal function, readmissions, mortality, quality of life, and psychosocial characteristics. The trial seeks to assess whether titration by HF nurses of drugs recommended in practice guidelines is safe and not inferior to direct management by cardiologists. The results could have an impact on clinical practice. © 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of

Integrated vehicle-based safety systems light-vehicle field operational test key findings report.

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2011-01-01

"This document presents key findings from the light-vehicle field operational test conducted as part of the Integrated Vehicle-Based Safety Systems program. These findings are the result of analyses performed by the University of Michigan Transportat...

Safety and efficacy of MIM D3 ophthalmic solutions in a randomized placebo controlled Phase 2 clinical trial in patients with dry eye

Directory of Open Access Journals (Sweden)

Meerovitch K

2013-06-01

Full Text Available Karen Meerovitch,1 Gail Torkildsen,2 John Lonsdale,3 Heidi Goldfarb,4 Teresa Lama,1 Garth Cumberlidge,1 George W Ousler III5 1Mimetogen Pharmaceuticals Inc, Montreal, QC, Canada; 2Andover Eye Associates, Andover, MA, USA; 3Central Maine Eye Care, Lewiston, ME, USA; 4SDC, Tempe, AZ, USA; 5Ora Inc, Andover, MA, USA Purpose: To evaluate the safety and efficacy of ophthalmic MIM-D3, a tyrosine kinase TrkA receptor agonist, in patients with dry eye. Design: A prospective, two-center, randomized, double-masked, placebo-controlled Phase 2 study. Methods: A total of 150 dry eye patients were randomized 1:1:1 to study medication (1% MIM-D3, 5% MIM-D3, or placebo and dosed twice daily (BID for 28 days. Key eligibility criteria included exacerbation in corneal staining and ocular discomfort in the Controlled Adverse Environment (CAESM on two visits, separated by 1 week of BID dosing with artificial tears. Safety and efficacy were evaluated at baseline, throughout treatment, and for 2 weeks post-treatment. The pre-specified primary outcome measures were fluorescein corneal staining post-CAE at day 28 and diary worst symptom scores over 28 days. Secondary outcomes included the pre-, post-, and the change from pre- to post-CAE fluorescein and lissamine green staining in both corneal and conjunctival regions, as well as individual diary symptoms. Results: The prespecified primary endpoints were not met. Compared with placebo, fluorescein corneal staining at day 28 was significantly improved (P < 0.05 in the 1% MIM-D3 group for the assessment of change from pre-CAE to post-CAE. In addition, following CAE exposure, patients in the 1% MIM-D3 group showed significant improvements versus placebo (P < 0.05 in inferior fluorescein and lissamine green staining after 14 and 28 days. Compared with placebo, patients in the 5% MIM-D3 group reported significantly lower daily diary scores for ocular dryness (P < 0.05. In a subgroup defined by higher symptom scores during

Involving fathers in teaching youth about farm tractor seatbelt safety--a randomized control study.

Science.gov (United States)

Jinnah, Hamida Amirali; Stoneman, Zolinda; Rains, Glen

2014-03-01

Farm youth continue to experience high rates of injury and deaths as a result of agricultural activities. Farm machinery, especially tractors, is the most common cause of casualties to youth. A Roll-Over Protection Structure (ROPS) along with a fastened seatbelt can prevent almost all injuries and fatalities from tractor overturns. Despite this knowledge, the use of seatbelts by farmers on ROPS tractors remains low. This study treats farm safety as a family issue and builds on the central role of parents as teachers and role models of farm safety for youth. This research study used a longitudinal, repeated-measures, randomized-control design in which youth 10-19 years of age were randomly assigned to either of two intervention groups (parent-led group and staff-led group) or the control group. Fathers in the parent-led group were less likely to operate ROPS tractors without a seatbelt compared with other groups. They were more likely to have communicated with youth about the importance of wearing seatbelts on ROPS tractors. Consequently, youth in the parent-led group were less likely to operate a ROPS tractor without a seatbelt than the control group at post-test. This randomized control trial supports the effectiveness of a home-based, father-led farm safety intervention as a promising strategy for reducing youth as well as father-unsafe behaviors (related to tractor seatbelts) on the farm. This intervention appealed to fathers' strong motivation to practice tractor safety for the sake of their youth. Involving fathers helped change both father as well as youth unsafe tractor-seatbelt behaviors. Copyright © 2014 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

Adverse events analysis as an educational tool to improve patient safety culture in primary care: a randomized trial.

Science.gov (United States)

González-Formoso, Clara; Martín-Miguel, María Victoria; Fernández-Domínguez, Ma José; Rial, Antonio; Lago-Deibe, Fernando Isidro; Ramil-Hermida, Luis; Pérez-García, Margarita; Clavería, Ana

2011-06-14

Patient safety is a leading item on the policy agenda of both major international health organizations and advanced countries generally. The quantitative description of the phenomena has given rise to intense concern with the issue in institutions and organizations, leading to a number of initiatives and research projects and the promotion of patient safety culture, with training becoming a priority both in Spain and internationally. To date, most studies have been conducted in a hospital setting, even though primary care is the type most commonly used by the public, in our experience. Our study aims to achieve the following:--Assess the registry of adverse events as an education tool to improve patient safety culture in the Family and Community Teaching Units of Galicia.--Find and analyze educational tools to improve patient safety culture in primary care.--Evaluate the applicability of the Hospital Survey on Patient Safety Culture by the Agency for Healthcare Research and Quality, Spanish version, in the context of primary health care. Experimental unifactorial study of two groups, control and intervention. Tutors and residents in Family and Community Medicine in last year of studies in Galicia, Spain. From the population universe through voluntary participation. Twenty-seven tutor-resident units in each group required, randomly assigned. Residents and their respective tutor (tutor-resident pair) in teaching units on Family and Community Medicine from throughout Galicia will be invited to participate. Tutor-resident pair that agrees to participate will be sent the Hospital Survey on Patient Safety Culture. Then, tutor-resident pair will be assigned to each group--either intervention or control--through simple random sampling. The intervention group will receive specific training to record the adverse effects found in patients under their care, with subsequent feedback, after receiving instruction on the process. No action will be taken in the control group. After

Dose finding of melatonin for chronic idiopathic childhood sleep onset insomnia: an RCT

OpenAIRE

van Geijlswijk, Ingeborg M.; van der Heijden, Kristiaan B.; Egberts, A. C. G.; Korzilius, Hubert P. L. M.; Smits, Marcel G.

2010-01-01

RATIONALE: Pharmacokinetics of melatonin in children might differ from that in adults. OBJECTIVES: This study aims to establish a dose-response relationship for melatonin in advancing dim light melatonin onset (DLMO), sleep onset (SO), and reducing sleep onset latency (SOL) in children between 6 and 12 years with chronic sleep onset insomnia (CSOI). METHODS: The method used for this study is the randomized, placebo-controlled double-blind trial. Children with CSOI (n = 72) received either mel...

Maximum tolerated dose evaluation of the AMPA modulator Org 26576 in healthy volunteers and depressed patients: a summary and method analysis of bridging research in support of phase II dose selection.

Science.gov (United States)

Nations, Kari R; Bursi, Roberta; Dogterom, Peter; Ereshefsky, Larry; Gertsik, Lev; Mant, Tim; Schipper, Jacques

2012-09-01

A key challenge to dose selection in early central nervous system (CNS) clinical drug development is that patient tolerability profiles often differ from those of healthy volunteers (HVs), yet HVs are the modal population for determining doses to be investigated in phase II trials. Without clear tolerability data from the target patient population, first efficacy trials may include doses that are either too high or too low, creating undue risk for study participants and the development program overall. Bridging trials address this challenge by carefully investigating safety and tolerability in the target population prior to full-scale proof-of-concept trials. Org 26576 is an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor positive allosteric modulator that acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. In preparation for phase II efficacy trials in major depressive disorder (MDD), two separate phase I trials were conducted to evaluate safety, tolerability, and pharmacokinetics in HVs and in the target patient population. Both trials were randomized and placebo controlled, and included multiple rising-dose cohorts (HV range 100-400 mg bid; MDD range 100-600 mg bid). HVs (n = 36) and patients with MDD (n = 54) were dosed under similarly controlled conditions in an inpatient facility, HVs for up to 14 days and MDD patients for up to 28 days. Safety, tolerability, and pharmacokinetics were assessed frequently. Despite comparable pharmacokinetic profiles, the maximum tolerated dose (MTD) in depressed patients was 450 mg bid, twice the MTD established in HVs. No clinically relevant safety issues associated with Org 26576 were noted. This article presents safety, tolerability, and pharmacokinetic data from two different populations examined under similar dosing conditions. The important implications of such bridging work in phase II dose selection are discussed, as are study

Safety and immunogenicity of an AMA1 malaria vaccine in Malian children: results of a phase 1 randomized controlled trial.

Directory of Open Access Journals (Sweden)

Mahamadou A Thera

2010-02-01

Full Text Available The objective was to evaluate the safety and immunogenicity of the AMA1-based malaria vaccine FMP2.1/AS02(A in children exposed to seasonal falciparum malaria.A Phase 1 double blind randomized controlled dose escalation trial was conducted in Bandiagara, Mali, West Africa, a rural town with intense seasonal transmission of Plasmodium falciparum malaria. The malaria vaccine FMP2.1/AS02(A is a recombinant protein (FMP2.1 based on apical membrane antigen 1 (AMA1 from the 3D7 clone of P. falciparum, formulated in the Adjuvant System AS02(A. The comparator vaccine was a cell-culture rabies virus vaccine (RabAvert. One hundred healthy Malian children aged 1-6 years were recruited into 3 cohorts and randomized to receive either 10 microg FMP2.1 in 0.1 mL AS02(A, or 25 microg FMP2.1 in 0.25 mL AS02(A, or 50 microg FMP2.1 50 microg in 0.5 mL AS02(A, or rabies vaccine. Three doses of vaccine were given at 0, 1 and 2 months, and children were followed for 1 year. Solicited symptoms were assessed for 7 days and unsolicited symptoms for 30 days after each vaccination. Serious adverse events were assessed throughout the study. Transient local pain and swelling were common and more frequent in all malaria vaccine dosage groups than in the comparator group, but were acceptable to parents of participants. Levels of anti-AMA1 antibodies measured by ELISA increased significantly (at least 100-fold compared to baseline in all 3 malaria vaccine groups, and remained high during the year of follow up.The FMP2.1/AS02(A vaccine had a good safety profile, was well-tolerated, and induced high and sustained antibody levels in malaria-exposed children. This malaria vaccine is being evaluated in a Phase 2 efficacy trial in children at this site.ClinicalTrials.gov NCT00358332 [NCT00358332].

Triangulating case-finding tools for patient safety surveillance: a cross-sectional case study of puncture/laceration.

Science.gov (United States)

Taylor, Jennifer A; Gerwin, Daniel; Morlock, Laura; Miller, Marlene R

2011-12-01

To evaluate the need for triangulating case-finding tools in patient safety surveillance. This study applied four case-finding tools to error-associated patient safety events to identify and characterise the spectrum of events captured by these tools, using puncture or laceration as an example for in-depth analysis. Retrospective hospital discharge data were collected for calendar year 2005 (n=48,418) from a large, urban medical centre in the USA. The study design was cross-sectional and used data linkage to identify the cases captured by each of four case-finding tools. Three case-finding tools (International Classification of Diseases external (E) and nature (N) of injury codes, Patient Safety Indicators (PSI)) were applied to the administrative discharge data to identify potential patient safety events. The fourth tool was Patient Safety Net, a web-based voluntary patient safety event reporting system. The degree of mutual exclusion among detection methods was substantial. For example, when linking puncture or laceration on unique identifiers, out of 447 potential events, 118 were identical between PSI and E-codes, 152 were identical between N-codes and E-codes and 188 were identical between PSI and N-codes. Only 100 events that were identified by PSI, E-codes and N-codes were identical. Triangulation of multiple tools through data linkage captures potential patient safety events most comprehensively. Existing detection tools target patient safety domains differently, and consequently capture different occurrences, necessitating the integration of data from a combination of tools to fully estimate the total burden.

Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty: The GIFT Randomized Clinical Trial.

Science.gov (United States)

Gage, Brian F; Bass, Anne R; Lin, Hannah; Woller, Scott C; Stevens, Scott M; Al-Hammadi, Noor; Li, Juan; Rodríguez, Tomás; Miller, J Philip; McMillin, Gwendolyn A; Pendleton, Robert C; Jaffer, Amir K; King, Cristi R; Whipple, Brandi DeVore; Porche-Sorbet, Rhonda; Napoli, Lynnae; Merritt, Kerri; Thompson, Anna M; Hyun, Gina; Anderson, Jeffrey L; Hollomon, Wesley; Barrack, Robert L; Nunley, Ryan M; Moskowitz, Gerard; Dávila-Román, Victor; Eby, Charles S

2017-09-26

Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown. To determine whether genotype-guided dosing improves the safety of warfarin initiation. The randomized clinical Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis included patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty and was conducted at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016. Patients were genotyped for the following polymorphisms: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. In a 2 × 2 factorial design, patients were randomized to genotype-guided (n = 831) or clinically guided (n = 819) warfarin dosing on days 1 through 11 of therapy and to a target international normalized ratio (INR) of either 1.8 or 2.5. The recommended doses of warfarin were open label, but the patients and clinicians were blinded to study group assignment. The primary end point was the composite of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Patients underwent a screening lower-extremity duplex ultrasound approximately 1 month after arthroplasty. Among 1650 randomized patients (mean age, 72.1 years [SD, 5.4 years]; 63.6% women; 91.0% white), 1597 (96.8%) received at least 1 dose of warfarin therapy and completed the trial (n = 808 in genotype-guided group vs n = 789 in clinically guided group). A total of 87 patients (10.8%) in the genotype-guided group vs 116 patients (14.7%) in the clinically guided warfarin dosing group met at least 1 of the end points (absolute difference, 3.9% [95% CI, 0.7%-7.2%], P = .02; relative rate [RR], 0.73 [95% CI, 0.56-0.95]). The numbers of individual events in the genotype-guided group vs the clinically guided group were 2 vs 8 for major bleeding (RR, 0.24; 95% CI, 0

A randomized, double-blind, placebo-controlled, dose-ranging study using Genz-644470 and sevelamer carbonate in hyperphosphatemic chronic kidney disease patients on hemodialysis

Directory of Open Access Journals (Sweden)

Moustafa M

2014-04-01

Full Text Available Moustafa Moustafa,1 Lawrence Lehrner,2 Fahd Al-Saghir,3 Mark Smith,4 Sunita Goyal,5 Maureen Dillon,5 John Hunter,5 Randy Holmes-Farley5 1South Carolina Nephrology and Hypertension Center Inc., Orangeburg, SC, USA; 2Kidney Specialists of Southern Nevada, Las Vegas, NV, USA; 3Michigan Kidney Consultants, Pontiac, MI, USA; 4Kidney Care Associates, LLC, Augusta, GA, USA; 5Genzyme, a Sanofi company, Cambridge, MA, USA Background: Genz-644470 is a new, nonabsorbed phosphate binding polymer. In an in vitro competitive phosphate binding assay, Genz-644470 bound significantly more phosphate per gram than sevelamer. As a consequence, this clinical study evaluated the ability of Genz-644470 to lower serum phosphorus in patients on hemodialysis and compared serum phosphorus lowering of Genz-644470 with sevelamer carbonate and placebo. Because three different fixed doses of Genz-644470 and sevelamer carbonate were used, phosphate-lowering dose-responses of each agent were also analyzed. Methods: A randomized, double-blind, dose-ranging study was conducted. After a 2-week phosphate binder washout, 349 hyperphosphatemic (serum phosphorus >5.5 mg/dL hemodialysis patients were randomized to one of seven fixed-dose groups: placebo, Genz-644470 2.4 g/day, Genz-644470 4.8 g/day, Genz-644470 7.2 g/day, sevelamer carbonate 2.4 g/day, sevelamer carbonate 4.8 g/day, or sevelamer carbonate 7.2 g/day. Indicated total daily doses were administered in fixed divided doses three times a day with meals for 3 weeks. The change in serum phosphorus during the treatment period and its dose-response patterns were assessed. Results: Dose-dependent reductions in serum phosphorus were observed with both Genz-644470 and sevelamer carbonate. Serum phosphorus-lowering responses to fixed doses of sevelamer carbonate and Genz-644470 were enhanced in a roughly linear fashion with increasing doses over a threefold range after 3 weeks of treatment. Genz-644470 did not show any advantage in

Keeping rail on track: preliminary findings on safety culture in Australian rail.

Science.gov (United States)

Blewett, Verna; Rainbird, Sophia; Dorrian, Jill; Paterson, Jessica; Cattani, Marcus

2012-01-01

'Safety culture' is identified in the literature as a critical element of healthy and safe workplaces. How can rail organizations ensure that consistently effective work health and safety cultures are maintained across the diversity of their operations? This paper reports on research that is currently underway in the Australian rail industry aimed at producing a Model of Best Practice in Safety Culture for the industry. Located in rail organizations dedicated to the mining industry as well as urban rail and national freight operations, the research examines the constructs of organizational culture that impact on the development and maintenance of healthy and safe workplaces. The research uses a multi-method approach incorporating quantitative (survey) and qualitative (focus groups, interviews and document analysis) methods along with a participative process to identify interventions to improve the organization and develop plans for their implementation. The research uses as its analytical framework the 10 Platinum Rules, from the findings of earlier research in the New South Wales (Australia) mining industry, Digging Deeper. Data collection is underway at the time of writing and preliminary findings are presented at this stage. The research method may be adapted for use as a form of organizational review of safety and health in organizational culture.

Efficacy and Safety of Tamsulosin in Medical Expulsive Therapy for Distal Ureteral Stones with Renal Colic: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial.

Science.gov (United States)

Ye, Zhangqun; Zeng, Guohua; Yang, Huan; Tang, Kun; Zhang, Xiaochun; Li, Hong; Li, Weibing; Wu, Zhong; Chen, Lingwu; Chen, Xingfa; Liu, Xiankui; Deng, Yaoliang; Pan, Tiejun; Xing, Jinchun; Wang, Shusheng; Cheng, Yue; Gu, Xiaojian; Gao, Wenxi; Yang, Jianggen; Zhang, Yonghai; Mi, Qiwu; Qi, Lin; Li, Jiongming; Hu, Weilie; Liang, Peiyu; Sun, Zhaolin; Xu, Changbao; Long, Yongfu; Liao, Yongbin; Liu, Siping; Liu, Guoqing; Xu, Xun; He, Wei; Chen, Zhiqiang; Xu, Hua

2017-11-12

Recent large high-quality trials have questioned the clinical effectiveness of medical expulsive therapy using tamsulosin for ureteral stones. To evaluate the efficacy and safety of tamsulosin for distal ureteral stones compared with placebo. We conducted a double-blind, placebo-controlled study of 3296 patients with distal ureteral stones, across 30 centers, to evaluate the efficacy and safety of tamsulosin. Participants were randomly assigned (1:1) into tamsulosin (0.4mg) or placebo groups for 4 wk. The primary end point of analysis was the overall stone expulsion rate, defined as stone expulsion, confirmed by negative findings on computed tomography, over a 28-d surveillance period. Secondary end points included time to stone expulsion, use of analgesics, and incidence of adverse events. Among 3450 patients randomized between September 1, 2011, and August 31, 2013, 3296 (96%) were included in the primary analysis. Tamsulosin benefits from a higher stone expulsion rate than the placebo (86% vs 79%; ptamsulosin for the treatment of large distal ureteral stones (>5mm). Considering the secondary end points, tamsulosin-treated patients reported a shorter time to expulsion (ptamsulosin use benefits distal ureteral stones in facilitating stone passage and relieving renal colic. Subgroup analyses find that tamsulosin provides a superior expulsion rate for stones >5mm, but no effect for stones ≤5mm. In this report, we looked at the efficacy and safety of tamsulosin for the treatment of distal ureteral stones. We find that tamsulosin significantly facilitates the passage of distal ureteral stones and relieves renal colic. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Twelve-week efficacy and safety study of mometasone furoate/formoterol 200/10 microg and 400/10 microg combination treatments in patients with persistent asthma previously receiving high-dose inhaled corticosteroids

DEFF Research Database (Denmark)

Weinstein, Steven F; Corren, Jonathan; Murphy, Kevin

2010-01-01

A significant unmet medical need exists in patients with uncontrolled asthma. The purpose of this study was to evaluate the efficacy and safety of mometasone furoate/formoterol (MF/F) 400/10 microg versus MF 400 microg administered twice-daily (b.i.d.) via metered-dose inhaler in patients...... with asthma uncontrolled on high-dose inhaled corticosteroids (ICS). In a 12-week, randomized, multicenter, double-blind, parallel-group study, patients (>or=12 years of age) were randomized to MF/F 200/10 microg, MF/F 400/10 microg, or MF 400 microg, b.i.d. after a 2- to 3-week open-label run in with MF 400...... microg b.i.d. The primary end point was mean change in area under the curve from 0 to 12 hours in forced expiratory volume in 1 second (FEV(1) AUC(0-12h)) from baseline to week 12 for MF/F 400/10 microg versus MF 400 microg. Effects of MF/F on asthma control and symptoms were evaluated and adverse events...

Robotic path-finding in inverse treatment planning for stereotactic radiosurgery with continuous dose delivery

Energy Technology Data Exchange (ETDEWEB)

Vandewouw, Marlee M., E-mail: marleev@mie.utoronto.ca; Aleman, Dionne M. [Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario M5S 3G8 (Canada); Jaffray, David A. [Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario M5G 2M9 (Canada)

2016-08-15

Purpose: Continuous dose delivery in radiation therapy treatments has been shown to decrease total treatment time while improving the dose conformity and distribution homogeneity over the conventional step-and-shoot approach. The authors develop an inverse treatment planning method for Gamma Knife® Perfexion™ that continuously delivers dose along a path in the target. Methods: The authors’ method is comprised of two steps: find a path within the target, then solve a mixed integer optimization model to find the optimal collimator configurations and durations along the selected path. Robotic path-finding techniques, specifically, simultaneous localization and mapping (SLAM) using an extended Kalman filter, are used to obtain a path that travels sufficiently close to selected isocentre locations. SLAM is novelly extended to explore a 3D, discrete environment, which is the target discretized into voxels. Further novel extensions are incorporated into the steering mechanism to account for target geometry. Results: The SLAM method was tested on seven clinical cases and compared to clinical, Hamiltonian path continuous delivery, and inverse step-and-shoot treatment plans. The SLAM approach improved dose metrics compared to the clinical plans and Hamiltonian path continuous delivery plans. Beam-on times improved over clinical plans, and had mixed performance compared to Hamiltonian path continuous plans. The SLAM method is also shown to be robust to path selection inaccuracies, isocentre selection, and dose distribution. Conclusions: The SLAM method for continuous delivery provides decreased total treatment time and increased treatment quality compared to both clinical and inverse step-and-shoot plans, and outperforms existing path methods in treatment quality. It also accounts for uncertainty in treatment planning by accommodating inaccuracies.

Robotic path-finding in inverse treatment planning for stereotactic radiosurgery with continuous dose delivery

International Nuclear Information System (INIS)

Vandewouw, Marlee M.; Aleman, Dionne M.; Jaffray, David A.

2016-01-01

Purpose: Continuous dose delivery in radiation therapy treatments has been shown to decrease total treatment time while improving the dose conformity and distribution homogeneity over the conventional step-and-shoot approach. The authors develop an inverse treatment planning method for Gamma Knife® Perfexion™ that continuously delivers dose along a path in the target. Methods: The authors’ method is comprised of two steps: find a path within the target, then solve a mixed integer optimization model to find the optimal collimator configurations and durations along the selected path. Robotic path-finding techniques, specifically, simultaneous localization and mapping (SLAM) using an extended Kalman filter, are used to obtain a path that travels sufficiently close to selected isocentre locations. SLAM is novelly extended to explore a 3D, discrete environment, which is the target discretized into voxels. Further novel extensions are incorporated into the steering mechanism to account for target geometry. Results: The SLAM method was tested on seven clinical cases and compared to clinical, Hamiltonian path continuous delivery, and inverse step-and-shoot treatment plans. The SLAM approach improved dose metrics compared to the clinical plans and Hamiltonian path continuous delivery plans. Beam-on times improved over clinical plans, and had mixed performance compared to Hamiltonian path continuous plans. The SLAM method is also shown to be robust to path selection inaccuracies, isocentre selection, and dose distribution. Conclusions: The SLAM method for continuous delivery provides decreased total treatment time and increased treatment quality compared to both clinical and inverse step-and-shoot plans, and outperforms existing path methods in treatment quality. It also accounts for uncertainty in treatment planning by accommodating inaccuracies.

Pharmacodynamics and safety of the novel selective progesterone receptor modulator vilaprisan: a double-blind, randomized, placebo-controlled phase 1 trial in healthy women.

Science.gov (United States)

Schütt, Barbara; Kaiser, Andreas; Schultze-Mosgau, Marcus-Hillert; Seitz, Christian; Bell, David; Koch, Manuela; Rohde, Beate

2016-08-01

signs and 12-lead electrocardiography. All 73 randomized participants received at least one dose of study medication and were included in safety analyses; six participants were excluded from the per-protocol analyses. A total of 69 completed the study. Observed non-bleeding rates increased with VPR dose: 0.1 mg (0%; 90% confidence interval [CI]: 0-23.8), 0.5 mg (27.3%; 90% CI: 7.9-56.4), 1 mg (80.0%; 90% CI: 49.3-96.3), 2 mg (100%; 90% CI: 77.9-100), 5 mg (90.9%; 90% CI: 63.6-99.5), compared with 0% (90% CI: 0-22.1) in the placebo group. Maximal non-bleeding rates were reached at doses of 2 mg and higher. Return of menstrual bleeding was observed in all women ≤52 days after VPR discontinuation. No treatment-emergent critical endometrial findings occurred. Follicular growth was not suppressed and minimum average estradiol levels remained above 40 pg/ml. No serious treatment-emergent AEs or study discontinuations due to AEs were reported. Clinically relevant changes in laboratory parameters or vital signs were not evident. The results of this small proof-of-concept study will need to be confirmed in larger trials in patients with UFs to establish the potential therapeutic benefits and safety of VPR. The high rates of non-bleeding (80-100% at VPR doses of 1-5 mg) support further evaluation of VPR in patients with UFs and heavy menstrual bleeding. This study was funded by Bayer Pharma AG. B.S., A.K., M.-H.S.M., C.S. and B.R. are employees of Bayer Pharma AG. B.S., A.K. and M.-H.S.M. are listed as inventors of an issued patent related to this work, and received payment for this from Bayer Pharma AG. D.B. is the founder of Biokinetic Europe Ltd, UK, which received funding for this study from Bayer Pharma AG. M.K. is an employee of Nuvisan GmbH, Germany, which received funding for this study from Bayer Pharma AG. Clinicaltrials.gov identifier: NCT01816815. 20 March 2013. 28 November 2011. © The Author 2016. Published by Oxford University Press on behalf of the European

Efficacy and safety of premedication with single dose of oral pregabalin in children with dental anxiety: A randomized double-blind placebo-controlled crossover clinical trial

Directory of Open Access Journals (Sweden)

Tahereh Eskandarian

2015-01-01

Full Text Available Background: Dental anxiety is a relatively frequent problem that can lead to more serious problems such as a child entering a vicious cycle as he/she becomes reluctant to accept the required dental treatments. The aim of this randomized double-blind clinical trial study was to evaluate the anxiolytic and sedative effect of pregabalin in children. Materials and Methods: Twenty-five children were randomized to a double-blind placebo-controlled crossover clinical trial. Two visits were scheduled for each patient. At the first visit, 75 mg pregabalin or placebo was given randomly, and the alternative was administered at the next visit. Anxiolytic and sedative effects were measured using the visual analogue scale. The child′s behavior was rated with the Frankl behavioral rating scale and the sedation level during the dental procedure was scored using the Ramsay sedation scale. The unpaired, two-tailed Student′s t-test was used to compare the mean changes of visual analog scale (VAS for anxiety in the pregabalin group with that of the placebo group. A repeated measures MANOVA model was used to detect differences in sedation level in the pregabalin and placebo groups regarding the interaction of 3-time measurements; sub-group analysis was performed using Student′s t-test. The Mann-Whitney U-test was used to analyze the nonparametric data of the Frankl and Ramsay scales. A P < 0.05 was considered significant. Results: The reduction of the VAS-anxiety score from 2 h post-dose was statistically significant in the pregabalin group. From 2 h to 4 h post-dose, the VAS-sedation score increased significantly in the pregabalin group. The child′s behavior rating was not significantly different between the groups. The number of "successful" treatment visits was higher in the pregabalin group compared to the placebo group. Conclusion: Significant anxiolytic and sedative effects can be anticipated 2 h after oral administration of pregabalin without serious

Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension.

Science.gov (United States)

Aman, Michael G; Findling, Robert L; Hardan, Antonio Y; Hendren, Robert L; Melmed, Raun D; Kehinde-Nelson, Ola; Hsu, Hai-An; Trugman, Joel M; Palmer, Robert H; Graham, Stephen M; Gage, Allyson T; Perhach, James L; Katz, Ephraim

2017-06-01

Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension. A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day. There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks. This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.

Open-label, dose escalation phase I study in healthy volunteers to evaluate the safety and pharmacokinetics of a human monoclonal antibody to Clostridium difficile toxin A.

Science.gov (United States)

Taylor, Claribel P; Tummala, Sanjeev; Molrine, Deborah; Davidson, Lisa; Farrell, Richard J; Lembo, Anthony; Hibberd, Patricia L; Lowy, Israel; Kelly, Ciaran P

2008-06-25

Recent data suggest that Clostridium difficile-associated diarrhea is becoming more severe and difficult to treat. Antibody responses to C. difficile toxin A are protective against symptomatic disease and recurrence. We examined the safety and pharmacokinetics (pk) of a novel neutralizing human monoclonal antibody against C. difficile toxin A (CDA1) in healthy adults. Five cohorts with 6 subjects each received a single intravenous infusion of CDA1 at escalating doses of 0.3, 1, 5, 10, and 20 mg/kg. Safety evaluations took place on days 1, 2, 3, 7, 14, 28, and 56 post-infusion. Samples for pk analysis were obtained before and after infusion, and at each safety evaluation. Serum CDA1 antibody concentrations and human anti-human antibody (HAHA) titers were measured with enzyme-linked immunosorbent assays. A noncompartmental model was used for pk analysis. Thirty subjects were enrolled. The median age was 27.5 yrs. There were no serious adverse events (AE) related to CDA1. Twenty-one of the 48 reported non-serious adverse events were possibly related to CDA1, and included transient blood pressure changes requiring no treatment, nasal congestion, headache, abdominal cramps, nausea, and self-limited diarrhea. Serum CDA1 concentrations increased with escalating doses: mean C(max) ranged from 6.82 microg/ml for the 0.3 mg/kg cohort to 511 microg/ml for the 20 mg/kg cohort. The geometric mean values of the half-life of CDA1 ranged between 25.3 and 31.8 days, and the volume of distribution approximated serum. No subject formed detectable HAHA titers. Administration of CDA1 as a single intravenous infusion was safe and well tolerated. C(max) increased proportionally with increasing doses. A randomized study of CDA1 in patients with C. difficile associated diarrhea is underway.

Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination

DEFF Research Database (Denmark)

Theander, Thor Grundtvig; Lusingu, John Peter Andrea

2014-01-01

BACKGROUND: A malaria vaccine could be an important addition to current control strategies. We report the safety and vaccine efficacy (VE) of the RTS,S/AS01 vaccine during 18 mo following vaccination at 11 African sites with varying malaria transmission. METHODS AND FINDINGS: 6,537 infants aged 6......-12 wk and 8,923 children aged 5-17 mo were randomized to receive three doses of RTS,S/AS01 or comparator vaccine. VE against clinical malaria in children during the 18 mo after vaccine dose 3 (per protocol) was 46% (95% CI 42% to 50%) (range 40% to 77%; VE, p... after vaccine dose 1 (intention to treat [ITT]) was 45% (95% CI 41% to 49%). VE against severe malaria, malaria hospitalization, and all-cause hospitalization was 34% (95% CI 15% to 48%), 41% (95% CI 30% to 50%), and 19% (95% CI 11% to 27%), respectively (ITT). VE against clinical malaria in infants...

Comparison of microdose flare-up and antagonist multiple-dose protocols for poor-responder patients: a randomized study.

Science.gov (United States)

Demirol, Aygul; Gurgan, Timur

2009-08-01

To compare the efficacy of the microdose flare-up and multiple-dose antagonist protocols for poor-responder patients in intracytoplasmic sperm injection-ET cycles. A randomized, prospective study. Center for assisted reproductive technology in Turkey. Ninety patients with poor ovarian response in a minimum of two previous IVF cycles. All women were prospectively randomized into two groups by computer-assisted randomization. The patients in group 1 were stimulated according to the microdose flare-up protocol (n = 45), while the patients in group 2 were stimulated according to antagonist multiple-dose protocol (n = 45). The mean number of mature oocytes retrieved was the primary outcome measure, and fertilization rate, implantation rate per embryo, and clinical pregnancy rates were secondary outcome measures. The mean age of the women, the mean duration of infertility, basal FSH level, and the number of previous IVF cycles were similar in both groups. The total gonadotropin dose used was significantly higher in group 2, while the number of oocytes retrieved was significantly greater in group 1. Although the fertilization and clinical pregnancy rates were nonsignificantly higher in group 1 compared with group 2, the implantation rate was significantly higher in the microdose flare-up group than in the multiple-dose antagonist group (22% vs. 11%). The microdose flare-up protocol seems to have a better outcome in poor-responder patients, with a significantly higher mean number of mature oocytes retrieved and higher implantation rate.

Do Dutch workers seek and find information on occupational safety and health?

Science.gov (United States)

Rhebergen, Martijn D F; Lenderink, Annet F; van Dijk, Frank J H; Hulshof, Carel T J

2012-03-01

Currently, little is known about workers' occupational safety and health (OSH) information-seeking behavior. We assessed whether Dutch workers have (OSH) questions, what motivates them to seek information or advice to solve these questions, and whether workers actually find the information they are looking for. A random sample of 888 workers from a large business panel were sent an online questionnaire. In total, 535 workers, likely parallel to the Dutch working population, returned the questionnaire (response rate 60%). In the last year, 380 of the 535 respondents (71%) had at least one OSH question. In total, 159 of the 380 respondents (42%) with an OSH question actively searched for information or advice. In a logistic regression analysis, three factors were identified to influence workers' information seeking: cognitions about personal benefits or costs of solving the question (OR = 2.8, 95% CI: 1.8-4.5), emotions that accompany the question (OR = 1.8, 95% CI: 1.1-3.0), and encouragement by the social environment (OR = 1.8, 95% CI: 1.0-3.0). In total, 50% of the respondents seeking information indicated they could not find (all) the information they sought. The barrier most often mentioned (47%) was the poor applicability of the information. Although most workers have OSH questions, only 40% seek information or advice to answer their questions. Moreover, many OSH questions remain unanswered by common information facilities. This study provides input on how to develop campaigns and new facilities that may induce workers to seek information and that offer more applicable information. Copyright © 2011 Wiley Periodicals, Inc.

Safety and immunogenicity of a tetravalent dengue vaccine in healthy children aged 2-11 years in Malaysia: a randomized, placebo-controlled, Phase III study.

Science.gov (United States)

Hss, Amar-Singh; Koh, Mia-Tuang; Tan, Kah Kee; Chan, Lee Gaik; Zhou, Lynn; Bouckenooghe, Alain; Crevat, Denis; Hutagalung, Yanee

2013-12-02

Dengue disease is a major public health problem across the Asia-Pacific region for which there is no licensed vaccine or treatment. We evaluated the safety and immunogenicity of Phase III lots of a candidate vaccine (CYD-TDV) in children in Malaysia. In this observer-blind, placebo-controlled, Phase III study, children aged 2-11 years were randomized (4:1) to receive CYD-TDV or placebo at 0, 6 and 12 months. Primary endpoints included assessment of reactogenicity following each dose, adverse events (AEs) and serious AEs (SAEs) reported throughout the study, and immunogenicity expressed as geometric mean titres (GMTs) and distribution of dengue virus (DENV) neutralizing antibody titres. 250 participants enrolled in the study (CYD-TDV: n=199; placebo: n=51). There was a trend for reactogenicity to be higher with CYD-TDV than with placebo post-dose 1 (75.4% versus 68.6%) and post-dose 2 (71.6% versus 62.0%) and slightly lower post-dose 3 (57.9% versus 64.0%). Unsolicited AEs declined in frequency with each subsequent dose and were similar overall between groups (CYD-TDV: 53.8%; placebo: 49.0%). Most AEs were of Grade 1 intensity and were transient. SAEs were reported by 5.5% and 11.8% of participants in the CYD-TDV and placebo groups, respectively. No deaths were reported. Baseline seropositivity against each of the four DENV serotypes was similar between groups, ranging from 24.0% (DENV-4) to 36.7% (DENV-3). In the CYD-TDV group, GMTs increased post-dose 2 for all serotypes compared with baseline, ranging from 4.8 (DENV-1) to 8.1-fold (DENV-3). GMTs further increased post-dose 3 for DENV-1 and DENV-2. Compared with baseline, individual titre increases ranged from 6.1-fold (DENV-1) to 7.96-fold (DENV-3). This study demonstrated a satisfactory safety profile and a balanced humoral immune response against all four DENV serotypes for CYD-TDV administered via a three-dose regimen to children in Malaysia. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All

A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease

Science.gov (United States)

Sperling, R.; Keren, R.; Porsteinsson, A.P.; van Dyck, C.H.; Tariot, P.N.; Gilman, S.; Arnold, D.; Abushakra, S.; Hernandez, C.; Crans, G.; Liang, E.; Quinn, G.; Bairu, M.; Pastrak, A.; Cedarbaum, J.M.

2011-01-01

Objective: This randomized, double-blind, placebo-controlled, dose-ranging phase 2 study explored safety, efficacy, and biomarker effects of ELND005 (an oral amyloid anti-aggregation agent) in mild to moderate Alzheimer disease (AD). Methods: A total of 353 patients were randomized to ELND005 (250, 1,000, or 2,000 mg) or placebo twice daily for 78 weeks. Coprimary endpoints were the Neuropsychological Test Battery (NTB) and Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale. The primary analysis compared 250 mg (n =84) to placebo (n =82) after an imbalance of infections and deaths led to early discontinuation of the 2 higher dose groups. Results: The 250 mg dose demonstrated acceptable safety. The primary efficacy analysis at 78 weeks revealed no significant differences between the treatment groups on the NTB or ADCS-ADL. Brain ventricular volume showed a small but significant increase in the overall 250 mg group (p =0.049). At the 250 mg dose, scyllo-inositol concentrations increased in CSF and brain and CSF Aβx-42 was decreased significantly compared to placebo (p =0.009). Conclusions: Primary clinical efficacy outcomes were not significant. The safety and CSF biomarker results will guide selection of the optimal dose for future studies, which will target earlier stages of AD. Classification of evidence: Due to the small sample sizes, this Class II trial provides insufficient evidence to support or refute a benefit of ELND005. PMID:21917766

On efficient randomized algorithms for finding the PageRank vector

Science.gov (United States)

Gasnikov, A. V.; Dmitriev, D. Yu.

2015-03-01

Two randomized methods are considered for finding the PageRank vector; in other words, the solution of the system p T = p T P with a stochastic n × n matrix P, where n ˜ 107-109, is sought (in the class of probability distributions) with accuracy ɛ: ɛ ≫ n -1. Thus, the possibility of brute-force multiplication of P by the column is ruled out in the case of dense objects. The first method is based on the idea of Markov chain Monte Carlo algorithms. This approach is efficient when the iterative process p {/t+1 T} = p {/t T} P quickly reaches a steady state. Additionally, it takes into account another specific feature of P, namely, the nonzero off-diagonal elements of P are equal in rows (this property is used to organize a random walk over the graph with the matrix P). Based on modern concentration-of-measure inequalities, new bounds for the running time of this method are presented that take into account the specific features of P. In the second method, the search for a ranking vector is reduced to finding the equilibrium in the antagonistic matrix game where S n (1) is a unit simplex in ℝ n and I is the identity matrix. The arising problem is solved by applying a slightly modified Grigoriadis-Khachiyan algorithm (1995). This technique, like the Nazin-Polyak method (2009), is a randomized version of Nemirovski's mirror descent method. The difference is that randomization in the Grigoriadis-Khachiyan algorithm is used when the gradient is projected onto the simplex rather than when the stochastic gradient is computed. For sparse matrices P, the method proposed yields noticeably better results.

Efficacy and safety comparison between liraglutide as add-on therapy to insulin and insulin dose-increase in Chinese subjects with poorly controlled type 2 diabetes and abdominal obesity

Directory of Open Access Journals (Sweden)

Li Chun-jun

2012-11-01

Full Text Available Abstract Objective To assess the efficacy and safety of adding liraglutide to established insulin therapy in poorly controlled Chinese subjects with type 2 diabetes and abdominal obesity compared with increasing insulin dose. Methods A 12-week, randomized, parallel-group study was carried out. A total of 84 patients completed the trial who had been randomly assigned to either the liraglutide-added group or the insulin-increasing group while continuing current insulin based treatment. Insulin dose was reduced by 0-30% upon the initiation of liraglutide. Insulin doses were subsequently adjusted to optimized glycemic control. Glycosylated hemoglobin (HbA1c values, blood glucose, total daily insulin dose, body weight, waist circumference, and the number of hypoglycemic events and adverse events were evaluated. Results At the end of study, the mean reduction in HbA1c between the liraglutide-added group and the insulin-increasing group was not significantly different (1.9% vs. 1.77%, p>0.05. However, the percentage of subjects reaching the composite endpoint of HbA1c ≤ 7.0% with no weight gain and no hypoglycemia, was significantly higher in the liraglutide-added group than in the insulin-increasing group (67% vs. 19%, p2, p Conclusions Addition of liraglutide to abdominally obese, insulin-treated patients led to improvement in glycemic control similar to that achieved by increasing insulin dosage, but with a lower daily dose of insulin and fewer hypoglycemic events. Adding liraglutide to insulin also induced a significant reduction in body weight and waist circumference. Liraglutide combined with insulin may be the best treatment option for poorly controlled type 2 diabetes and abdominal obesity.

Nonclinical safety of mavrilimumab, an anti-GMCSF receptor alpha monoclonal antibody, in cynomolgus monkeys: Relevance for human safety

Energy Technology Data Exchange (ETDEWEB)

Ryan, Patricia C., E-mail: ryanp@medimmune.com [MedImmune, LLC, Gaithersburg, MD (United States); Sleeman, Matthew A. [MedImmune, LLC, Cambridge (United Kingdom); Rebelatto, Marlon [MedImmune, LLC, Gaithersburg, MD (United States); Wang, Bing; Lu, Hong [MedImmune, LLC, Moutain View, CA (United States); Chen, Xiaomin [Novartis, East Hanover, NJ (United States); Wu, Chi-Yuan [MedImmune, LLC, Moutain View, CA (United States); Hinrichs, Mary Jane; Roskos, Lorin [MedImmune, LLC, Gaithersburg, MD (United States); Towers, Heidi [MedImmune, LLC, Cambridge (United Kingdom); McKeever, Kathleen; Dixit, Rakesh [MedImmune, LLC, Gaithersburg, MD (United States)

2014-09-01

Mavrilimumab (CAM-3001) is an investigational human IgG4 monoclonal antibody (MAb) targeting GM-CSF receptor alpha which is currently being developed for the treatment of RA. GM-CSF plays a central role in the pathogenesis of rheumatoid arthritis (RA) through the activation, differentiation, and survival of macrophages and neutrophils. To support clinical development, the nonclinical safety of mavrilimumab was evaluated in several studies with cynomolgus monkeys as the pharmacologically relevant species. Comprehensive toxicity parameters were assessed in each study, and treatment duration ranged from 4 to 26 weeks. Mavrilimumab has an acceptable safety profile in monkeys with no changes in any parameters other than microscopic findings in lung. In several studies, minimal accumulation of foamy alveolar macrophages was observed. This finding was only seen in studies of at least 11 weeks duration, was reversible following a dose-free recovery period and was considered non-adverse. At higher dose levels (≥ 30 mg/kg/week), in a 26-week repeat-IV dose study, the presence of lung foreign material, cholesterol clefts, and granulomatous inflammation was also observed in a few animals and was considered adverse. The dose- and time-related accumulation of foamy macrophages in lung following exposure to mavrilimumab observed in several NHP studies was expected based upon the known role of GM-CSFRα signaling in the function of alveolar macrophages. Overall, a clean no-observed-adverse-effect-level (NOAEL) without any effects in lung was established and provided adequate clinical safety margins. In clinical studies in RA patients, mavrilimumab has demonstrated good clinical activity with adequate safety to support further clinical development. A Phase 2b study of mavrilimumab in subjects with RA is in progress. - Highlights: • Mavrilimumab is a MAB targeting GM-CSFRα being developed for RA therapy. • Mavrilimumab has an acceptable safety profile in cynomolgus monkeys. �

Nonclinical safety of mavrilimumab, an anti-GMCSF receptor alpha monoclonal antibody, in cynomolgus monkeys: Relevance for human safety

International Nuclear Information System (INIS)

Ryan, Patricia C.; Sleeman, Matthew A.; Rebelatto, Marlon; Wang, Bing; Lu, Hong; Chen, Xiaomin; Wu, Chi-Yuan; Hinrichs, Mary Jane; Roskos, Lorin; Towers, Heidi; McKeever, Kathleen; Dixit, Rakesh

2014-01-01

Mavrilimumab (CAM-3001) is an investigational human IgG4 monoclonal antibody (MAb) targeting GM-CSF receptor alpha which is currently being developed for the treatment of RA. GM-CSF plays a central role in the pathogenesis of rheumatoid arthritis (RA) through the activation, differentiation, and survival of macrophages and neutrophils. To support clinical development, the nonclinical safety of mavrilimumab was evaluated in several studies with cynomolgus monkeys as the pharmacologically relevant species. Comprehensive toxicity parameters were assessed in each study, and treatment duration ranged from 4 to 26 weeks. Mavrilimumab has an acceptable safety profile in monkeys with no changes in any parameters other than microscopic findings in lung. In several studies, minimal accumulation of foamy alveolar macrophages was observed. This finding was only seen in studies of at least 11 weeks duration, was reversible following a dose-free recovery period and was considered non-adverse. At higher dose levels (≥ 30 mg/kg/week), in a 26-week repeat-IV dose study, the presence of lung foreign material, cholesterol clefts, and granulomatous inflammation was also observed in a few animals and was considered adverse. The dose- and time-related accumulation of foamy macrophages in lung following exposure to mavrilimumab observed in several NHP studies was expected based upon the known role of GM-CSFRα signaling in the function of alveolar macrophages. Overall, a clean no-observed-adverse-effect-level (NOAEL) without any effects in lung was established and provided adequate clinical safety margins. In clinical studies in RA patients, mavrilimumab has demonstrated good clinical activity with adequate safety to support further clinical development. A Phase 2b study of mavrilimumab in subjects with RA is in progress. - Highlights: • Mavrilimumab is a MAB targeting GM-CSFRα being developed for RA therapy. • Mavrilimumab has an acceptable safety profile in cynomolgus monkeys. �

Radiotherapy for calcaneodynia. Results of a single center prospective randomized dose optimization trial

Energy Technology Data Exchange (ETDEWEB)

Ott, O.J.; Jeremias, C.; Gaipl, U.S.; Frey, B.; Schmidt, M.; Fietkau, R. [University Hospital Erlangen (Germany). Dept. of Radiation Oncology

2013-04-15

The aim of this work was to compare the efficacy of two different dose fractionation schedules for radiotherapy of patients with calcaneodynia. Between February 2006 and April 2010, 457 consecutive evaluable patients were recruited for this prospective randomized trial. All patients received radiotherapy using the orthovoltage technique. One radiotherapy series consisted of 6 single fractions/3 weeks. In case of insufficient remission of pain after 6 weeks a second radiation series was performed. Patients were randomly assigned to receive either single doses of 0.5 or 1.0 Gy. Endpoint was pain reduction. Pain was measured before, immediately after, and 6 weeks after radiotherapy using a visual analogue scale (VAS) and a comprehensive pain score (CPS). The overall response rate for all patients was 87 % directly after and 88 % 6 weeks after radiotherapy. The mean VAS values before, immediately after, and 6 weeks after treatment for the 0.5 and 1.0 Gy groups were 65.5 {+-} 22.1 and 64.0 {+-} 20.5 (p = 0.188), 34.8 {+-} 24.7 and 39.0 {+-} 26.3 (p = 0.122), and 25.1 {+-} 26.8 and 28.9 {+-} 26.8 (p = 0.156), respectively. The mean CPS before, immediately after, and 6 weeks after treatment was 10.1 {+-} 2.7 and 10.0 {+-} 3.0 (p = 0.783), 5.6 {+-} 3.7 and 6.0 {+-} 3.9 (p = 0.336), 4.0 {+-} 4.1 and 4.3 {+-} 3.6 (p = 0.257), respectively. No statistically significant differences between the two single dose trial arms for early (p = 0.216) and delayed response (p = 0.080) were found. Radiotherapy is an effective treatment option for the management of calcaneodynia. For radiation protection reasons, the dose for a radiotherapy series is recommended not to exceed 3-6 Gy. (orig.)

Some Findings from Thermal-Hydraulic Validation Tests for SMART Passive Safety System

Energy Technology Data Exchange (ETDEWEB)

Park, Hyun Sik; Bae, Hwang; Ryu, Sung-Uk; Ryu, Hyobong; Shin, Yong-Cheol; Min, Kyoung-Ho; Yi, Sung-Jae [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

2014-10-15

To satisfy the domestic and international needs for nuclear safety improvement after the Fukushima accident, an effort to improve its safety has been studied, and a Passive Safety System (PSS) for SMART has been designed. In addition, an Integral Test Loop for the SMART design (SMART-ITL, or FESTA) has been constructed and it finished its commissioning tests in 2012. Consequently, a set of Design Base Accident (DBA) scenarios have been simulated using SMARTITL. Recently, a test program to validate the performance of the SMART PSS was launched and its scaled-down test facility was additionally installed at the existing SMART-ITL facility. In this paper, some findings from the validation tests for the SMART PSS will be summarized. The acquired data will be used to validate the safety analysis code and its related models, to evaluate the performance of SMART PSS, and to provide base data during the application phase of SDA revision and construction licensing. A test program to validate the performance of SMARS PSS was launched with an additional scaleddown test facility of SMART PSS, which will be installed at the existing SMART-ITL facility. In this paper, some findings from the validation tests of the SMART passive safety system during 2013-2014 were summarized. They include a couple of SMART PSS tests using active pumps and several 1-train SMART PSS tests. From the test results it was estimated that the SMART PSS has sufficient cooling capability to deal with the SBLOCA scenario of SMART. During the SBLOCA scenario, in the CMT the water layer inventory was well stratified thermally and the safety injection water was injected efficiently into the RPV from the initial period and cools down the RCS properly.

Phase I clinical studies of the advanced glycation end-product (AGE)-breaker TRC4186: safety, tolerability and pharmacokinetics in healthy subjects.

Science.gov (United States)

Chandra, Kumar P; Shiwalkar, Ajay; Kotecha, Jignesh; Thakkar, Purav; Srivastava, Ambrish; Chauthaiwale, Vijay; Sharma, Sanjay K; Cross, Maurice R; Dutt, Chaitanya

2009-01-01

Advanced glycation end-products (AGEs) have been implicated in the pathogenesis of diabetic complications through a variety of mechanisms including endothelial dysfunction and structural abnormalities in the vasculature and myocardium. Reducing the AGEs burden and their ensuing pro-inflammatory, pro-oxidative and pro-coagulant effect with associated dysfunctional proteins in various target tissues may retard the progression of and even reverse diabetic macro- and microvascular complications. Pyridinium, 3-[[2-(methylsulfonyl) hydrazino] carbonyl]-1-[2-oxo-2-2-thienyl) ethyl]-chloride (TRC4186) has demonstrated AGE-breaking activities in in vitro experiments and improvement in the endothelial and myocardial function in animal models of diabetes mellitus with reduction of AGEs accumulation in tissues over time. The safety of TRC4186 has been established in in vitro and in vivo preclinical studies. Thus, this drug is being developed for the treatment of complications associated with diabetes. This investigation set out to evaluate the safety, tolerability and pharmacokinetics of TRC4186 in healthy human subjects after single and multiple ascending doses, fixed doses in elderly male and female subjects, and with food and different formulations of the compound. Four studies were conducted during phase I clinical development of TRC4186. These were: (i) a randomized, double-blind, placebo-controlled, single-dose, dose-ascending study in healthy male subjects with doses of TRC4186 ranging from 250 to 2500 mg administered as an oral solution (total six doses); (ii) a randomized, double-blind, placebo-controlled, multiple-dose, dose-ascending study in healthy male subjects with three doses of TRC4186 ranging from 500 to 2000 mg twice daily for 6 days with a final single dose on day 7; (iii) a randomized, open-label, three-way crossover study to assess the effect of food (fasted vs fed) and formulation (solution vs tablet) with TRC4186 500 mg; (iv) a randomized, double

Acute and chronic safety and efficacy of dose dependent creatine nitrate supplementation and exercise performance

OpenAIRE

Galvan, Elfego; Walker, Dillon K.; Simbo, Sunday Y.; Dalton, Ryan; Levers, Kyle; O?Connor, Abigail; Goodenough, Chelsea; Barringer, Nicholas D.; Greenwood, Mike; Rasmussen, Christopher; Smith, Stephen B.; Riechman, Steven E.; Fluckey, James D.; Murano, Peter S.; Earnest, Conrad P.

2016-01-01

Background Creatine monohydrate (CrM) and nitrate are popular supplements for improving exercise performance; yet have not been investigated in combination. We performed two studies to determine the safety and exercise performance-characteristics of creatine nitrate (CrN) supplementation. Methods Study 1 participants (N?=?13) ingested 1.5?g CrN (CrN-Low), 3?g CrN (CrN-High), 5?g CrM or a placebo in a randomized, crossover study (7d washout) to determine supplement safety (hepatorenal and musc...

Single Intravenous Dose of Oritavancin for Treatment of Acute Skin and Skin Structure Infections Caused by Gram-Positive Bacteria: Summary of Safety Analysis from the Phase 3 SOLO Studies.

Science.gov (United States)

Corey, G Ralph; Loutit, Jeffery; Moeck, Greg; Wikler, Matthew; Dudley, Michael N; O'Riordan, William

2018-04-01

Oritavancin is a lipoglycopeptide with bactericidal activity against Gram-positive organisms. Its rapid concentration-dependent bactericidal activity and long elimination half-life allow single-dose treatment of acute bacterial skin and skin structure infections (ABSSSI). SOLO I and SOLO II were randomized, double-blind studies evaluating the efficacy and safety of a single 1,200-mg intravenous (i.v.) dose of oritavancin versus twice-daily i.v. vancomycin for 7 to 10 days in ABSSSI patients. Safety data from both studies were pooled for safety analysis. The database comprised pooled safety data for 976 oritavancin-treated patients and 983 vancomycin-treated patients. The incidences of adverse events, serious adverse events, and discontinuations due to adverse events were similar for oritavancin (55.3, 5.8, and 3.7%, respectively) and vancomycin (56.9, 5.9, and 4.2%, respectively). The median time to onset (3.8 days versus 3.1 days, respectively) and the duration (3.0 days for both groups) of adverse events were also similar between the two groups. The most frequently reported events were nausea, headache, and vomiting. Greater than 90% of all events were mild or moderate in severity. There were slightly more infections and infestations, abscesses or cellulitis, and hepatic and cardiac adverse events in the oritavancin group; however, more than 80% of these events were mild or moderate. Subgroup analyses did not identify clinically meaningful differences in the incidence of adverse events attributed to oritavancin. A single 1,200-mg dose of oritavancin was well tolerated and had a safety profile similar to that of twice-daily vancomycin. The long elimination half-life of oritavancin compared to that of vancomycin did not result in a clinically meaningful delay to the onset or prolongation of adverse events. (This study has been registered at ClinicalTrials.gov under registration no. NCT01252719 and NCT01252732.). Copyright © 2018 American Society for Microbiology.

Efficacy and safety of extended- versus immediate-release pramipexole in Japanese patients with advanced and L-dopa-undertreated Parkinson disease: a double-blind, randomized trial.

Science.gov (United States)

Mizuno, Yoshikuni; Yamamoto, Mitsutoshi; Kuno, Sadako; Hasegawa, Kazuko; Hattori, Nobutaka; Kagimura, Tatsuro; Sarashina, Akiko; Rascol, Olivier; Schapira, Anthony H V; Barone, Paolo; Hauser, Robert A; Poewe, Werner

2012-01-01

To compare the efficacy, safety, tolerability, and trough plasma levels of pramipexole extended-release (ER) and pramipexole immediate-release (IR), and to assess the effects of overnight switching from an IR to an ER formulation, in L-dopa-treated patients with Parkinson disease (PD). After a 1- to 4-week screening/enrollment, 112 patients who had exhibited L-dopa-related problems or were receiving suboptimal L-dopa dosage were randomized in double-blind, double-dummy, 1:1 fashion to pramipexole ER once daily or pramipexole IR 2 to 3 times daily for 12 weeks, both titrated to a maximum daily dose of 4.5 mg. Successful completers of double-blind treatment were switched to open-label pramipexole ER, beginning with a 4-week dose-adjustment phase. Among the double-blind treatment patients (n = 56 in each group), Unified Parkinson's Disease Rating Scale Parts II+III total scores decreased significantly from baseline and to a similar degree with pramipexole ER and IR formulations. In each group, 47 double-blind patients (83.9%) reported adverse events (AEs), requiring withdrawal of 3 ER patients (5.4%) and 2 IR patients (3.6%). Trough plasma levels at steady state (at the same doses and dose-normalized concentrations) were also similar with both formulations. Among open-label treatment patients (n = 53 from IR to ER), 83% were successfully switched (no worsening of PD symptoms) to pramipexole ER. In L-dopa-treated patients, pramipexole ER and pramipexole IR demonstrated similar efficacy, safety, tolerability, and trough plasma levels. Patients can be safely switched overnight from pramipexole IR to pramipexole ER with no impact on efficacy.

Efficacy, safety and immunogenicity of a human rotavirus vaccine (RIX4414) in Hong Kong children up to three years of age: a randomized, controlled trial.

Science.gov (United States)

Lau, Yu-Lung; Nelson, E Anthony S; Poon, Kin-Hung; Chan, Paul K S; Chiu, Susan; Sung, Rita; Leung, Chi Wai; Ng, Daniel; Ma, Yee Man; Chan, Desmond; Lee, Tsz Leung; Tang, Joyce; Kwan, Yat Wah; Ip, Patricia; Ho, Marco; Fung, Lai-Wah Eva; Tang, Haiwen; Suryakiran, P V; Han, Htay Htay; Bock, Hans

2013-04-26

A phase III, double-blind, randomized, controlled trial was conducted in Hong Kong to evaluate the efficacy, safety and immunogenicity of a human rotavirus vaccine, RIX4414 (Rotarix) against severe rotavirus gastroenteritis in children up to three years of age. Healthy infants aged 6-12 weeks were enrolled between 08-December-2003 and 31-August-2005 and received two oral doses of either RIX4414 vaccine (N=1513) or placebo (N=1512) given 2 months apart. Vaccine efficacy was assessed from two weeks post-Dose 2 until the children were two and three years of age. Anti-rotavirus IgA seroconversion rate was calculated pre-vaccination and 1-2 months post-Dose 2 using ELISA (cut-off=20 U/mL) for 100 infants. Safety was assessed until the children were two years of age; serious adverse events (SAEs) were recorded throughout the study period. In children aged two and three years of life, vaccine efficacy against severe rotavirus gastroenteritis was 95.6% (95% CI: 73.1%-99.9%) and 96.1% (95% CI: 76.5%-99.9%), respectively. The seroconversion rate 1-2 months after the second dose of RIX4414 was 97.5% (95% CI: 86.8%-99.9%). At least one SAE was recorded in 439 and 477 infants who were administered RIX4414 and placebo, respectively (p-value=0.130). Six intussusception cases were reported (RIX4414=4; placebo=2) and none was assessed to be vaccine-related. RIX4414 was efficacious, immunogenic and safe in the prevention of rotavirus gastroenteritis for at least two years post-vaccination in Hong Kong children. Copyright © 2013 Elsevier Ltd. All rights reserved.

Intraoperative use of low-dose recombinant activated factor VII during thoracic aortic operations.

Science.gov (United States)

Andersen, Nicholas D; Bhattacharya, Syamal D; Williams, Judson B; Fosbol, Emil L; Lockhart, Evelyn L; Patel, Mayur B; Gaca, Jeffrey G; Welsby, Ian J; Hughes, G Chad

2012-06-01

Numerous studies have supported the effectiveness of recombinant activated factor VII (rFVIIa) for the control of bleeding after cardiac procedures; however safety concerns persist. Here we report the novel use of intraoperative low-dose rFVIIa in thoracic aortic operations, a strategy intended to improve safety by minimizing rFVIIa exposure. Between July 2005 and December 2010, 425 consecutive patients at a single referral center underwent thoracic aortic operations with cardiopulmonary bypass (CPB); 77 of these patients received intraoperative low-dose rFVIIa (≤60 μg/kg) for severe coagulopathy after CPB. Propensity matching produced a cohort of 88 patients (44 received intraoperative low-dose rFVIIa and 44 controls) for comparison. Matched patients receiving intraoperative low-dose rFVIIa got an initial median dose of 32 μg/kg (interquartile range [IQR], 16-43 μg/kg) rFVIIa given 51 minutes (42-67 minutes) after separation from CPB. Patients receiving intraoperative low-dose rFVIIa demonstrated improved postoperative coagulation measurements (partial thromboplastin time 28.6 versus 31.5 seconds; p=0.05; international normalized ratio, 0.8 versus 1.2; pproduct transfusions (2.5 versus 5.0 units; p=0.05) compared with control patients. No patient receiving intraoperative low-dose rFVIIa required postoperative rFVIIa administration or reexploration for bleeding. Rates of stroke, thromboembolism, myocardial infarction, and other adverse events were equivalent between groups. Intraoperative low-dose rFVIIa led to improved postoperative hemostasis with no apparent increase in adverse events. Intraoperative rFVIIa administration in appropriately selected patients may correct coagulopathy early in the course of refractory blood loss and lead to improved safety through the use of smaller rFVIIa doses. Appropriately powered randomized studies are necessary to confirm the safety and efficacy of this approach. Copyright © 2012 The Society of Thoracic Surgeons

Pharmacokinetic properties and tolerability of low-dose SoluMatrix diclofenac.

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Desjardins, Paul J; Olugemo, Kemi; Solorio, Daniel; Young, Clarence L

2015-02-01

This study compared the pharmacokinetic properties and safety profile of low-dose (18- and 35-mg) diclofenac capsules manufactured using SoluMatrix Fine Particle Technology (Trademark of iCeutica Inc. (Philadelphia, Pennsylvania), and the technology is licensed to Iroko Pharmaceuticals, LLC (Philadelphia, Pennsylvania) for exclusive use in NSAIDs), which produces submicron-sized drug particles with enhanced dissolution properties, to those of diclofenac potassium immediate-release (IR) 50-mg tablets. This Phase 1, single-center, randomized, open-label, single-dose crossover study was conducted in 40 healthy volunteers. Subjects received, in randomized order, SoluMatrix diclofenac 18- or 35-mg capsules in the fasting condition, SoluMatrix diclofenac 35-mg capsules under fed conditions, and diclofenac potassium IR 50-mg tablets under fasting and fed conditions. Pharmacokinetic parameters (T(max), C(max), AUC(0-t), AUC(0-∞)) were calculated from the concentrations of diclofenac in the plasma. Absorption, food effect, and dose proportionality were determined using a mixed-model ANOVA for C(max), AUC(0-t), AUC(0-∞). Tolerability was assessed by recording adverse events, physical examination findings, vital sign measurements: clinical laboratory test results. Overall, 35 healthy volunteers aged 18 to 52 years completed the study. The mean age of the subjects was 33.4 years, and approximately half were men (47.5%). Median T(max) values were similar between the low-dose SoluMatrix diclofenac 35-mg capsules and the diclofenac potassium IR 50-mg tablets (both, ~1.0 hour). The mean maximum plasma concentration (C(max)) after the administration of low-dose SoluMatrix diclofenac 35-mg capsules was 26% lower than that with diclofenac potassium IR 50-mg tablets under fasting conditions (868.72 vs 1194.21 ng/mL). The administration of low-dose SoluMatrix diclofenac 35-mg capsules was associated with a 23% lower overall systemic exposure compared with that of diclofenac

Safety and efficacy of low-dose, subacute exposure of mature ewes to sodium chlorate

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The objective was to determine the safety and efficacy of low-dose, subacute exposure of mature ewes to NaClO3 in the drinking water. Twenty-five ewes (BW = 62.5 ± 7.3 kg) were placed indoors in individual pens with ad libitum access to water and feed. After 7 d of adaptation, ewes were assigned ran...

Moderate- vs high-dose methadone in the treatment of opioid dependence: a randomized trial.

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Strain, E C; Bigelow, G E; Liebson, I A; Stitzer, M L

1999-03-17

Methadone hydrochloride treatment is the most common pharmacological intervention for opioid dependence, and recent interest has focused on expanding methadone treatment availability beyond traditional specially licensed clinics. However, despite recommendations regarding effective dosing of methadone, controlled clinical trials of higher-dose methadone have not been conducted. To compare the relative clinical efficacy of moderate- vs high-dose methadone in the treatment of opioid dependence. A 40-week randomized, double-blind clinical trial starting in June 1992 and ending in October 1995. Outpatient substance abuse treatment research clinic at the Johns Hopkins University Bayview Campus, Baltimore, Md. One hundred ninety-two eligible clinic patients. Daily oral methadone hydrochloride in the dose range of 40 to 50 mg (n = 97) or 80 to 100 mg (n = 95), with concurrent substance abuse counseling. Opioid-positive urinalysis results and retention in treatment. By intent-to-treat analysis through week 30 patients in the high-dose group had significantly lower rates of opioid-positive urine samples compared with patients in the moderate-dose group (53.0% [95% confidence interval [CI], 46.9%-59.2%] vs 61.9% [95% CI, 55.9%-68.0%]; P = .047. These differences persisted during withdrawal from methadone. Through day 210 no significant difference was evident between dose groups in treatment retention (high-dose group mean retention, 159 days; moderate-dose group mean retention, 157 days). Nineteen (33%) of 57 patients in the high-dose group and 11 (20%) of 54 patients in the moderate-dose group completed detoxification. Both moderate- and high-dose methadone treatment resulted in decreased illicit opioid use during methadone maintenance and detoxification. The high-dose group had significantly greater decreases in illicit opioid use.

Application of non-dose/risk indicators for confidence-building in the H12 safety assessment

International Nuclear Information System (INIS)

Miyahara, K.; Makino, H.; Takasu, A.; Naito, M.; Umeke, H.; Wakasugi, K.; Ishiguro, K.

2002-01-01

In the H12 study, non-dose/risk safety indicators have also been considered with a view to increasing confidence in the safety assessment. The H12 safety assessment considers system evolution for a range of scenarios; not only normal groundwater scenarios but also isolation failure scenarios due to unlikely natural disruptive events. The calculated nuclide concentrations and fluxes in the surface environment for the reference groundwater scenario were compared with measurements of naturally occurring nuclides. This comparison indicated that the concentration and fluxes of radionuclides released from the repository would be several orders of magnitude lower than those of natural radionuclides. There may exist cases, such as some natural disruptive events, where the likelihood of occurrence is extremely low and the 'Reference Biosphere' approach is difficult to be applied for biosphere modelling. The use of qualitative assessment to allow comparison with naturally occurring nuclides based on observations of natural systems may play a role in supporting the robustness of the system concept. These examples suggest that relevant application of these non-dose/risk indicators supports a more robust case. An advantage to applying such indicators is that both technical and non-technical audiences can judge the relative, long-term impact of a deep geological repository. (author)

Onset of efficacy and tolerability following the initiation dosing of long-acting paliperidone palmitate: post-hoc analyses of a randomized, double-blind clinical trial

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Fu Dong-Jing

2011-05-01

Full Text Available Abstract Background Paliperidone palmitate is a long-acting injectable atypical antipsychotic for the acute and maintenance treatment of adults with schizophrenia. The recommended initiation dosing regimen is 234 mg on Day 1 and 156 mg on Day 8 via intramuscular (deltoid injection; followed by 39 to 234 mg once-monthly thereafter (deltoid or gluteal. These post-hoc analyses addressed two commonly encountered clinical issues regarding the initiation dosing: the time to onset of efficacy and the associated tolerability. Methods In a 13-week double-blind trial, 652 subjects with schizophrenia were randomized to paliperidone palmitate 39, 156, or 234 mg (corresponding to 25, 100, or 150 mg equivalents of paliperidone, respectively or placebo (NCT#00590577. Subjects randomized to paliperidone palmitate received 234 mg on Day 1, followed by their randomized fixed dose on Day 8, and monthly thereafter, with no oral antipsychotic supplementation. The onset of efficacy was defined as the first timepoint where the paliperidone palmitate group showed significant improvement in the Positive and Negative Syndrome Scale (PANSS score compared to placebo (Analysis of Covariance [ANCOVA] models and Last Observation Carried Forward [LOCF] methodology without adjusting for multiplicity using data from the Days 4, 8, 22, and 36 assessments. Adverse event (AE rates and relative risks (RR with 95% confidence intervals (CI versus placebo were determined. Results Paliperidone palmitate 234 mg on Day 1 was associated with greater improvement than placebo on Least Squares (LS mean PANSS total score at Day 8 (p = 0.037. After the Day 8 injection of 156 mg, there was continued PANSS improvement at Day 22 (p ≤ 0.007 vs. placebo and Day 36 (p Conclusions Significantly greater symptom improvement was observed by Day 8 with paliperidone palmitate (234 mg on Day 1 compared to placebo; this effect was maintained after the 156 mg Day 8 injection, with a trend towards a dose

Random safety auditing, root cause analysis, failure mode and effects analysis.

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Ursprung, Robert; Gray, James

2010-03-01

Improving quality and safety in health care is a major concern for health care providers, the general public, and policy makers. Errors and quality issues are leading causes of morbidity and mortality across the health care industry. There is evidence that patients in the neonatal intensive care unit (NICU) are at high risk for serious medical errors. To facilitate compliance with safe practices, many institutions have established quality-assurance monitoring procedures. Three techniques that have been found useful in the health care setting are failure mode and effects analysis, root cause analysis, and random safety auditing. When used together, these techniques are effective tools for system analysis and redesign focused on providing safe delivery of care in the complex NICU system. Copyright 2010 Elsevier Inc. All rights reserved.

Single and Multiple Ascending-dose Studies of Oral Delafloxacin: Effects of Food, Sex, and Age.

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Hoover, Randall; Hunt, Thomas; Benedict, Michael; Paulson, Susan K; Lawrence, Laura; Cammarata, Sue; Sun, Eugene

2016-01-01

The objective of this report is describe the results of 2 studies that examined the pharmacokinetic parameters, safety profile, and tolerability of single and multiple ascending doses of oral delafloxacin and the effects of food, sex, and age on oral delafloxacin pharmacokinetic parameters, safety profile, and tolerability. The first study contained 3 parts and used unformulated delafloxacin in a capsule. Part 1 was a randomized, double-blind, placebo-controlled, single (50, 100, 200, 400, 800, 1200, and 1600 mg) ascending-dose study of oral delafloxacin in healthy men. Part 2 was a single-dose crossover study in which 20 men received 250 mg delafloxacin with or without food. Part 2 also included a parallel group, double-blind, placebo-controlled study in 16 women and 16 elderly men and women who were randomized (3:1) to receive 250 mg delafloxacin or placebo. Part 3 was a randomized, double-blind, placebo-controlled, multiple (100, 200, 400, 800, 1200 mg once daily for 5 days) ascending-dose study of oral delafloxacin in healthy men. The second study was a single-dose, randomized, 3-period crossover study in which participants received 900 mg delafloxacin (2 × 450-mg tablets) under fasted conditions, with a high-fat meal, or fasted with a high-fat meal 2 hours after dosing. Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were determined. Delafloxacin Cmax and AUC0-∞ increased with increasing oral dose over the dose range of 50 to 1600 mg. The increases in delafloxacin AUC0-∞ were dose proportional at doses of ≥200 mg. Steady state was reached by day 3 of dosing with minimal accumulation of delafloxacin. The Cmax of delafloxacin was decreased slightly in the presence of food. No sex difference in delafloxacin pharmacokinetic parameters was observed. In the elderly men and women, mean delafloxacin Cmax and AUC0-∞ were 35% higher than observed for young adults, which could be partially explained by a decrease in

Phase 2, Randomized, Double-Blind, Dose-Ranging Study Evaluating the Safety, Tolerability, Population Pharmacokinetics, and Efficacy of Oral Torezolid Phosphate in Patients with Complicated Skin and Skin Structure Infections▿ † ‡

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Prokocimer, P.; Bien, P.; Surber, J.; Mehra, P.; DeAnda, C.; Bulitta, J. B.; Corey, G. R.

2011-01-01

Torezolid (TR-700) is the active moiety of the prodrug torezolid phosphate ([TP] TR-701), a second-generation oxazolidinone with 4- to 16-fold greater potency than linezolid against Gram-positive species including methicillin-resistant Staphylococcus aureus (MRSA). A double-blind phase 2 study evaluated three levels (200, 300, or 400 mg) of oral, once-daily TP over 5 to 7 days for complicated skin and skin structure infections (cSSSI). Patients 18 to 75 years old with cSSSI caused by suspected or confirmed Gram-positive pathogens were randomized 1:1:1. Of 188 treated patients, 76.6% had abscesses, 17.6% had extensive cellulitis, and 5.9% had wound infections. S. aureus, the most common pathogen, was isolated in 90.3% of patients (139/154) with a baseline pathogen; 80.6% were MRSA. Cure rates in clinically evaluable patients were 98.2% at 200 mg, 94.4% at 300 mg, and 94.4% at 400 mg. Cure rates were consistent across diagnoses, regardless of lesion size or the presence of systemic signs of infection. Clinical cure rates in patients with S. aureus isolated at baseline were 96.6% overall and 96.8% for MRSA. TP was safe and well tolerated at all dose levels. No patients discontinued treatment due to an adverse event. Three-stage hierarchical population pharmacokinetic modeling yielded a geometric mean clearance of 8.28 liters/h (between-patient variability, 32.3%), a volume of the central compartment of 71.4 liters (24.0%), and a volume of the peripheral compartment of 27.9 liters (35.7%). Results of this study show a high degree of efficacy at all three dose levels without significant differences in the safety profile and support the continued evaluation of TP for the treatment of cSSSI in phase 3 trials. PMID:21115795

Partial safety factor calibration from stochastic finite element computation of welded joint with random geometries

International Nuclear Information System (INIS)

Schoefs, Franck; Chevreuil, Mathilde; Pasqualini, Olivier; Cazuguel, Mikaël

2016-01-01

Welded joints are used in various structures and infrastructures like bridges, ships and offshore structures, and are submitted to cyclic stresses. Their fatigue behaviour is an industrial key issue to deal with and still offers original research subjects. One of the available methods relies on the computing of the stress concentration factor. Even if some studies were previously driven to evaluate this factor onto some cases of welded structures, the shape of the weld joint is generally idealized through a deterministic parametric geometry. Previous experimental works however have shown that this shape plays a key role in the lifetime assessment. We propose in this paper a methodology for computing the stress concentration factor in presence of random geometries of welded joints. In view to make the results available by engineers, this method merges stochastic computation and semi-probabilistic analysis by computing partial safety factors with a dedicated method. - Highlights: • Numerical computation of stress concentration factor with random geometry of weld. • Real data are used for probabilistic modelling. • Identification of partial safety factor from SFEM computation in case of random geometries.

Phase I/II dose-finding study of nanoparticle albumin-bound paclitaxel (nab®-Paclitaxel) plus Cisplatin as Treatment for Metastatic Nasopharyngeal Carcinoma.

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Huang, Yan; Liang, Wenhua; Yang, Yunpeng; Zhao, Liping; Zhao, Hongyun; Wu, Xuan; Zhao, Yuanyuan; Zhang, Yang; Zhang, Li

2016-07-13

This phase I/II study aimed to determine the maximum tolerated dose (MTD) of nanoparticle albumin-bound paclitaxel (nab (®)-paclitaxel) plus cisplatin as treatment for metastatic nasopharyngeal carcinoma (NPC). Patients were enrolled into 1 of 3 dose cohorts, each with 21-day treatment cycles: 1) intravenous (IV) nab-paclitaxel 260 mg/m(2) on day 1; 2) IV nab-paclitaxel 140 mg/m(2) on days 1 and 8; 3) IV nab-paclitaxel 100 mg/m(2) on days 1, 8, and 15. All patients received IV cisplatin 75 mg/m(2) on day 1. Treatment continued for 4-6 cycles, or until progression or unacceptable toxicity. If more than one-third of the patients in a cohort experienced a dose-limiting toxicity (DLT), the dose used in the previous cohort would be designated the MTD. Secreted protein acidic and rich in cysteine (SPARC) expression was detected by immunohistochemistry staining. Sixty-nine patients were enrolled, of whom 64 and 67 were eligible for efficacy and safety analysis, respectively. Two DLTs occurred in cohort 1 (grade 4 febrile neutropenia, grade 3 myalgia), none occurred in cohort 2, and 2 occurred in cohort 3 (both grade 3 fatigue). The MTD was not reached. Partial responses were achieved by 42 patients, 15 had stable disease, and 7 had progressive disease, giving an overall response rate of 66 %. Median progression-free survival was 9 months (95 % CI, 6-12 months). Grade ≥ 3 adverse events were mainly hematologic. There was no significant difference between the 3 cohorts with respect to efficacy or safety. Biomarker analyses indicated that stromal, rather than tumoral, SPARC may predict the response to nab-paclitaxel in NPC. Our findings suggest that nab-paclitaxel plus cisplatin is a highly active regimen with moderate toxicity for the treatment of metastatic NPC, which warrants further investigation in a phase III study. ClinicalTrials.gov ID: NCT01735409 . The trial was registered on November 20th, 2012.

Pharmacokinetics and pharmacodynamics of MD1003 (high-dose biotin) in the treatment of progressive multiple sclerosis.

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Peyro Saint Paul, Laure; Debruyne, Danièle; Bernard, Delphine; Mock, Donald M; Defer, Gilles L

2016-01-01

Multiple sclerosis (MS) is a chronic, potentially highly disabling neurological disorder. No disease-modifying treatments are approved in the progressive and not active forms of the disease. High doses of biotin were tested in an open-label pilot study involving 23 patients with progressive MS and reported positive results. A randomized, double-blind, placebo-controlled trial in 154 progressive MS patients confirmed the beneficial effect of MD1003 (high-dose biotin) on reversing or stabilizing disability progression, with a good safety profile. It is proposed that MD1003 in progressive MS 1) increases energy production in demyelinated axons and/or 2) enhances myelin synthesis in oligodendrocytes. Biotin is highly bioavailable; absorption and excretion are rapid. The major route of elimination is urinary excretion. A high oral dose of biotin seems generally well tolerated but a few important safety concerns were identified: 1) teratogenicity in one species and 2) interference with some biotin-based laboratory immunoassays. The animal toxicity data are limited at such high doses. Further preclinical studies would be useful to address the mechanism of action of MD1003. Assessment of clinical benefit duration in responders will be also very important to set. Results of randomized, placebo-controlled trial are reassuring and provide hope for the treatment of progressive MS.

Efficacy and safety of sublingual ramelteon as an adjunctive therapy in the maintenance treatment of bipolar I disorder in adults: A phase 3, randomized controlled trial.

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Mahableshwarkar, Atul R; Calabrese, Joseph R; Macek, Thomas A; Budur, Kumar; Adefuye, Adedeji; Dong, Xinxin; Hanson, Elizabeth; Sachs, Gary S

2017-10-15

The optimal long-term management strategy for bipolar I disorder patients is not yet established. Evidence supports the rationale for circadian rhythm regulation to prevent mood episode relapse in bipolar patients. This study evaluated the efficacy and safety of a new sublingual formulation of the melatonin receptor agonist ramelteon (ramelteon SL) as adjunctive therapy in the maintenance treatment of bipolar I patients. In a double-blinded trial in the United States and Latin America, adult bipolar I disorder patients stable for ≥ 8 weeks before baseline and with a mood episode 8 weeks to 9 months before screening, were randomized to once-daily ramelteon SL 0.1mg (n = 164), 0.4mg (n = 160), or 0.8mg (n = 154), or placebo (n = 164), in addition to their existing treatment. The primary endpoint was time from randomization to relapse of symptoms. The prespecified futility criterion in a planned, unblinded, independent interim analysis was the failure of all ramelteon SL doses to achieve a conditional power ≥ 30% compared with placebo. No significant differences between any dose of ramelteon SL and placebo were observed. The study was terminated after meeting the futility criteria. Ramelteon SL was well tolerated, with a safety profile consistent with that for oral ramelteon. A low rate of relapse events precluded detection of any statistically significant difference between groups. The study failed to demonstrate the efficacy of ramelteon SL as adjunctive maintenance therapy for bipolar disorder. Interim analyses for futility in clinical studies are valuable in preventing unnecessary exposure of subjects to interventions. Copyright © 2017. Published by Elsevier B.V.

78 FR 71036 - Pipeline Safety: Random Drug Testing Rate; Contractor Management Information System Reporting...

Science.gov (United States)

2013-11-27

... PHMSA-2013-0248] Pipeline Safety: Random Drug Testing Rate; Contractor Management Information System Reporting; and Obtaining Drug and Alcohol Management Information System Sign-In Information AGENCY: Pipeline... Management Information System (MIS) Data; and New Method for Operators to Obtain User Name and Password for...

[Epidural anaesthesia: Simulated intravascular test dose with S(+) ketamine, lidocaine and adrenaline. A prospective, randomized, double blind and placebo controlled study].

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Higueras, R; Errando, C L; Soriano-Bru, J L

2015-02-01

The use of a test dose in epidural anaesthesia is a safety recommendation. However specificity and sensitivity of the drugs used with this indication have been not conclusive. The main objective of this study was to compare the effectiveness and the adverse effects of a simulated intravascular test dose of adrenaline, lidocaine and S(+)-ketamine. A prospective, randomized, double blinded, placebo controlled study was designed. ASA I patients scheduled for elective surgery were included. These were randomized to the following study groups: S(+)-ketamine 0.5 mg.kg-1 (S+K group), 5% lidocaine 1.5 mg.kg-1 (L5% group), adrenaline 15μg (ADR group), and physiological saline 3 ml (SF group; control group). An evaluation was made during the first 15 minutes after the study drug was administered. Variables including heart rate (HR) systolic and diastolic blood pressure (sBP and dBP), mean arterial pressure (MAP), and SpO2 were recorded at 0 min (baseline) and at 2, 5, 8, 10 and 15 minutes after drug injection. An increase of at least 20 beats per minute (bpm) in relation to the baseline measurement was considered a positive result, as was an increase sBP >15 mmHg. The clinical effects described as related to iv injection of the study drugs recorded were: sedation-hypnosis, dizziness, nystagmus, metallic taste perception, perioral or facial paresthesias, tinnitus, as well as any other effect the patients mentioned. Sensitivity and specificity were calculated as was the percent increase in the parameters in order to see if these were clinically useful. A total of 80 patients, 20 per group, were included. The sBP, dBP, and MAP were significantly raised at the 2, 5, 8 and 10 minutes measurements in the S(+)K group compared to the rest of the groups (Padrenaline at the scheduled doses showed low sensitivity and specificity as a simulated iv epidural test dose. S(+)-ketamine could be a feasible marker after accidental iv injection during epidural anaesthesia or analgesia

Safety, immunogenicity, and protective efficacy of two doses of RIX4414 live attenuated human rotavirus vaccine in healthy infants.

Science.gov (United States)

Araujo, Eliete C; Clemens, Sue Ann C; Oliveira, Consuelo S; Justino, Maria Cleonice A; Rubio, Pilar; Gabbay, Yvone B; da Silva, Veronilce B; Mascarenhas, Joana D P; Noronha, Vânia L; Clemens, Ralf; Gusmão, Rosa Helena P; Sanchez, Nervo; Monteiro, Talita Antônia F; Linhares, Alexandre C

2007-01-01

To determine the safety, immunogenicity and efficacy of two doses of rotavirus vaccine in healthy Brazilian infants. A randomized, multicenter, double-blind, placebo-controlled trial was conducted in Brazil, Mexico and Venezuela. Infants received two oral doses of vaccine or placebo at 2 and 4 months of age, concurrently with routine immunizations, except for oral poliomyelitis vaccine (OPV). This paper reports results from Belém, Brazil, where the number of subjects per group and the viral vaccine titers were: 194 (10(4.7) focus forming units - FFU), 196 (10(5.2) FFU), 194 (10(5.8) FFU) and 194 (placebo). Anti-rotavirus (anti-RV) antibody response was assessed in 307 subjects. Clinical severity of gastroenteritis episodes was measured using a 20-point scoring system with a score of >or= 11 defined as severe GE. The rates of solicited general symptoms were similar in vaccine and placebo recipients. At 2 months after the second dose, a serum IgA response to RV occurred in 54.7 to 74.4% of vaccinees. No interference was seen in the immunogenicity of routine vaccines. Vaccine efficacy against any rotavirus gastroenteritis (RVGE) was 63.5% (95%CI 20.8-84.4) for the highest concentration (10(5.8) FFU). Efficacy was 81.5% (95%CI 44.5-95.4) against severe RVGE. At its highest concentration (10(5.8) FFU), RIX4414 provided 79.8% (95%CI 26.4-96.3) protection against severe RVGE by G9 strain. RIX4414 was highly immunogenic with a low reactogenicity profile and did not interfere with seroresponse to diphtheria, tetanus, pertussis, hepatitis B and Hib antigens. Two doses of RIX4414 provided significant protection against severe GE caused by RV.

Pharmacokinetics and Safety of DW1029M, a Botanical Drug for the Treatment of Diabetic Nephropathy, Following Single Doses in Healthy Subjects.

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Kim, Yunjeong; Jeon, Ji-Young; Kim, Eun-Young; Lim, Cheol-Hee; Jang, Hwan Bong; Kim, Min-Gul

2017-09-01

DW1029M is a botanical extract of Morus albalinne root bark and Puerariae radix that is used for the treatment of diabetic nephropathy. This study evaluated the safety and pharmacokinetics of DW1029M following its administration in healthy Korean subjects. We conducted a randomized, open-label, single-dose, crossover phase 1 clinical study. During each period, subjects received 300, 600, or 1200 mg oral doses of DW1029M. Plasma concentrations of puerarin, daidzin, and daidzein were analyzed using a liquid chromatography-tandem mass spectrometry. Six healthy male subjects completed the study. The maximum concentration of the drug in the plasma (C max ) and area under the plasma drug concentration-time curve to the last measurable concentration (AUC last ) for puerarin, daidzin, and daidzein were assessed after oral administration of DW1029M. No serious adverse events or clinically or statistically significant adverse events associated with any of the drug levels were observed. The results of the measurement of vital signs, electrocardiogram, laboratory tests, and physical examinations indicated that no clinically significant changes occurred during this study. The DW1029M tablet was safe and well tolerated over a single dose range of 300-1200 mg. This pharmacokinetic study of a botanical drug may aid in the development of DW1029M. © 2017, The American College of Clinical Pharmacology.

Randomized Controlled Trial of Low-Dose Estradiol and the SNRI Venlafaxine for Vasomotor Symptoms

Science.gov (United States)

Joffe, Hadine; Guthrie, Katherine A.; LaCroix, Andrea Z.; Reed, Susan D.; Ensrud, Kristine E.; Manson, JoAnn E.; Newton, Katherine M.; Freeman, Ellen W.; Anderson, Garnet L.; Larson, Joseph C.; Hunt, Julie; Shifren, Jan; Rexrode, Kathryn M.; Caan, Bette; Sternfeld, Barbara; Carpenter, Janet S.; Cohen, Lee

2014-01-01

Importance Estrogen therapy is the gold standard treatment for hot flashes and night sweats, but some women are unable or unwilling to use it because of associated risks. The serotonin-norepinephrine reuptake inhibitor venlafaxine is used widely as a non-hormonal treatment. While clinical impression is that serotonin-norepinephrine reuptake inhibitors are less effective than estrogen, these medications have not been simultaneously evaluated in one clinical trial. Objective To determine the efficacy and tolerability of low-dose oral 17-beta-estradiol and low-dose venlafaxine XR in alleviating vasomotor symptoms. Design and Participants 339 peri- and postmenopausal women with ≥2 bothersome vasomotor symptoms per day (mean 8.1, SD 5.3/day) were recruited from the community to MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) clinical network sites November 2011—October 2012. Interventions Participants were randomized to double-blinded treatment with low-dose oral 17-beta-estradiol 0.5-mg/day (n=97), low-dose venlafaxine XR 75-mg/day (n=96), or placebo (n=146) for 8 weeks. Main Outcomes Primary outcome was the mean daily frequency of vasomotor symptoms after 8 weeks of treatment. Secondary outcomes were vasomotor symptom severity, bother and interference. Intent-to-treat analyses compared change in vasomotor symptom frequency between each active intervention and placebo and between the two active treatments. Results Compared to baseline, mean vasomotor symptom frequency at week 8 decreased by 53% with estradiol, 48% with venlafaxine, and 29% with placebo. Estradiol reduced the frequency of symptoms by 2.3 (95% CI 1.3–3.4) more per day than placebo (p<0.001), and venlafaxine by 1.8 (95% CI 0.8–2.7) more per day than placebo (p=0.005). Results were consistent for VMS severity, bother and interference. Low-dose estradiol reduced symptom frequency by 0.6 more per day than venlafaxine (95% CI, 1.8 more per day to 0.6 fewer per day than

Evaluation of dose reduction versus standard dosing for maintenance of remission in patients with spondyloarthritis and clinical remission with anti-TNF (REDES-TNF): study protocol for a randomized controlled trial.

Science.gov (United States)

Pontes, Caridad; Gratacós, Jordi; Torres, Ferran; Avendaño, Cristina; Sanz, Jesús; Vallano, Antoni; Juanola, Xavier; de Miguel, Eugenio; Sanmartí, Raimon; Calvo, Gonzalo

2015-08-20

Dose reduction schedules of tumor necrosis factor antagonists (anti-TNF) as maintenance therapy in patients with spondyloarthritis are used empirically in clinical practice, despite the lack of clinical trials providing evidence for this practice. To address this issue the Spanish Society of Rheumatology (SER) and Spanish Society of Clinical Pharmacology (SEFC) designed a 3-year multicenter, randomized, open-label, controlled clinical trial (2 years for inclusion and 1 year of follow-up). The study is expected to include 190 patients with axial spondyloarthritis on stable maintenance treatment (≥4 months) with any anti-TNF agent at doses recommended in the summary of product characteristics. Patients will be randomized to either a dose reduction arm or maintenance of the dosing regimen as per the official labelling recommendations. Randomization will be stratified according to the anti-TNF agent received before study inclusion. Patient follow-up, visit schedule, and examinations will be maintained as per normal clinical practice recommendations according to SER guidelines. The study aims to test the hypothesis of noninferiority of the dose reduction strategy compared with standard treatment. The first patients were recruited in July 2012, and study completion is scheduled for the end of April 2015. The REDES-TNF study is a pragmatic clinical trial that aims to provide evidence to support a medical decision now made empirically. The study results may help inform clinical decisions relevant to both patients and healthcare decision makers. EudraCT 2011-005871-18 (21 December 2011).

A prospective randomized evaluation of the prophylactic use of low-dose dopamine in cancer patients receiving interleukin-2.

Science.gov (United States)

Cormier, J N; Hurst, R; Vasselli, J; Lee, D; Kim, C J; McKee, M; Venzon, D; White, D; Marincola, F M; Rosenberg, S A

1997-07-01

The administration of high-dose interleukin-2 (IL-2) causes tumor regression in 17-25% of patients with metastatic melanoma or renal cell carcinoma. Renal dysfunction is a common dose-limiting toxicity of IL-2 administration, limiting 26% of treatment cycles. We have conducted a prospective randomized trial to evaluate whether the prophylactic administration of low-dose dopamine (2 mg/kg/min) can minimize renal toxicity and thus affect the amount of IL-2 administered. Forty-two patients were randomly assigned to receive systemic high-dose IL-2 with standard supportive measures (group A = 21 patients) or with the addition of prophylactic dopamine (group B = 21 patients) at 2 mg/kg/min. For patients in group B, dopamine was instituted 1 h before the initiation of IL-2 administration and was discontinued 6-12 h after the maximum number of doses of IL-2 were given. There was no difference in the amount of IL-2 administered for each course of therapy for groups A and B. Despite differences in urine flow (milliliters per kilogram per day), fluid balance (liters per day), and overall weight gain, prophylactic low-dose dopamine did not significantly alter maximum plasma urea or creatinine levels in group B when compared with the control group (group A). The overall toxicity profile considering all grade 3 and 4 toxicities for patients in groups A and B was comparable. Thus, there is no evidence to support the routine use of prophylactic low-dose dopamine in patients receiving high-dose IL-2.

Structured versus long-chain triglycerides: a safety, tolerance, and efficacy randomized study in colorectal surgical patients.

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Bellantone, R; Bossola, M; Carriero, C; Malerba, M; Nucera, P; Ratto, C; Crucitti, P; Pacelli, F; Doglietto, G B; Crucitti, F

1999-01-01

After trauma or surgery, researchers have suggested that medium-chain triglycerides have metabolic advantages, although they are toxic in large doses. To try to reduce this potential toxicity, structured lipids, which provide a higher oxidation rate, faster clearance from blood, improved nitrogen balance, and less accumulation in the reticuloendothelial system, could be used. Therefore, we evaluated, through a blind randomized study, the safety, tolerance, and efficacy of structured triglycerides, compared with long-chain triglycerides (LCT), in patients undergoing colorectal surgery. Nineteen patients were randomized to receive long-chain or structured triglycerides as a lipid source. They received the same amount of calories (27.2/kg/d), glucose (4 g/kg/d), protein (0.2 g/kg/d), and lipids (11.2 kcal/kg/d). Patients were evaluated during and after the treatment for clinical and laboratory variables, daily and cumulative nitrogen balance, urinary excretion of 3-methyl-histidine, and urinary 3-methylhistidine/creatinine ratio. No adverse effect that required the interruption of the treatment was observed. Triglyceride levels and clinical and laboratory variables were similar in the two groups. A predominantly positive nitrogen balance was observed from day 2 until day 5 in the LCT group and from day 1 until day 4 in the structured triglycerides group. The cumulative nitrogen balance (in grams) for days 1 to 3 was 9.7+/-5.2 in the experimental group and 4.4+/-11.8 in the control group (p = .2). For days 1 to 5 it was 10.7+/-10.5 and 6.5+/-17.9 (p = .05), respectively. The excretion of 3-methylhistidine was higher in the control group but decreased in the following days and was similar to the experimental group on day 5. This study represents the first report in which structured triglycerides are administered in postoperative patients to evaluate safety, tolerance, and efficacy. It suggests that Fe73403 is safe, well tolerated, and efficacious in terms of nitrogen

Evaluating higher doses of Shunthi - Guduchi formulations for safety in treatment of osteoarthritis knees: A Government of India NMITLI arthritis project

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Arvind Chopra

2012-01-01

Full Text Available Background: Results of an exploratory trial suggested activity trends of Zingiber officinale-Tinopsora cordifolia (platform combination-based formulations in the treatment of Osteoarthritis (OA Knees. These formulations were "platform combination+Withania somnifera+Tribulus terrestris0" (formulation B and "platform combination+Emblica officinale" (formulation C. This paper reports safety of these formulations when used in higher doses (1.5-2 times along with Sallaki Guggul and Bhallataka Parpati (a Semecarpus anacardium preparation. Materials and Methods: Ninety-two patients with symptomatic OA knees were enrolled in a 6 weeks investigator blind, randomized parallel efficacy 4-arm multicenter drug trial. The 4 arms were (I formulation B, 2 t.i.d.; (II formulation B, 2 q.i.d.; (III platform combination+Sallaki Guggul; (IV Bhallataka Parpati+formulation C. A detailed enquiry was carried out for adverse events (AE and drug toxicity as per a priori check list and volunteered information. Laboratory evaluation included detailed hematology and metabolic parameters. Patients were examined at baseline, first and fourth weeks, and on completion. Standard statistical program (SPSS version 12.5 was used for analysis. Results: None of the patients reported serious AE or withdrew due to any drug-related toxicity. Mild gut-related (mostly epigastric burning AE was reported. A mild increase in liver enzymes [serum glutamic pyruvate transaminase (SGPT, serum glutamic oxaloacetic transaminase (SGOT] without any other hepatic abnormality was reported in 2 patients (group IV. Other laboratory parameters remained normal. The mean improvement in active pain visual analog scale (1.4, CI 0.5-2.22, WOMAC (functional activity questionnaire pain score (1.37, CI 0.22-2.5, and urinary C-TAX (cartilage collagen breakdown product assay was maximum (NS in group IV. Lower dose group I showed numerically superior improvement compared with higher dose group II. Conclusion: The

Evidence for single-dose protection by the bivalent HPV vaccine-Review of the Costa Rica HPV vaccine trial and future research studies.

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Kreimer, Aimée R; Herrero, Rolando; Sampson, Joshua N; Porras, Carolina; Lowy, Douglas R; Schiller, John T; Schiffman, Mark; Rodriguez, Ana Cecilia; Chanock, Stephen; Jimenez, Silvia; Schussler, John; Gail, Mitchell H; Safaeian, Mahboobeh; Kemp, Troy J; Cortes, Bernal; Pinto, Ligia A; Hildesheim, Allan; Gonzalez, Paula

2018-01-20

The Costa Rica Vaccine Trial (CVT), a phase III randomized clinical trial, provided the initial data that one dose of the HPV vaccine could provide durable protection against HPV infection. Although the study design was to administer all participants three doses of HPV or control vaccine, 20% of women did not receive the three-dose regimens, mostly due to involuntary reasons unrelated to vaccination. In 2011, we reported that a single dose of the bivalent HPV vaccine could be as efficacious as three doses of the vaccine using the endpoint of persistent HPV infection accumulated over the first four years of the trial; findings independently confirmed in the GSK-sponsored PATRICIA trial. Antibody levels after one dose, although lower than levels elicited by three doses, were 9-times higher than levels elicited by natural infection. Importantly, levels remained essentially constant over at least seven years, suggesting that the observed protection provided by a single dose might be durable. Much work has been done to assure these non-randomized findings are valid. Yet, the group of recipients who received one dose of the bivalent HPV vaccine in the CVT and PATRICIA trials was small and not randomly selected nor blinded to the number of doses received. The next phase of research is to conduct a formal randomized, controlled trial to evaluate the protection afforded by a single dose of HPV vaccine. Complementary studies are in progress to bridge our findings to other populations, and to further document the long-term durability of antibody response following a single dose. Published by Elsevier Ltd.

Global real-time dose measurements using the Automated Radiation Measurements for Aerospace Safety (ARMAS) system

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Tobiska, W. Kent; Bouwer, D.; Smart, D.; Shea, M.; Bailey, J.; Didkovsky, L.; Judge, K.; Garrett, H.; Atwell, W.; Gersey, B.; Wilkins, R.; Rice, D.; Schunk, R.; Bell, D.; Mertens, C.; Xu, X.; Wiltberger, M.; Wiley, S.; Teets, E.; Jones, B.; Hong, S.; Yoon, K.

2016-11-01

The Automated Radiation Measurements for Aerospace Safety (ARMAS) program has successfully deployed a fleet of six instruments measuring the ambient radiation environment at commercial aircraft altitudes. ARMAS transmits real-time data to the ground and provides quality, tissue-relevant ambient dose equivalent rates with 5 min latency for dose rates on 213 flights up to 17.3 km (56,700 ft). We show five cases from different aircraft; the source particles are dominated by galactic cosmic rays but include particle fluxes for minor radiation periods and geomagnetically disturbed conditions. The measurements from 2013 to 2016 do not cover a period of time to quantify galactic cosmic rays' dependence on solar cycle variation and their effect on aviation radiation. However, we report on small radiation "clouds" in specific magnetic latitude regions and note that active geomagnetic, variable space weather conditions may sufficiently modify the magnetospheric magnetic field that can enhance the radiation environment, particularly at high altitudes and middle to high latitudes. When there is no significant space weather, high-latitude flights produce a dose rate analogous to a chest X-ray every 12.5 h, every 25 h for midlatitudes, and every 100 h for equatorial latitudes at typical commercial flight altitudes of 37,000 ft ( 11 km). The dose rate doubles every 2 km altitude increase, suggesting a radiation event management strategy for pilots or air traffic control; i.e., where event-driven radiation regions can be identified, they can be treated like volcanic ash clouds to achieve radiation safety goals with slightly lower flight altitudes or more equatorial flight paths.

Efficacy and Safety of Single and Double Doses of Ivermectin versus 7-Day High Dose Albendazole for Chronic Strongyloidiasis

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Suputtamongkol, Yupin; Premasathian, Nalinee; Bhumimuang, Kid; Waywa, Duangdao; Nilganuwong, Surasak; Karuphong, Ekkapun; Anekthananon, Thanomsak; Wanachiwanawin, Darawan; Silpasakorn, Saowaluk

2011-01-01

Background Strongyloidiasis, caused by an intestinal helminth Strongyloides stercoralis, is common throughout the tropics. It remains an important health problem due to autoinfection, which may result in hyperinfection and disseminated infection in immunosuppressed patients, especially patients receiving chemotherapy or corticosteroid treatment. Ivermectin and albendazole are effective against strongyloidiasis. However, the efficacy and the most effective dosing regimen are to be determined. Methods A prospective, randomized, open study was conducted in which a 7-day course of oral albendazole 800 mg daily was compared with a single dose (200 microgram/kilogram body weight), or double doses, given 2 weeks apart, of ivermectin in Thai patients with chronic strongyloidiasis. Patients were followed-up with 2 weeks after initiation of treatment, then 1 month, 3 months, 6 months, 9 months, and 1 year after treatment. Combination of direct microscopic examination of fecal smear, formol-ether concentration method, and modified Koga agar plate culture were used to detect strongyloides larvae in two consecutive fecal samples in each follow-up visit. The primary endpoint was clearance of strongyloides larvae from feces after treatment and at one year follow-up. Results Ninety patients were included in the analysis (30, 31 and 29 patients in albendazole, single dose, and double doses ivermectin group, respectively). All except one patient in this study had at least one concomitant disease. Diabetes mellitus, systemic lupus erythrematosus, nephrotic syndrome, hematologic malignancy, solid tumor and human immunodeficiency virus infection were common concomitant diseases in these patients. The median (range) duration of follow-up were 19 (2–76) weeks in albendazole group, 39 (2–74) weeks in single dose ivermectin group, and 26 (2–74) weeks in double doses ivermectin group. Parasitological cure rate were 63.3%, 96.8% and 93.1% in albendazole, single dose oral ivermectin

A phase I, randomized, single-dose study evaluating the pharmacokinetic equivalence of biosimilar ABP 215 and bevacizumab in healthy adult men.

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Markus, Richard; Chow, Vincent; Pan, Zhiying; Hanes, Vladimir

2017-10-01

This study compared the pharmacokinetic (PK) profiles of the proposed biosimilar ABP 215 with bevacizumab in healthy males. In this randomized, single-blind, single-dose, three-arm, parallel-group study, healthy subjects were randomized to receive ABP 215 (n = 68), bevacizumab (US) (n = 67), or bevacizumab (EU) (n = 67) 3 mg/kg intravenously. Primary endpoints were area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC inf ) and the maximum observed concentration (C max ). Secondary endpoints included safety and immunogenicity. AUC inf and C max were similar across the three groups. Geometric means ratio (GMR) for C max and AUC inf , respectively, was 0.98 and 0.99 for ABP 215 versus bevacizumab (US); 1.03 and 0.96 for ABP 215 versus bevacizumab (EU); and 1.05 and 0.97 for bevacizumab (US) versus bevacizumab (EU). The 90% confidence intervals for the GMRs of AUC inf and C max were within the prespecified standard PK bioequivalence criteria of 0.80 to 1.25. The incidence of adverse events (AEs) was 47.1, 32.8, and 61.2% in the ABP 215, bevacizumab (US) and bevacizumab (EU) groups, respectively. When analyzed by investigational site, the incidence and severity of AEs were comparable in the ABP 215 and bevacizumab groups. There were no AEs leading to study discontinuation. No binding or neutralizing anti-drug anti-bodies was detected. This study demonstrated the PK similarity of ABP 215 to both bevacizumab (US) and bevacizumab (EU), and of bevacizumab (US) to bevacizumab (EU). Safety and tolerability were comparable between treatments and no subject developed binding or neutralizing anti-drug anti-bodies.

HALF-DOSE DEPOT TRIPTORELIN COMPARABLE TO REDUCED DAILY BUSERELIN: A RANDOMIZED CLINICAL TRIAL

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L. Safdarian

2007-09-01

Full Text Available Pituitary suppression by depot GnRH agonist may be excessive for ovarian stimulation. This study compares the efficacy of a single half-dose depot triptorelin and reduced-dose daily buserelin in a long protocol ICSI/ET. METHODS: A total of 182 patients were randomized into two groups using sealed envelopes. Pituitary desensitization was obtained in group 1 (91 patients with half-dose (1.87 mg depot triptorelin in the mid-luteal phase of their menstrual cycle, and in group 2 (91 patients with standard daily dose (0.5 mg buserelin, which was then reduced to 0.25 mg at the start of human menopausal gonadotropin (HMG stimulation. RESULTS: No significant differences were found among those who received HCG in terms of clinical pregnancy rate (34.4% in both groups, implantation rate (14.8% in group 1 versus 11.1% in group 2, fertilization rate (93.3 versus 95.6%, poor response rate (11.1 versus 6.7%, and miscarriage rate (11.1 versus 7.8%. No significant differences were seen in number of HMG ampoules used, follicles at HCG administration, and oocytes retrieved. The number of days of stimulation was significantly reduced in group 2 (11.2 +/- 1.8 in group 1 versus 10.6 +/- 1.9, p = 0.030. CONCLUSION: A half-dose of depot triptorelin can be successfully used in ovarian stimulation instead of reduced-dose daily buserelin, with more patient comfort and reduced stress and cost of injections.

Evaluation of a 12-Hour Sustained-Release Acetaminophen (Paracetamol) Formulation: A Randomized, 3-Way Crossover Pharmacokinetic and Safety Study in Healthy Volunteers.

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Yue, Yong; Collaku, Agron; Liu, Dongzhou J

2018-01-01

Acetaminophen (paracetamol) is a first-line treatment for mild and moderate pain. A twice-daily sustained-release (SR) formulation may be more convenient for chronic users than standard immediate-release (IR) acetaminophen. This randomized, 3-way crossover study evaluated pharmacokinetics and safety of single-dose 1500- and 2000-mg SR acetaminophen formulations and 2 doses of IR acetaminophen 1000 mg given 6 hours apart in healthy adults (n = 14). Primary outcome was time that plasma acetaminophen concentration was ≥4 μg/mL (T C≥4μg/mL ). Key secondary outcomes were area under the plasma concentration-time curve (AUC) from time 0 to time t, when plasma acetaminophen was detectable (AUC 0-t ), AUC from 0 to infinity (AUC 0-inf ), and maximum plasma acetaminophen concentration (C max ). T C≥4μg/mL from 2000-mg SR acetaminophen was similar to that from 2 doses of IR acetaminophen, whereas T C≥4μg/mL for 1500-mg SR acetaminophen was significantly shorter than that for IR acetaminophen (P = .004). The extent of acetaminophen absorption from 2000-mg SR and 2 doses of the IR formulation was similar and within bioequivalence limits with regard to AUC 0-12 , AUC 0-t , and AUC 0-inf . The extent of acetaminophen absorption from 1500-mg SR was significantly lower than that from IR acetaminophen. The 2000-mg SR represents a potential candidate formulation for 12-hour dosing with acetaminophen. © 2017, The American College of Clinical Pharmacology.

High-Dose Versus Low-Dose Pitavastatin in Japanese Patients With Stable Coronary Artery Disease (REAL-CAD): A Randomized Superiority Trial.

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Taguchi, Isao; Iimuro, Satoshi; Iwata, Hiroshi; Takashima, Hiroaki; Abe, Mitsuru; Amiya, Eisuke; Ogawa, Takanori; Ozaki, Yukio; Sakuma, Ichiro; Nakagawa, Yoshihisa; Hibi, Kiyoshi; Hiro, Takafumi; Fukumoto, Yoshihiro; Hokimoto, Seiji; Miyauchi, Katsumi; Yamazaki, Tsutomu; Ito, Hiroshi; Otsuji, Yutaka; Kimura, Kazuo; Takahashi, Jun; Hirayama, Atsushi; Yokoi, Hiroyoshi; Kitagawa, Kazuo; Urabe, Takao; Okada, Yasushi; Terayama, Yasuo; Toyoda, Kazunori; Nagao, Takehiko; Matsumoto, Masayasu; Ohashi, Yasuo; Kaneko, Tetsuji; Fujita, Retsu; Ohtsu, Hiroshi; Ogawa, Hisao; Daida, Hiroyuki; Shimokawa, Hiroaki; Saito, Yasushi; Kimura, Takeshi; Inoue, Teruo; Matsuzaki, Masunori; Nagai, Ryozo

2018-05-08

Current guidelines call for high-intensity statin therapy in patients with cardiovascular disease on the basis of several previous "more versus less statins" trials. However, no clear evidence for more versus less statins has been established in an Asian population. In this prospective, multicenter, randomized, open-label, blinded end point study, 13 054 Japanese patients with stable coronary artery disease who achieved low-density lipoprotein cholesterol (LDL-C) fashion to high-dose (pitavastatin 4 mg/d; n=6526) or low-dose (pitavastatin 1 mg/d; n=6528) statin therapy. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. The secondary composite end point was a composite of the primary end point and clinically indicated coronary revascularization excluding target-lesion revascularization at sites of prior percutaneous coronary intervention. The mean age of the study population was 68 years, and 83% were male. The mean LDL-C level before enrollment was 93 mg/dL with 91% of patients taking statins. The baseline LDL-C level after the run-in period on pitavastatin 1 mg/d was 87.7 and 88.1 mg/dL in the high-dose and low-dose groups, respectively. During the entire course of follow-up, LDL-C in the high-dose group was lower by 14.7 mg/dL than in the low-dose group ( P Japanese patients with stable coronary artery disease. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01042730. © 2018 The Authors.

Off-label biologic regimens in psoriasis: a systematic review of efficacy and safety of dose escalation, reduction, and interrupted biologic therapy.

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Elizabeth A Brezinski

Full Text Available OBJECTIVES: While off-label dosing of biologic treatments may be necessary in selected psoriasis patients, no systematic review exists to date that synthesizes the efficacy and safety of these off-label dosing regimens. The aim of this systematic review is to evaluate efficacy and safety of off-label dosing regimens (dose escalation, dose reduction, and interrupted treatment with etanercept, adalimumab, infliximab, ustekinumab, and alefacept for psoriasis treatment. DATA SOURCES AND STUDY SELECTION: We searched OVID Medline from January 1, 1990 through August 1, 2011 for prospective clinical trials that studied biologic therapy for psoriasis treatment in adults. Individual articles were screened for studies that examined escalated, reduced, or interrupted therapy with etanercept, adalimumab, infliximab, ustekinumab, or alefacept. DATA SYNTHESIS: A total of 23 articles with 12,617 patients matched the inclusion and exclusion criteria for the systematic review. Data were examined for primary and secondary efficacy outcomes and adverse events including infections, malignancies, cardiovascular events, and anti-drug antibodies. The preponderance of data suggests that continuous treatment with anti-TNF agents and anti-IL12/23 agent was necessary for maintenance of disease control. Among non-responders, dose escalation with etanercept, adalimumab, ustekinumab, and alefacept typically resulted in greater efficacy than standard dosing. Dose reduction with etanercept and alefacept resulted in reduced efficacy. Withdrawal of the examined biologics led to an increase in disease activity; efficacy from retreatment did not result in equivalent initial response rates for most biologics. Safety data on off-label dosing regimens are limited. CONCLUSION: Dose escalation in non-responders generally resulted in increased efficacy in the examined biologics used to treat moderate-to-severe psoriasis. Continuous treatment with anti-TNF agents and anti-IL12/23 agent

A randomized trial of a low-dose Rasagiline and Pramipexole combination (P2B001) in early Parkinson's disease.

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Olanow, C Warren; Kieburtz, Karl; Leinonen, Mika; Elmer, Lawrence; Giladi, Nir; Hauser, Robert A; Klepiskaya, Olga S; Kreitzman, David L; Lew, Mark F; Russell, David S; Kadosh, Shaul; Litman, Pninit; Friedman, Hadas; Linvah, Nurit; The P B Study Group, For

2017-05-01

Rasagiline and pramipexole act to improve striatal dopaminergic transmission in PD via distinct and potentially synergistic mechanisms. We performed a placebo-controlled study to determine whether 2 doses of a novel slow-release, low-dose combination of rasagiline and pramipexole (P2B001) are effective and have a good safety profile in patients with early untreated PD. Previously untreated patients with early PD were randomized (1:1:1) to once-daily treatment with P2B001 (0.3 mg pramipexole/0.75 mg rasagiline), P2B001 (0.6 mg pramipexole/0.75 mg rasagiline) or placebo in a 12-week multicenter double-blind, placebo-controlled trial. The primary endpoint was the change from baseline to final visit in Total-UPDRS score versus placebo. Secondary measures included responder analyses of patients achieving ≥4 UPDRS point reduction, and changes in Parkinson Disease Quality of Life Scale-39 and UPDRS activities of daily living and motor scores. A total of 149 participants were randomized and 136 (91.3%) completed the study. Adjusted mean change from baseline to final visit versus placebo in Total-UPDRS score was -4.67 ± 1.28 points for the P2B001 0.6/0.75 mg group (P = .0004) and -3.84 ± 1.25 points for the 0.3/0.75 mg group (P = .003). Significant benefits were also observed for both doses in the responder analysis (P = .0002 and P = .0001), Parkinson Disease Quality of Life Scale-39 scores (P = .05 and P = .01), and the UPDRS motor (P = .02 and P = .006) and activities of daily living (P = .005 and P = .0004) subscores. Adverse events of P2B001 were comparable to placebo apart from transient nausea and somnolence, which were more common with P2B001 treatment. P2B001 offers a promising treatment option for patients with early PD with good clinical efficacy and a low risk of adverse events. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder

Dose-Finding Study of Omeprazole on Gastric pH in Neonates with Gastro-Esophageal Acid Reflux Using a Bayesian Sequential Approach.

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Kaguelidou, Florentia; Alberti, Corinne; Biran, Valerie; Bourdon, Olivier; Farnoux, Caroline; Zohar, Sarah; Jacqz-Aigrain, Evelyne

2016-01-01

Proton pump inhibitors are frequently administered on clinical symptoms in neonates but benefit remains controversial. Clinical trials validating omeprazole dosage in neonates are limited. The objective of this trial was to determine the minimum effective dose (MED) of omeprazole to treat pathological acid reflux in neonates using reflux index as surrogate marker. Double blind dose-finding trial with continual reassessment method of individual dose administration using a Bayesian approach, aiming to select drug dose as close as possible to the predefined target level of efficacy (with a credibility interval of 95%). Neonatal Intensive Care unit of the Robert Debré University Hospital in Paris, France. Neonates with a postmenstrual age ≥ 35 weeks and a pathologic 24-hour intra-esophageal pH monitoring defined by a reflux index ≥ 5% over 24 hours were considered for participation. Recruitment was stratified to 3 groups according to gestational age at birth. Five preselected doses of oral omeprazole from 1 to 3 mg/kg/day. Primary outcome, measured at 35 weeks postmenstrual age or more, was a reflux index reflux index ranging from 5.06 to 27.7% were included. Median age was 37.5 days and median postmenstrual age was 36 weeks. In neonates born at less than 32 weeks of GA (n = 30), the MED was 2.5mg/kg/day with an estimated mean posterior probability of success of 97.7% (95% credibility interval: 90.3-99.7%). The MED was 1mg/kg/day for neonates born at more than 32 GA (n = 24). Omeprazole is extensively prescribed on clinical symptoms but efficacy is not demonstrated while safety concerns do exist. When treatment is required, the daily dose needs to be validated in preterm and term neonates. Optimal doses of omeprazole to increase gastric pH and decrease reflux index below 5% over 24 hours, determined using an adaptive Bayesian design differ among neonates. Both gestational and postnatal ages account for these differences but their differential impact on omeprazole

Determination of Initial Conditions for the Safety Analysis by Random Sampling of Operating Parameters

International Nuclear Information System (INIS)

Jeong, Hae-Yong; Park, Moon-Ghu

2015-01-01

In most existing evaluation methodologies, which follow a conservative approach, the most conservative initial conditions are searched for each transient scenario through tremendous assessment for wide operating windows or limiting conditions for operation (LCO) allowed by the operating guidelines. In this procedure, a user effect could be involved and a remarkable time and human resources are consumed. In the present study, we investigated a more effective statistical method for the selection of the most conservative initial condition by the use of random sampling of operating parameters affecting the initial conditions. A method for the determination of initial conditions based on random sampling of plant design parameters is proposed. This method is expected to be applied for the selection of the most conservative initial plant conditions in the safety analysis using a conservative evaluation methodology. In the method, it is suggested that the initial conditions of reactor coolant flow rate, pressurizer level, pressurizer pressure, and SG level are adjusted by controlling the pump rated flow, setpoints of PLCS, PPCS, and FWCS, respectively. The proposed technique is expected to contribute to eliminate the human factors introduced in the conventional safety analysis procedure and also to reduce the human resources invested in the safety evaluation of nuclear power plants

Efficacy and Safety of Nitazoxanide, Albendazole, and Nitazoxanide-Albendazole against Trichuris trichiura Infection: A Randomized Controlled Trial

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Speich, Benjamin; Ame, Shaali M.; Ali, Said M.; Alles, Rainer; Hattendorf, Jan; Utzinger, Jürg; Albonico, Marco; Keiser, Jennifer

2012-01-01

Background The currently used anthelmintic drugs, in single oral application, have low efficacy against Trichuris trichiura infection, and hence novel anthelmintic drugs are needed. Nitazoxanide has been suggested as potential drug candidate. Methodology The efficacy and safety of a single oral dose of nitazoxanide (1,000 mg), or albendazole (400 mg), and a nitazoxanide-albendazole combination (1,000 mg–400 mg), with each drug administered separately on two consecutive days, were assessed in a double-blind, randomized, placebo-controlled trial in two schools on Pemba, Tanzania. Cure and egg reduction rates were calculated by per-protocol analysis and by available case analysis. Adverse events were assessed and graded before treatment and four times after treatment. Principal Findings Complete data for the per-protocol analysis were available from 533 T. trichiura-positive children. Cure rates against T. trichiura were low regardless of the treatment (nitazoxanide-albendazole, 16.0%; albendazole, 14.5%; and nitazoxanide, 6.6%). Egg reduction rates were 54.9% for the nitazoxanide-albendazole combination, 45.6% for single albendazole, and 13.4% for single nitazoxanide. Similar cure and egg reduction rates were calculated using the available case analysis. Children receiving nitazoxanide had significantly more adverse events compared to placebo recipients. Most of the adverse events were mild and had resolved within 24 hours posttreatment. Conclusions/Significance Nitazoxanide shows no effect on T. trichiura infection. The low efficacy of albendazole against T. trichiura in the current setting characterized by high anthelmintic drug pressure is confirmed. There is a pressing need to develop new anthelmintics against trichuriasis. Trial Registration Controlled-Trials.com ISRCTN08336605 PMID:22679525

Efficacy and safety of fosfomycin-trometamol in the prophylaxis for transrectal prostate biopsy. Prospective randomized comparison with ciprofloxacin.

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Lista, F; Redondo, C; Meilán, E; García-Tello, A; Ramón de Fata, F; Angulo, J C

2014-01-01

Prostate biopsy is the standardized diagnostic method for prostate cancer. However, although there is not a standardized protocol, there are recommendations in order to reduce the incidence of complications. The objective of the present work is to assess the efficacy and safety of antibiotic prophylaxis in the prostate biopsy by comparing two antibiotic regimes: two doses of fosfomycin-trometamol 3g (FMT) every 48 hours with 10 doses of oral ciprofloxacin 500 mg every 12 hours during 5 days. Randomized prospective study was performed with 671 patients who had undergone to walking transrectal ultrasound guided prostate biopsy. Patients of group A (n=312) were treated with ciprofloxacin, and patients of group B (n=359) with FMT. Efficacy and tolerability of two prophylactic regimes were compared. Urine culture was carried out at 2 weeks after biopsy. Initially, patients with asymptomatic bacteriuria were not treated with antibiotics; urine culture was repeated after 1 month, persistent bacteriuria was treated according to antibiogram. No differences between groups were found in age (P=.78), cancer presence (P=.9) or number of biopsy cylinders (P=.93). The mean number of cores obtained was 11.3 ± 3.25 (range 6-20). Digestive intolerance was observed for 9 patients (2.9%) of group A and 10 patients (2.8%) in group B. One patient (.3%) of group A showed severe allergic reaction. In total, 167 patients (24.6%) had complications: 16 (2.4%) fever, 47 (6.9%) hemospermia, 81 (11.9%) hematuria, 7 (1%) rectal bleeding and 16 (2.4%) urinary retention. No statistically differences between groups were observed (27.6% vs. 22.6%; P=.17). However, hemospermia was more frequent in group A (9.9% vs. 4.5%; P=.006). Bacteriuria after biopsy was detected in 44 patients (6.6%), being more frequent in group B patients (4.2% vs. 8.6%; P=.02) although a higher number of second treatment cycles were not needed (53.9% vs. 29%; P=.17). The likelihood of resistance to ciprofloxacin in patients

A tailored online safety and health intervention for women experiencing intimate partner violence: the iCAN Plan 4 Safety randomized controlled trial protocol

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Marilyn Ford-Gilboe

2017-03-01

Full Text Available Abstract Background Intimate partner violence (IPV threatens the safety and health of women worldwide. Safety planning is a widely recommended, evidence-based intervention for women experiencing IPV, yet fewer than 1 in 5 Canadian women access safety planning through domestic violence services. Rural, Indigenous, racialized, and immigrant women, those who prioritize their privacy, and/or women who have partners other than men, face unique safety risks and access barriers. Online IPV interventions tailored to the unique features of women’s lives, and to maximize choice and control, have potential to reduce access barriers, and improve fit and inclusiveness, maximizing effectiveness of these interventions for diverse groups. Methods/Design In this double blind randomized controlled trial, 450 Canadian women who have experienced IPV in the previous 6 months will be randomized to either a tailored, interactive online safety and health intervention (iCAN Plan 4 Safety or general online safety information (usual care. iCAN engages women in activities designed to increase their awareness of safety risks, reflect on their plans for their relationships and priorities, and create a personalize action plan of strategies and resources for addressing their safety and health concerns. Self-reported outcome measures will be collected at baseline and 3, 6, and 12 months post-baseline. Primary outcomes are depressive symptoms (Center for Epidemiological Studies Depression Scale, Revised and PTSD Symptoms (PTSD Checklist, Civilian Version. Secondary outcomes include helpful safety actions, safety planning self-efficacy, mastery, and decisional conflict. In-depth qualitative interviews with approximately 60 women who have completed the trial and website utilization data will be used to explore women’s engagement with the intervention and processes of change. Discussion This trial will contribute timely evidence about the effectiveness of online safety and

Clinical Utility and Safety of a Model-Based Patient-Tailored Dose of Vancomycin in Neonates.

Science.gov (United States)

Leroux, Stéphanie; Jacqz-Aigrain, Evelyne; Biran, Valérie; Lopez, Emmanuel; Madeleneau, Doriane; Wallon, Camille; Zana-Taïeb, Elodie; Virlouvet, Anne-Laure; Rioualen, Stéphane; Zhao, Wei

2016-04-01

Pharmacokinetic modeling has often been applied to evaluate vancomycin pharmacokinetics in neonates. However, clinical application of the model-based personalized vancomycin therapy is still limited. The objective of the present study was to evaluate the clinical utility and safety of a model-based patient-tailored dose of vancomycin in neonates. A model-based vancomycin dosing calculator, developed from a population pharmacokinetic study, has been integrated into the routine clinical care in 3 neonatal intensive care units (Robert Debré, Cochin Port Royal, and Clocheville hospitals) between 2012 and 2014. The target attainment rate, defined as the percentage of patients with a first therapeutic drug monitoring serum vancomycin concentration achieving the target window of 15 to 25 mg/liter, was selected as an endpoint for evaluating the clinical utility. The safety evaluation was focused on nephrotoxicity. The clinical application of the model-based patient-tailored dose of vancomycin has been demonstrated in 190 neonates. The mean (standard deviation) gestational and postnatal ages of the study population were 31.1 (4.9) weeks and 16.7 (21.7) days, respectively. The target attainment rate increased from 41% to 72% without any case of vancomycin-related nephrotoxicity. This proof-of-concept study provides evidence for integrating model-based antimicrobial therapy in neonatal routine care. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Recent findings relating to firefighter safety zones

Science.gov (United States)

Bret Butler; Russ Parsons; William Mell

2015-01-01

Designation of safety zones is a primary duty of all wildland firefighters. Unfortunately, information regarding what constitutes an adequate safety zone is inadequately defined. Measurements of energy release from wildland fires have been used to develop an empirically based safety zone guideline. The basis for this work is described here.

Prevention of laryngospasm with rocuronium in cats: a dose-finding study.

Science.gov (United States)

Martin-Flores, Manuel; Sakai, Daniel M; Portela, Diego A; Borlle, Lucia; Campoy, Luis; Gleed, Robin D

2016-09-01

To identify the dose of rocuronium that will prevent a laryngeal response to water spraying of the glottis in anesthetized cats. Randomized crossover study. Eight healthy, adult, short-haired cats, aged 1-4 years, weighing 3.2-6.0 kg. Each cat was anesthetized four times and administered one of four doses of rocuronium (0.1, 0.2, 0.3 and 0.6 mg kg(-1) ) in random order. The larynx was observed with a video-endoscope inserted through a laryngeal mask airway. Video-clips of the laryngeal response to a sterile water spray (0.2 mL) were obtained at baseline (without rocuronium) and at maximal effect of each treatment. Glottal closure score (0-2), duration of glottal closure, and number of adductive arytenoid movements were obtained from video-clips of laryngeal responses (reproduced in slow motion) at baseline and after treatment. Two observers blinded to treatment allocation scored the vigor of the laryngeal response on a visual analog scale (VAS). The duration of apnea (up to 5 minutes) was recorded for each treatment. Compared with baseline, rocuronium 0.3 mg kg(-1) and 0.6 mg kg(-1) significantly decreased all glottal scores obtained from the videos (all p rocuronium 0.1, 0.2, 0.3 and 0.6 mg kg(-1) , respectively. Rocuronium 0.3 mg kg(-1) and 0.6 mg kg(-1) consistently decreased the completeness and duration of the laryngeal response to water spray, and reduced the number of arytenoid adductive movements in response to that stimulus. However, a laryngeal response was never completely prevented. Rocuronium 0.3 mg kg(-1) may be useful for facilitating tracheal intubation. Positive pressure ventilation must be available for cats administered rocuronium. © 2016 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

Implementation of a safety action plan: reduction of the dose limits in a research centre

International Nuclear Information System (INIS)

Deworm, J.P.

1992-01-01

The Belgian Regulations require an annual Action Plan to improve the Safety and health conditions of works. Taking into consideration the preliminary versions of the new ICRP-recommendations, the 1990 Action Plan of the Belgian research Centre aimed to reduce the personal dose limit to 20 mSv/year and the annual collective dose by 10%. Major means used in the campaign were sensibility through information, consultation between hierarchy and executors and the application of a policy of discouragement at certain limits. As a result, the maximum level reaches was 16.5 mSv, while only 7 people received a dose above 10 mSv (of 219 who received a measurable dose, mean value 3,4 mSv). This success is due to the commitment at all levels of responsibilities. In 1991, the 20 mSv-limit is imposed as an obligation by the management, and a feasibility study to impose 10 mSv in near future is being undertaken. (author)

CT findings of pancreatic carcinoma. Evaluation with the combined method of early enhancement CT and high dose enhancement CT

International Nuclear Information System (INIS)

Itoh, Shigeki; Endo, Tokiko; Isomura, Takayuki; Ishigaki, Takeo; Ikeda, Mitsuru; Senda, Kouhei.

1995-01-01

Computed tomographic (CT) findings of pancreatic ductal adenocarcinoma were studied with the combined method of early enhancement CT and high dose enhancement CT in 72 carcinomas. Common Findings were change in pancreatic contour, abnormal attenuation in a tumor and dilatation of the main pancreatic duct. The incidence of abnormal attenuation and dilatation of the main pancreatic duct and bile duct was constant regardless of tumor size. The finding of hypoattenuation at early enhancement CT was most useful for demonstrating a carcinoma. However, this finding was negative in ten cases, five of which showed inhomogenous hyperattenuation at high dose enhancement CT. The detection of change in pancreatic contour and dilatation of the main pancreatic duct was most frequent at high dose enhancement CT. The finding of change in pancreatic contour and/or abnormal attenuation in a tumor could be detected in 47 cases at plain CT, 66 at early enhancement CT and 65 at high dose enhancement CT. Since the four cases in which neither finding was detected by any CT method showed dilatated main pancreatic duct, there was no case without abnormal CT findings. This combined CT method will be a reliable diagnostic technique in the imaging of pancreatic carcinoma. (author)

Reliability assessment for safety critical systems by statistical random testing

International Nuclear Information System (INIS)

Mills, S.E.

1995-11-01

In this report we present an overview of reliability assessment for software and focus on some basic aspects of assessing reliability for safety critical systems by statistical random testing. We also discuss possible deviations from some essential assumptions on which the general methodology is based. These deviations appear quite likely in practical applications. We present and discuss possible remedies and adjustments and then undertake applying this methodology to a portion of the SDS1 software. We also indicate shortcomings of the methodology and possible avenues to address to follow to address these problems. (author). 128 refs., 11 tabs., 31 figs

Reliability assessment for safety critical systems by statistical random testing

Energy Technology Data Exchange (ETDEWEB)

Mills, S E [Carleton Univ., Ottawa, ON (Canada). Statistical Consulting Centre

1995-11-01

In this report we present an overview of reliability assessment for software and focus on some basic aspects of assessing reliability for safety critical systems by statistical random testing. We also discuss possible deviations from some essential assumptions on which the general methodology is based. These deviations appear quite likely in practical applications. We present and discuss possible remedies and adjustments and then undertake applying this methodology to a portion of the SDS1 software. We also indicate shortcomings of the methodology and possible avenues to address to follow to address these problems. (author). 128 refs., 11 tabs., 31 figs.

324 building safety analysis report supplement

International Nuclear Information System (INIS)

Dodd, A.O.; Wittenbrock, N.G.

1977-01-01

Process engineering designs, major equipment and plant facilities to be utilized in commercial nuclear waste preparation and vitrification in the 324 Radiochemical Engineering Building are reviewed with regard to accident potential and consequences. This Safety Analysis Report Supplement compares calculated environmental doses anticipated from the Commercial Nuclear Waste Vitrification Project (CNWVP) routine operations with the average doses from past waste management operations conducted at the Hanford Project and finds them to be significantly less. The calculated CNWVP environmental doses are found to be far below presently applicable ERDA standards and standards proposed by the EPA for nuclear power operations

Efficacy and safety of tofacitinib for active rheumatoid arthritis with an inadequate response to methotrexate or disease-modifying antirheumatic drugs: a meta-analysis of randomized controlled trials

Science.gov (United States)

Song, Gwan Gyu; Bae, Sang-Cheol

2014-01-01

Background/Aims The aim of this study was to assess the efficacy and safety of tofacitinib (5 and 10 mg twice daily) in patients with active rheumatoid arthritis (RA). Methods A systematic review of randomized controlled trials (RCTs) that examined the efficacy and safety of tofacitinib in patients with active RA was performed using the Medline, Embase, and Cochrane Controlled Trials Register databases as well as manual searches. Results Five RCTs, including three phase-II and two phase-III trials involving 1,590 patients, met the inclusion criteria. The three phase-II RCTs included 452 patients with RA (144 patients randomized to 5 mg of tofacitinib twice daily, 156 patients randomized to 10 mg of tofacitinib twice daily, and 152 patients randomized to placebo) who were included in this meta-analysis. The American College of Rheumatology 20% response rate was significantly higher in the tofacitinib 5- and 10-mg groups than in the control group (relative risk [RR], 2.445; 95% confidence interval [CI], 1.229 to 4.861; p = 0.011; and RR, 2.597; 95% CI, 1.514 to 4.455; p = 0.001, respectively). The safety outcomes did not differ between the tofacitinib 5- and 10-mg groups and placebo groups with the exception of infection in the tofacitinib 10-mg group (RR, 2.133; 95% CI, 1.268 to 3.590; p = 0.004). The results of two phase-III trials (1,123 patients) confirmed the findings in the phase-II studies. Conclusions Tofacitinib at dosages of 5 and 10 mg twice daily was found to be effective in patients with active RA that inadequately responded to methotrexate or disease-modifying antirheumatic drugs, and showed a manageable safety profile. PMID:25228842

Randomized, controlled, assessor-blind clinical trial to assess the efficacy of single- versus repeated-dose albendazole to treat ascaris lumbricoides, trichuris trichiura, and hookworm infection.

Science.gov (United States)

Adegnika, Ayola A; Zinsou, Jeannot F; Issifou, Saadou; Ateba-Ngoa, Ulysse; Kassa, Roland F; Feugap, Eliane N; Honkpehedji, Yabo J; Dejon Agobe, Jean-Claude; Kenguele, Hilaire M; Massinga-Loembe, Marguerite; Agnandji, Selidji T; Mordmüller, Benjamin; Ramharter, Michael; Yazdanbakhsh, Maria; Kremsner, Peter G; Lell, Bertrand

2014-05-01

In many regions where soil-transmitted helminth infections are endemic, single-dose albendazole is used in mass drug administration programs to control infections. There are little data on the efficacy of the standard single-dose administration compared to that of alternative regimens. We conducted a randomized, controlled, assessor-blinded clinical trial to determine the efficacies of standard and extended albendazole treatment against soil-transmitted helminth infection in Gabon. A total of 175 children were included. Adequate cure rates and egg reduction rates above 85% were found with a single dose of albendazole for Ascaris infection, 85% (95% confidence interval [CI], 73, 96) and 93.8% (CI, 87.6, 100), respectively, while two doses were necessary for hookworm infestation (92% [CI, 78, 100] and 92% [CI, 78, 100], respectively). However, while a 3-day regimen was not sufficient to cure Trichuris (cure rate, 83% [CI, 73, 93]), this regimen reduced the number of eggs up to 90.6% (CI, 83.1, 100). The rate ratios of two- and three-dose regimens compared to a single-dose treatment were 1.7 (CI, 1.1, 2.5) and 2.1 (CI, 1.5, 2.9) for Trichuris and 1.7 (CI, 1.0, 2.9) and 1.7 (CI, 1.0, 2.9) for hookworm. Albendazole was safe and well tolerated in all regimens. A single-dose albendazole treatment considerably reduces Ascaris infection but has only a moderate effect on hookworm and Trichuris infections. The single-dose option may still be the preferred regimen because it balances efficacy, safety, and compliance during mass drug administration, keeping in mind that asymptomatic low-level helminth carriage may also have beneficial effects. (This study has been registered at ClinicalTrials.gov under registration number NCT01192802.).

Safety of fenbendazole in Chinese ring-necked pheasants (Phasianus colchicus).

Science.gov (United States)

Griffith, R; Yaeger, M; Hostetter, S; Tell, L A; Wetzlich, S; Vickroy, T; Lillie, B; MacFarlane, W; Laudenslager, T; Whitley, E; Dzikamunhenga, R; Larson, W

2014-03-01

Ring-necked pheasants raised on propagation farms can be severely parasitized with Syngamus trachea (gapeworm) and other parasitic worms. Fenbendazole is a highly effective benzimidazole-class anthelmintic that is not currently approved for game bird species in the United States. The objective of this work was to provide target animal safety data to support a label claim for fenbendazole in pheasants at 100 parts per million (ppm) in the feed for 7 consecutive days. Demonstration of safety in young pheasants and a separate demonstration of reproductive safety in adult birds were required. In the young bird study, 160 Chinese ring-necked pheasants (Phasianus colchicus, 80 males and 80 females) were fed a commercial game bird starter ration containing no antibiotics, growth promoters, or coccidiostats until day 0 of the study (approximately 21 days of age). On day 0 the birds were placed on their respective study diets containing fenbendazole at 0, 100, 300, and 500 ppm for 21 days (three times the normal treatment duration). Clinical observations were recorded twice daily. Feed consumption, feed conversion rate, and body weights were determined for each pen. Three birds from each pen were randomly selected for necropsy, histopathology, and clinical pathology. Birds were carefully examined for feathering abnormalities immediately following euthanasia. The remaining birds in each pen were submitted for drug concentration analysis so that concentrations (for low vs. high treatment levels) could be correlated with clinical observations, clinical pathology, and histologic findings. There no morbidities or mortalities after study day--1. There were no statistically significant treatment-related differences in feed consumption, feed conversion rates, body weights, serum biochemistry profiles, hematologic profiles, gross necropsy findings, histopathologic examination, and feathering. Allowable liver and muscle concentrations of fenbendazole sulfone in turkeys are 6 and 2

Clonidine as an adjunct to intravenous regional anesthesia: A randomized, double-blind, placebo-controlled dose ranging study

Directory of Open Access Journals (Sweden)

Clarence S Ivie

2011-01-01

Full Text Available Background : The addition of clonidine to lidocaine intravenous regional anesthesia (IVRA has been previously reported to improve postoperative analgesia in patients undergoing upper extremity surgery. Our objective was to perform a dose ranging study in order to determine the optimal dose of clonidine used with lidocaine in IVRA. Design & Setting : We performed a double-blinded randomized placebo-controlled study with 60 patients scheduled for elective endoscopic carpal tunnel release under IVRA with 50 ml lidocaine 0.5%. University-affiliated outpatient surgery center. Data collected in operating rooms, recovery room, and by telephone after discharge from surgery center. Materials & Methods : Sixty adult ASA I or II patients undergoing outpatient endoscopic carpal tunnel release under intravenous regional anesthesia.Patients were randomized into five study groups receiving different doses of clonidine in addition to 50 ml 0.5% lidocaine in their IVRA. Group A received 0 mcg/kg, group B 0.25 mcg/kg, group C 0.5 mcg/kg, group D 1.0 mcg/kg and group E 1.5 mcg/kg of clonidine.Intraoperative fentanyl, recovery room pain scores, time to first postsurgical analgesic, total number of acetaminophen/codeine tablets consumed postsurgery, incidence of sedation, hypotension and bradycardia. Results & Conclusions : There was no benefit from any dose of clonidine compared to placebo. There were no clonidine-related side effects seen within the dose range studied. In short duration minor hand surgery, the addition of clonidine to lidocaine-based intravenous regional anesthesia provides no measurable benefit.

Efficacy and Safety of AmBisome in Combination with Sodium Stibogluconate or Miltefosine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II Randomized Trial.

Directory of Open Access Journals (Sweden)

Monique Wasunna

2016-09-01

Full Text Available SSG&PM over 17 days is recommended as first line treatment for visceral leishmaniasis in eastern Africa, but is painful and requires hospitalization. Combination regimens including AmBisome and miltefosine are safe and effective in India, but there are no published data from trials of combination therapies including these drugs from Africa.A phase II open-label, non-comparative randomized trial was conducted in Sudan and Kenya to evaluate the efficacy and safety of three treatment regimens: 10 mg/kg single dose AmBisome plus 10 days of SSG (20 mg/kg/day, 10 mg/kg single dose AmBisome plus 10 days of miltefosine (2.5mg/kg/day and miltefosine alone (2.5 mg/kg/day for 28 days. The primary endpoint was initial parasitological cure at Day 28, and secondary endpoints included definitive cure at Day 210, and pharmacokinetic (miltefosine and pharmacodynamic assessments.In sequential analyses with 49-51 patients per arm, initial cure was 85% (95% CI: 73-92 in all arms. At D210, definitive cure was 87% (95% CI: 77-97 for AmBisome + SSG, 77% (95% CI 64-90 for AmBisome + miltefosine and 72% (95% CI 60-85 for miltefosine alone, with lower efficacy in younger patients, who weigh less. Miltefosine pharmacokinetic data indicated under-exposure in children compared to adults.No major safety concerns were identified, but point estimates of definitive cure were less than 90% for each regimen so none will be evaluated in Phase III trials in their current form. Allometric dosing of miltefosine in children needs to be evaluated.The study was registered with ClinicalTrials.gov, number NCT01067443.

The efficacy and safety of palonosetron compared with granisetron in preventing highly emetogenic chemotherapy-induced vomiting in the Chinese cancer patients: a phase II, multicenter, randomized, double-blind, parallel, comparative clinical trial.

Science.gov (United States)

Yu, Zhaocai; Liu, Wenchao; Wang, Ling; Liang, Houjie; Huang, Ying; Si, Xiaoming; Zhang, Helong; Liu, Duhu; Zhang, Hongmei

2009-01-01

This clinical trial was conducted to evaluate the efficacy and safety of Palonosetron in preventing chemotherapy-induced vomiting (CIV) among the Chinese cancer patients. Two hundred and forty patients were scheduled to be enrolled and randomized to receive a single intravenous dose of palonosetron 0.25 mg, or granisetron 3 mg, 30 min before receiving highly emetogenic chemotherapy. The primary efficacy endpoint was the complete response (CR) rate for acute CIV (during the 0-24-h interval after chemotherapy). Secondary endpoints included the CR rates for delayed CIV (more than 24 h after chemotherapy). Two hundred and eight patients were accrued and received study medication. CR rates for acute CIV were 82.69% for palonosetron and 72.12% for granisetron, which demonstrated that palonosetron was not inferior to granisetron in preventing acute CIV. Comparisons of CR rates for delayed CIV yielded no statistical difference between palonosetron and granisetron groups and did not reveal non-inferiority of palonosetron to granisetron. Adverse events were mostly mild to moderate, with quite low rates among the two groups. A single dose (0.25 mg) of palonosetron is not inferior to a single dose (3 mg) of granisetron in preventing CIV and possesses an acceptable safety profile in the Chinese population.

Efficacy and safety of electroacupuncture in acute decompensated heart failure: a study protocol for a randomized, patient- and assessor-blinded, sham controlled trial.

Science.gov (United States)

Leem, Jungtae; Lee, Seung Min Kathy; Park, Jun Hyeong; Lee, Suji; Chung, Hyemoon; Lee, Jung Myung; Kim, Weon; Lee, Sanghoon; Woo, Jong Shin

2017-07-11

The purpose of this trial is to evaluate the effectiveness and safety of electroacupuncture in the treatment of acute decompensated heart failure compared with sham electroacupuncture. This protocol is for a randomized, sham controlled, patient- and assessor-blinded, parallel group, single center clinical trial that can overcome the limitations of previous trials examining acupuncture and heart failure. Forty-four acute decompensated heart failure patients admitted to the cardiology ward will be randomly assigned into the electroacupuncture treatment group (n = 22) or the sham electroacupuncture control group (n = 22). Participants will receive electroacupuncture treatment for 5 days of their hospital stay. The primary outcome of this study is the difference in total diuretic dose between the two groups during hospitalization. On the day of discharge, follow-up heart rate variability, routine blood tests, cardiac biomarkers, high-sensitivity C-reactive protein (hs-CRP) level, and N-terminal pro b-type natriuretic peptide (NT-pro BNP) level will be assessed. Four weeks after discharge, hs-CRP, NT-pro BNP, heart failure symptoms, quality of life, and a pattern identification questionnaire will be used for follow-up analysis. Six months after discharge, major cardiac adverse events and cardiac function measured by echocardiography will be assessed. Adverse events will be recorded during every visit. The result of this clinical trial will offer evidence of the effectiveness and safety of electroacupuncture for acute decompensated heart failure. Clinical Research Information Service: KCT0002249 .

Safety and Pharmacokinetic Profiles of Repeated-Dose Micafungin in Children and Adolescents Treated for Invasive Candidiasis

Science.gov (United States)

Benjamin, Daniel K.; Deville, Jaime G.; Azie, Nkechi; Kovanda, Laura; Roy, Mike; Wu, Chunzhang; Arrieta, Antonio

2013-01-01

Background Micafungin is an echinocandin with proven efficacy against a broad range of fungal infections, including those caused by Candida species. Objective To evaluate the safety and pharmacokinetics of once-daily 3 mg/kg and 4.5 mg/kg micafungin in children with proven, probable, or suspected invasive candidiasis. Methods Micafungin safety and pharmacokinetics were assessed in two Phase I, open-label, repeat-dose trials. In Study 2101, children aged 2–16 years were grouped by weight to receive 3 mg/kg (≥25 kg) or 4.5 mg/kg (<25 kg) intravenous micafungin for 10–14 days. In Study 2102, children aged 4 months to <2 years received 4.5 mg/kg micafungin. Study protocols were otherwise identical. Results Safety was analyzed in seventy-eight and nine children in Studies 2101 and 2102, respectively. Although adverse events were experienced by most children (2101: n = 62; 2102: n = 9), micafungin-related adverse events were less common (2101: n = 28; 2102: n = 1), and the number of patients discontinuing due to adverse events was low (2101: n = 4; 2102: n = 1). The most common micafungin-related adverse events were infusion-associated symptoms, pyrexia, and hypomagnesemia (Study 2101), and liver function abnormalities (Study 2102). The micafungin pharmacokinetic profile was similar to that seen in other studies conducted in children, but different than that observed in adults. Conclusions In this small cohort of children, once-daily doses of 3 mg/kg and 4.5 mg/kg micafungin were well tolerated. Pharmacokinetic data will be combined in a population pharmacokinetic analysis to support U.S. dosing recommendations in children. PMID:23958810

Impact of Vitamin D Supplementation on Gross Motor Development of Healthy Term Infants: A Randomized Dose-Response Trial.

Science.gov (United States)

Wicklow, Brandy; Gallo, Sina; Majnemer, Annette; Vanstone, Catherine; Comeau, Kathryn; Jones, Glenville; L'Abbe, Mary; Khamessan, Ali; Sharma, Atul; Weiler, Hope; Rodd, Celia

2016-08-01

In addition to benefits for bone health, vitamin D is implicated in muscle function in children and adults. To determine if vitamin D dosage positively correlated with gross motor development at 3 and 6 months of age. We hypothesized that higher doses would be associated with higher scores for gross motor skills. A consecutive sample of 55 healthy, term, and breastfed infants from Montreal, Canada were recruited from a randomized trial of vitamin D supplementation between 2009 and 2012. Infants were randomized to 400 International Units (IU) (n = 19), 800 IU (n = 18) or 1,200 IU (n = 18) vitamin D3/day. Motor performance at 3 and 6 months was quantified by the Alberta Infant Motor Scale (AIMS). Plasma vitamin D3 metabolites were measured by tandem mass spectrometry. AIMS scores did not differ at 3 months. However, total AIMS scores and sitting subscores were significantly higher at 6 months in infants receiving 400 IU/day compared to 800 IU/day and 1,200 IU/day groups (p gross motor achievements were significantly higher in infants receiving 400 IU/day vitamin D. Our findings also support longer infants being slightly delayed.

High and low dose-rate brachytherapy for cervical carcinoma

International Nuclear Information System (INIS)

Orton, C.G.

1998-01-01

For the brachytherapy component of the r[iation treatment of cervical carcinoma, high dose rate (HDR) is slowly replacing conventional low dose rate (LDR) due primarily to r[iation safety and other physical benefits attributed to the HDR modality. Many r[iation oncologists are reluctant to make this change because of perceived r[iobiological dis[vantages of HDR. However, in clinical practice HDR appears to be as effective as LDR but with a lower risk of late complications, as demonstrated by one randomized clinical trial and two comprehensive literature and practice surveys. The reason for this appears to be that the r[iobiological dis[vantages of HDR are outweighed by the physical [vantages. (orig.)

High-dose estradiol improves cognition for women with AD: results of a randomized study.

Science.gov (United States)

Asthana, S; Baker, L D; Craft, S; Stanczyk, F Z; Veith, R C; Raskind, M A; Plymate, S R

2001-08-28

To characterize the cognitive and neuroendocrine response to treatment with a high dose of estrogen for postmenopausal women with AD. Twenty postmenopausal women with AD were randomized to receive either 0.10 mg/day of 17 beta-estradiol by skin patch or a placebo patch for 8 weeks. Subjects were evaluated at baseline, at weeks 3, 5, and 8 during treatment, and again 8 weeks after treatment termination. During each visit, cognition was assessed with a battery of neuropsychological tests, and blood samples were collected to measure plasma estradiol as well as several other neuroendocrine markers of interest. Significant effects of estrogen treatment were observed on attention (Stroop Color Word Interference Test), verbal memory (Buschke Selective Reminding Test), and visual memory (Figure Copy/Memory). In addition, women treated with estrogen demonstrated improved performance on a test of semantic memory (Boston Naming Test) compared with subjects who received a placebo. Estrogen appeared to have a suppressive effect on the insulin-like growth factor (IGF) system such that plasma concentration of IGF binding protein-3 was significantly reduced and plasma levels of estradiol and IGF-I were negatively correlated during estrogen treatment. Administration of a higher dose of estrogen may enhance attention and memory for postmenopausal women with AD. Although these findings provide further clinical evidence to support a cognitive benefit of estrogen for women with AD, studies evaluating the effect of estradiol administration, in particular, using larger sample sizes and for longer treatment durations are warranted before the therapeutic potential of estrogen replacement for women with AD can be firmly established.

Efficacy and Safety of Omalizumab in Patients with Chronic Idiopathic/Spontaneous Urticaria Who Remain Symptomatic on H1 Antihistamines: A Randomized, Placebo-Controlled Study

Science.gov (United States)

Saini, Sarbjit S; Bindslev-Jensen, Carsten; Maurer, Marcus; Grob, Jean-Jacques; Bülbül Baskan, Emel; Bradley, Mary S; Canvin, Janice; Rahmaoui, Abdelkader; Georgiou, Panayiotis; Alpan, Oral; Spector, Sheldon; Rosén, Karin

2015-01-01

ASTERIA I was a 40-week, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of subcutaneous omalizumab as add-on therapy for 24 weeks in patients with chronic idiopathic urticaria/spontaneous urticaria (CIU/CSU) who remained symptomatic despite H1 antihistamine treatment at licensed doses. Patients aged 12–75 years with CIU/CSU who remained symptomatic despite treatment with approved doses of H1 antihistamines were randomized (1:1:1:1) in a double-blind manner to subcutaneous omalizumab 75 mg, 150 mg, or 300 mg or placebo every 4 weeks for 24 weeks followed by 16 weeks of follow-up. The primary end point was change from baseline in weekly itch severity score (ISS) at week 12. Among randomized patients (N=319: placebo n=80, omalizumab 75 mg n=78, 150 mg n=80, 300 mg n=81), 262 (82.1%) completed the study. Compared with placebo (n=80), mean weekly ISS was reduced from baseline to week 12 by an additional 2.96 points (95% confidence interval (CI): −4.71 to −1.21; P=0.0010), 2.95 points (95% CI: −4.72 to −1.18; P=0.0012), and 5.80 points (95% CI: −7.49 to −4.10; Pomalizumab 75-mg (n=77), 150-mg (n=80), and 300-mg groups (n=81), respectively. The omalizumab 300-mg group met all nine secondary end points, including a significant decrease in the duration of time to reach minimally important difference response (⩾5-point decrease) in weekly ISS (Pomalizumab 75-mg, 150-mg, 300-mg, and placebo groups, respectively, experienced a serious adverse event. Omalizumab 300 mg administered subcutaneously every 4 weeks reduced weekly ISS and other symptom scores versus placebo in CIU/CSU patients who remained symptomatic despite treatment with approved doses of H1 antihistamines. PMID:25046337

A randomized study of the immunogenicity and safety of Japanese encephalitis chimeric virus vaccine (JE-CV) in comparison with SA14-14-2 vaccine in children in the Republic of Korea.

Science.gov (United States)

Kim, Dong Soo; Houillon, Guy; Jang, Gwang Cheon; Cha, Sung-Ho; Choi, Soo-Han; Lee, Jin; Kim, Hwang Min; Kim, Ji Hong; Kang, Jin Han; Kim, Jong-Hyun; Kim, Ki Hwan; Kim, Hee Soo; Bang, Joon; Naimi, Zulaikha; Bosch-Castells, Valérie; Boaz, Mark; Bouckenooghe, Alain

2014-01-01

A new live attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) has been developed based on innovative technology to give protection against JE with an improved immunogenicity and safety profile. In this phase 3, observer-blind study, 274 children aged 12-24 months were randomized 1:1 to receive one dose of JE-CV (Group JE-CV) or the SA14-14-2 vaccine currently used to vaccinate against JE in the Republic of Korea (Group SA14-14-2). JE neutralizing antibody titers were assessed using PRNT50 before and 28 days after vaccination. The primary endpoint of non-inferiority of seroconversion rates on D28 was demonstrated in the Per Protocol analysis set as the difference between Group JE-CV and Group SA14-14-2 was 0.9 percentage points (95% confidence interval [CI]: -2.35; 4.68), which was above the required -10%. Seroconversion and seroprotection rates 28 days after administration of a single vaccine dose were 100% in Group JE-CV and 99.1% in Group SA14-14-2; all children except one (Group SA14-14-2) were seroprotected. Geometric mean titers (GMTs) increased in both groups from D0 to D28; GM of titer ratios were slightly higher in Group JE-CV (182 [95% CI: 131; 251]) than Group SA14-14-2 (116 [95% CI: 85.5, 157]). A single dose of JE-CV was well tolerated and no safety concerns were identified. In conclusion, a single dose of JE-CV or SA14-14-2 vaccine elicited a comparable immune response with a good safety profile. Results obtained in healthy Korean children aged 12-24 months vaccinated with JE-CV are consistent with those obtained in previous studies conducted with JE-CV in toddlers.

The 'Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen' (HOST-ASSURE trial: study protocol for a randomized controlled trial

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Park Kyung

2012-03-01

Full Text Available Abstract Background Second-generation drug-eluting stents (DES have raised the bar of clinical performance. These stents are mostly made from cobalt chromium alloy. A newer generation DES has been developed from platinum chromium alloy, but clinical data regarding the efficacy and safety of the platinum chromium-based everolimus-eluting stent (PtCr-EES is limited, with no comparison data against the cobalt chromium-based zotarolimus-eluting stent (CoCr-ZES. In addition, an antiplatelet regimen is an integral component of medical therapy after percutaneous coronary intervention (PCI. A 1-week duration of doubling the dose of clopidogrel (double-dose antiplatelet therapy (DDAT was shown to improve outcome at 1 month compared with conventional dose in acute coronary syndrome (ACS patients undergoing PCI. However in Asia, including Korea, the addition of cilostazol (triplet antiplatelet therapy (TAT is used more commonly than doubling the dose of clopidogrel in high-risk patients. Methods In the 'Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen' (HOST-ASSURE trial, approximately 3,750 patients are being prospectively and randomly assigned in a 2 × 2 factorial design according to the type of stent (PtCr-EES vs CoCr-ZES and antiplatelet regimen (TAT vs DDAT. The first primary endpoint is target lesion failure at 1 year for the stent comparison, and the second primary endpoint is net clinical outcome at 1 month for comparison of antiplatelet therapy regimen. Discussion The HOST-ASSURE trial is the largest study yet performed to directly compare the efficacy and safety of the PtCr-EES versus CoCr-ZES in an 'all-comers' population. In addition, this study will also compare the clinical outcome of TAT versus DDAT for 1-month post PCI. Trial registration ClincalTrials.gov number NCT01267734.

EFFICIENCY AND SAFETY ASSESSMENT OF GENERIC ATORVASTATINE IN PATIENTS WITH HYPERLIPIDEMIA

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J. E. Semyonova

2015-12-01

Full Text Available Aim. To assess in a short-term study efficiency and safety of hypolipidemic therapy with atorvastatine generic, Tulip, in comparison with simvastatine generic, Vasilip, in hyperlipidemic patients.Material and methods. Open, randomized, comparative, cross over study included 87 patients with hyperlipidemia, who didn’t receive hypolipidemic drugs within 6 weeks, or followed hypolipidemic diet for 4 weeks. Each patient received therapy with one of the studied drugs within 6 weeks. Then after 4-week wash-out period the second therapy with the other drug was held. Consequence of courses with each drug was set by randomization. Initial dose of both drugs was 10 mg daily. Dose was adjusted after 3 weeks. The dose was increased to 20 mg daily if cholesterol of low density lipoproteid (CLDL hadn’t reached target level (< 115 mg/dl. of Treatment safety was assessed on the basis of clinical data, hepatic enzymes activity and creatine phosphokinase levels.Results. It is shown, that to reach target figures of plasma lipid spectrum, Vasilip dose was increased significantly more often, than Tulip dose. Average Tulip dose after titration was 14,8 mg daily, Vasilip dose – 15,6 mg daily. Patients with initially higher level of triglycerides (TG > 170 mg/dl after 6 weeks with Tulip treatment showed TG reduction by 38% and with Vasilip treatment – by 20%. Both drugs showed good tolerance, no significant differences in number of side-effects were observed.Conclusion. 6-week treatment with atorvastatine generic Tulip shows significant hypolipidemic effect, which appears in significant reduction of CLDL, total cholesterol, TG compared to the initial levels. Degree of total cholesterol reduction is significantly higher with Tulip treatment compared to Vasilip treatment. Analyses shown that target levels of the assessed figures were reached in more patients, treated with Tulip. Side-effects in Tulip treatment were not severe.

EFFICIENCY AND SAFETY ASSESSMENT OF GENERIC ATORVASTATINE IN PATIENTS WITH HYPERLIPIDEMIA

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J. E. Semyonova

2005-01-01

Full Text Available Aim. To assess in a short-term study efficiency and safety of hypolipidemic therapy with atorvastatine generic, Tulip, in comparison with simvastatine generic, Vasilip, in hyperlipidemic patients.Material and methods. Open, randomized, comparative, cross over study included 87 patients with hyperlipidemia, who didn’t receive hypolipidemic drugs within 6 weeks, or followed hypolipidemic diet for 4 weeks. Each patient received therapy with one of the studied drugs within 6 weeks. Then after 4-week wash-out period the second therapy with the other drug was held. Consequence of courses with each drug was set by randomization. Initial dose of both drugs was 10 mg daily. Dose was adjusted after 3 weeks. The dose was increased to 20 mg daily if cholesterol of low density lipoproteid (CLDL hadn’t reached target level (< 115 mg/dl. of Treatment safety was assessed on the basis of clinical data, hepatic enzymes activity and creatine phosphokinase levels.Results. It is shown, that to reach target figures of plasma lipid spectrum, Vasilip dose was increased significantly more often, than Tulip dose. Average Tulip dose after titration was 14,8 mg daily, Vasilip dose – 15,6 mg daily. Patients with initially higher level of triglycerides (TG > 170 mg/dl after 6 weeks with Tulip treatment showed TG reduction by 38% and with Vasilip treatment – by 20%. Both drugs showed good tolerance, no significant differences in number of side-effects were observed.Conclusion. 6-week treatment with atorvastatine generic Tulip shows significant hypolipidemic effect, which appears in significant reduction of CLDL, total cholesterol, TG compared to the initial levels. Degree of total cholesterol reduction is significantly higher with Tulip treatment compared to Vasilip treatment. Analyses shown that target levels of the assessed figures were reached in more patients, treated with Tulip. Side-effects in Tulip treatment were not severe.

Immunophenotyping and efficacy of low dose ATG in non-sensitized kidney recipients undergoing early steroid withdrawal: a randomized pilot study.

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Monica Grafals

Full Text Available Rabbit antithymocyte globulin (ATG is commonly used as an induction therapy in renal transplant recipients, but the ideal dosage in tacrolimus-based early steroid withdrawal protocols has not been established. The purpose of this pilot study was to determine the immunophenotyping and efficacy of lower dose ATG in low immunological-risk kidney transplant recipients. In this prospective study, 45 patients were randomized (1∶1 to our standard dose ATG (total dose 3.75 mg/kg(sATG vs. lower dose 2.25 mg/kg (lowATG. All patients underwent early steroid withdrawal within 7 days. The primary end point was biopsy-proven acute rejection at 12 months. Prospective immunophenotyping of freshly isolated PBMCs was performed at baseline, 3, 6, 12 months post-transplant. The rate of acute rejection was 17% and 10% in the sATG and lowATG, respectively. Effector memory T cells, Tregs and recent thymic emigrants T cells had similar kinetics post-transplant in both groups. No statistically significant differences were found in graft survival, patient survival or infections between the two groups, though there was a non-significant increase in leukopenia (43%v s. 30%, CMV (8% vs. 0 and BK (4% vs. 0 infections in sATG group vs. lowATG. In sum, in low immunological risk kidney recipients undergoing steroid withdrawal, low dose ATG seems to be efficacious in preventing acute rejection and depleting T cells with potentially lower infectious complications. A larger study is warranted to confirm these findings.ClinicalTrials.gov NCT00548405.

Safety of fenbendazole in common peafowl (Pavo cristatus).

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Umar, Sajid; Abbas, Seema; Khan, Muhammad Irfan; Nisa, Qamarun; Younus, Muhammad; Aqil, Kiran; Qayyum, Rizwan; Yaqoob, Muhammad; Ali, Asif; Yaseen, Muhammad Asif; Shah, Muhammad Ali

2018-01-01

The present study was undertaken to find out the safety levels of fenbendazole in common peafowl. This bird, raised on aviaries and zoos, can be severely parasitized with Ascaridia galli (enteric worms) and Syngamus trachea (gapeworm) along with other parasitic worms. Fenbendazole is a highly effective benzimidazole-class anthelmintic in animals. The objective of this work was to provide target animal safety data in young peafowl and to demonstrate reproductive safety in adult birds. During the experimental study, diets containing fenbendazole at 0, 100, 200 and 300 ppm were fed for 21 days (three times the normal treatment duration). Data for feed consumption, feed conversion rate, and body weights were recorded for each bird in each group. Drug concentrations in different tissues of birds were determined to correlate concentrations with clinical observations, clinical pathology, and histologic findings. There were no morbidities or mortalities after study day 21. Additionally, there were no statistically significant treatment-related differences among above mentioned parameters. Analysis of fenbendazole concentrations in kidney, liver, leg/thigh, and breast muscle and skin with associated fat revealed that, even at the highest dose level used and with no feed withdrawal, fenbendazole concentrations were relatively low in these tissues. These findings indicate that fenbendazole has a relatively wide margin of safety in young peafowl and that the proposed dose of 100 ppm in the feed for 7 consecutive days is well within the margin of safety. In the reproductive safety study, five breeder peafowl farms fed fendbendazole at 100ppm for 7 days and collected data on hatching percentage of peahen eggs before and after treatment. Reproductive performance in peahen was not adversely affected.

Pilot Randomized Controlled Trial of Titrated Subcutaneous Ketamine in Older Patients with Treatment-Resistant Depression.

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George, Duncan; Gálvez, Verònica; Martin, Donel; Kumar, Divya; Leyden, John; Hadzi-Pavlovic, Dusan; Harper, Simon; Brodaty, Henry; Glue, Paul; Taylor, Rohan; Mitchell, Philip B; Loo, Colleen K

2017-11-01

To assess the efficacy and safety of subcutaneous ketamine for geriatric treatment-resistant depression. Secondary aims were to examine if repeated treatments were safe and more effective in inducing or prolonging remission than a single treatment. In this double-blind, controlled, multiple-crossover study with a 6-month follow-up (randomized controlled trial [RCT] phase), 16 participants (≥60 years) with treatment-resistant depression who relapsed after remission or did not remit in the RCT were administered an open-label phase. Up to five subcutaneous doses of ketamine (0.1, 0.2, 0.3, 0.4, and 0.5 mg/kg) were administered in separate sessions (≥1 week apart), with one active control (midazolam) randomly inserted (RCT phase). Twelve ketamine treatments were given in the open-label phase. Mood, hemodynamic, and psychotomimetic outcomes were assessed by blinded raters. Remitters in each phase were followed for 6 months. Seven of 14 RCT-phase completers remitted with ketamine treatment. Five remitted at doses below 0.5 mg/kg. Doses ≥ 0.2 mg/kg were significantly more effective than midazolam. Ketamine was well tolerated. Repeated treatments resulted in higher likelihood of remission or longer time to relapse. Results provide preliminary evidence for the efficacy and safety of ketamine in treating elderly depressed. Dose titration is recommended for optimizing antidepressant and safety outcomes on an individual basis. Subcutaneous injection is a practical method for giving ketamine. Repeated treatments may improve remission rates (clinicaltrials.gov; NCT01441505). Copyright © 2017 American Association for Geriatric Psychiatry. All rights reserved.

Phase II, randomized, open, controlled study of AS03-adjuvanted H5N1 pre-pandemic influenza vaccine in children aged 3 to 9 years: follow-up of safety and immunogenicity persistence at 24 months post-vaccination.

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Díez-Domingo, Javier; Baldó, José-María; Planelles-Catarino, Maria Victoria; Garcés-Sánchez, María; Ubeda, Isabel; Jubert-Rosich, Angels; Marès, Josep; Garcia-Corbeira, Pilar; Moris, Philippe; Teko, Maurice; Vanden Abeele, Carline; Gillard, Paul

2015-03-01

An AS03-adjuvanted H5N1 influenza vaccine elicited broad and persistent immune responses with an acceptable safety profile up to 6 months following the first vaccination in children aged 3-9 years. In this follow-up of the Phase II study, we report immunogenicity persistence and safety at 24 months post-vaccination in children aged 3-9 years. The randomized, open-label study assessed two doses of H5N1 A/Vietnam/1194/2004 influenza vaccine (1·9 μg or 3·75 μg hemagglutinin antigen) formulated with AS03A or AS03B (11·89 mg or 5·93 mg tocopherol, respectively). Control groups received seasonal trivalent influenza vaccine. Safety was assessed prospectively and included potential immune-mediated diseases (pIMDs). Immunogenicity was assessed by hemagglutination-inhibition assay 12 and 24 months after vaccination; cross-reactivity and cell-mediated responses were also assessed. (NCT00502593). The safety population included 405 children. Over 24 months, five events fulfilled the criteria for pIMDs, of which four occurred in H5N1 vaccine recipients, including uveitis (n = 1) and autoimmune hepatitis (n = 1), which were considered to be vaccine-related. Overall, safety profiles of the vaccines were clinically acceptable. Humoral immune responses at 12 and 24 months were reduced versus those observed after the second dose of vaccine, although still within the range of those observed after the first dose. Persistence of cell-mediated immunity was strong, and CD4(+) T cells with a TH 1 profile were observed. Two doses of an AS03-adjuvanted H5N1 influenza vaccine in children showed low but persistent humoral immune responses and a strong persistence of cell-mediated immunity, with clinically acceptable safety profiles up to 24 months following first vaccination. © 2014 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.

A randomized, double-blind, phase III study comparing two doses of erlotinib for second-line treatment of current smokers with advanced non-small-cell lung cancer (CurrentS).

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Smit, Egbert F; Wu, Yi-Long; Gervais, Radj; Zhou, Caicun; Felip, Enriqueta; Feng, Jifeng; Guclu, Salih Zeki; Hoiczyk, Mathias; Dorokhova, Elena; Freudensprung, Ulrich; Grange, Susan; Perez-Moreno, Pablo Diego; Mitchell, Lada; Reck, Martin

2016-09-01

Active smokers with non-small-cell lung cancer (NSCLC) have increased erlotinib metabolism versus non-smoking patients, which reduces exposure. Therefore, an increased erlotinib dose may be beneficial. The CurrentS study (NCT01183858) assessed efficacy and safety of 300mg erlotinib (E300) as second-line therapy in current smokers with locally advanced or metastatic NSCLC versus the standard 150mg dose (E150). Patients with stage IIIB/IV NSCLC (current smokers who failed first-line platinum-based chemotherapy) were randomized to receive E150 or E300 until progression/death/unacceptable toxicity. progression-free survival (PFS). Secondary endpoints: overall survival (OS), disease control rate and safety. A total of 342 patients were screened; the intent-to-treat population comprised 159 E300 patients and 154 E150 patients. Median PFS was 7.0 versus 6.9 weeks with E300 versus E150, respectively (unstratified hazard ratio [HR]=1.05, 95% confidence interval [CI]: 0.83-1.33; unstratified log-rank P=0.671). Median OS was 6.8 months in both arms (unstratified HR=1.03, 95% CI: 0.80-1.32; unstratified log-rank P=0.846). Overall, 89.2% (E300 arm) and 84.4% (E150 arm) experienced ≥1 adverse event (AE) of any grade (44.3% and 37%, respectively, experienced grade ≥3 AEs); AEs of special interest were reported in 67.7% and 47.4% of patients, respectively. E300 resulted in higher mean plasma concentrations versus E150, however, this did not improve efficacy. Despite the difference in erlotinib exposure, there was no evidence of an incremental efficacy benefit of a higher erlotinib dose versus the standard dose in this population of highly active smokers. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Bayesian dose selection design for a binary outcome using restricted response adaptive randomization.

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Meinzer, Caitlyn; Martin, Renee; Suarez, Jose I

2017-09-08

In phase II trials, the most efficacious dose is usually not known. Moreover, given limited resources, it is difficult to robustly identify a dose while also testing for a signal of efficacy that would support a phase III trial. Recent designs have sought to be more efficient by exploring multiple doses through the use of adaptive strategies. However, the added flexibility may potentially increase the risk of making incorrect assumptions and reduce the total amount of information available across the dose range as a function of imbalanced sample size. To balance these challenges, a novel placebo-controlled design is presented in which a restricted Bayesian response adaptive randomization (RAR) is used to allocate a majority of subjects to the optimal dose of active drug, defined as the dose with the lowest probability of poor outcome. However, the allocation between subjects who receive active drug or placebo is held constant to retain the maximum possible power for a hypothesis test of overall efficacy comparing the optimal dose to placebo. The design properties and optimization of the design are presented in the context of a phase II trial for subarachnoid hemorrhage. For a fixed total sample size, a trade-off exists between the ability to select the optimal dose and the probability of rejecting the null hypothesis. This relationship is modified by the allocation ratio between active and control subjects, the choice of RAR algorithm, and the number of subjects allocated to an initial fixed allocation period. While a responsive RAR algorithm improves the ability to select the correct dose, there is an increased risk of assigning more subjects to a worse arm as a function of ephemeral trends in the data. A subarachnoid treatment trial is used to illustrate how this design can be customized for specific objectives and available data. Bayesian adaptive designs are a flexible approach to addressing multiple questions surrounding the optimal dose for treatment efficacy

A Phase I randomized clinical trial testing the safety, tolerability and preliminary pharmacokinetics of the mGluR5 negative allosteric modulator GET 73 following single and repeated doses in healthy volunteers.

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Haass-Koffler, Carolina L; Goodyear, Kimberly; Long, Victoria M; Tran, Harrison H; Loche, Antonella; Cacciaglia, Roberto; Swift, Robert M; Leggio, Lorenzo

2017-11-15

Preclinical work suggests that the metabotropic glutamate receptor subtype 5 (mGlu5) may represent a novel target to treat neuropsychiatric disorders, including alcohol use disorder and obesity. The goal of this first-in-man study was to evaluate the safety, tolerability and pharmacokinetics (PK) of GET 73 (PubChem SID: 329974174), a novel mGluR5 negative allosteric modulator. This was a double-blind, placebo-controlled, ascending dose, Phase I study conducted in healthy male volunteers in two experiments. GET 73 was administered as single ascending doses (N=48; Experiment 1; 10, 30, 100, 300, 450, 600-mg) or multiple ascending doses (N=32; Experiment 2; 100, 300, 450, 450-mg twice a day). Primary endpoints were the incidence of adverse events (AEs) among drug conditions and drug tolerability. The secondary endpoints were the PK parameters of GET 73 and its metabolite MET 2. Single GET 73 doses of up to 600-mg and repeated ascending doses of up to 450-mg twice/day were safe and well-tolerated. There were no serious or severe AEs. All AEs were mild or moderate in severity. Total GET 73 exposure increased with each increased GET 73 dose. A dose-related increase in mean maximum plasma drug concentration was observed after repeated dosing. Maximum plasma drug concentrations occurred between 0.5 and 2.05h after administration in all groups for both single and repeated doses. This first-in-human study indicates that GET 73, as single or multiple ascending doses, is safe and well-tolerated when administered to healthy male volunteers. Copyright © 2017 Elsevier B.V. All rights reserved.

Computerized clinical decision support systems for therapeutic drug monitoring and dosing: A decision-maker-researcher partnership systematic review

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Weise-Kelly Lorraine

2011-08-01

Full Text Available Abstract Background Some drugs have a narrow therapeutic range and require monitoring and dose adjustments to optimize their efficacy and safety. Computerized clinical decision support systems (CCDSSs may improve the net benefit of these drugs. The objective of this review was to determine if CCDSSs improve processes of care or patient outcomes for therapeutic drug monitoring and dosing. Methods We conducted a decision-maker-researcher partnership systematic review. Studies from our previous review were included, and new studies were sought until January 2010 in MEDLINE, EMBASE, Evidence-Based Medicine Reviews, and Inspec databases. Randomized controlled trials assessing the effect of a CCDSS on process of care or patient outcomes were selected by pairs of independent reviewers. A study was considered to have a positive effect (i.e., CCDSS showed improvement if at least 50% of the relevant study outcomes were statistically significantly positive. Results Thirty-three randomized controlled trials were identified, assessing the effect of a CCDSS on management of vitamin K antagonists (14, insulin (6, theophylline/aminophylline (4, aminoglycosides (3, digoxin (2, lidocaine (1, or as part of a multifaceted approach (3. Cluster randomization was rarely used (18% and CCDSSs were usually stand-alone systems (76% primarily used by physicians (85%. Overall, 18 of 30 studies (60% showed an improvement in the process of care and 4 of 19 (21% an improvement in patient outcomes. All evaluable studies assessing insulin dosing for glycaemic control showed an improvement. In meta-analysis, CCDSSs for vitamin K antagonist dosing significantly improved time in therapeutic range. Conclusions CCDSSs have potential for improving process of care for therapeutic drug monitoring and dosing, specifically insulin and vitamin K antagonist dosing. However, studies were small and generally of modest quality, and effects on patient outcomes were uncertain, with no convincing

Safety of dose escalation by simultaneous integrated boosting radiation dose within the primary tumor guided by 18FDG-PET/CT for esophageal cancer

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Yu, Wen; Cai, Xu-Wei; Liu, Qi; Zhu, Zheng-Fei; Feng, Wen; Zhang, Qin; Zhang, Ying-Jian; Yao, Zhi-Feng; Fu, Xiao-Long

2015-01-01

Purpose: To observe the safety of selective dose boost to the pre-treatment high 18 F-deoxyglucose (FDG) uptake areas of the esophageal GTV. Methods: Patients with esophageal squamous cell carcinoma were treated with escalating radiation dose of 4 levels, with a simultaneous integrated boost (SIB) to the pre-treatment 50% SUVmax area of the primary tumor. Patients received 4 monthly cycles of cisplatin and fluorouracil. Dose-limiting toxicity (DLT) was defined as any Grade 3 or higher acute toxicities causing continuous interruption of radiation for over 1 week. Results: From April 2012 to February 2014, dose has been escalated up to LEVEL 4 (70 Gy). All of the 25 patients finished the prescribed dose without DLT, and 10 of them developed Grade 3 acute esophagitis. One patient of LEVEL 2 died of esophageal hemorrhage within 1 month after completion of radiotherapy, which was not definitely correlated with treatment yet. Late toxicities remained under observation. With median follow up of 8.9 months, one-year overall survival and local control was 69.2% and 77.4%, respectively. Conclusions: Dose escalation in esophageal cancer based on 18 FDG-PET/CT has been safely achieved up to 70 Gy using the SIB technique. Acute toxicities were well tolerated, whereas late toxicities and long-term outcomes deserved further observation

Efficiency and effectiveness of the use of an acenocoumarol pharmacogenetic dosing algorithm versus usual care in patients with venous thromboembolic disease initiating oral anticoagulation: study protocol for a randomized controlled trial

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Carcas Antonio J

2012-12-01

Full Text Available Abstract Background Hemorrhagic events are frequent in patients on treatment with antivitamin-K oral anticoagulants due to their narrow therapeutic margin. Studies performed with acenocoumarol have shown the relationship between demographic, clinical and genotypic variants and the response to these drugs. Once the influence of these genetic and clinical factors on the dose of acenocoumarol needed to maintain a stable international normalized ratio (INR has been demonstrated, new strategies need to be developed to predict the appropriate doses of this drug. Several pharmacogenetic algorithms have been developed for warfarin, but only three have been developed for acenocoumarol. After the development of a pharmacogenetic algorithm, the obvious next step is to demonstrate its effectiveness and utility by means of a randomized controlled trial. The aim of this study is to evaluate the effectiveness and efficiency of an acenocoumarol dosing algorithm developed by our group which includes demographic, clinical and pharmacogenetic variables (VKORC1, CYP2C9, CYP4F2 and ApoE in patients with venous thromboembolism (VTE. Methods and design This is a multicenter, single blind, randomized controlled clinical trial. The protocol has been approved by La Paz University Hospital Research Ethics Committee and by the Spanish Drug Agency. Two hundred and forty patients with VTE in which oral anticoagulant therapy is indicated will be included. Randomization (case/control 1:1 will be stratified by center. Acenocoumarol dose in the control group will be scheduled and adjusted following common clinical practice; in the experimental arm dosing will be following an individualized algorithm developed and validated by our group. Patients will be followed for three months. The main endpoints are: 1 Percentage of patients with INR within the therapeutic range on day seven after initiation of oral anticoagulant therapy; 2 Time from the start of oral anticoagulant treatment

Efficiency and effectiveness of the use of an acenocoumarol pharmacogenetic dosing algorithm versus usual care in patients with venous thromboembolic disease initiating oral anticoagulation: study protocol for a randomized controlled trial.

Science.gov (United States)

Carcas, Antonio J; Borobia, Alberto M; Velasco, Marta; Abad-Santos, Francisco; Díaz, Manuel Quintana; Fernández-Capitán, Carmen; Ruiz-Giménez, Nuria; Madridano, Olga; Sillero, Pilar Llamas

2012-12-13

Hemorrhagic events are frequent in patients on treatment with antivitamin-K oral anticoagulants due to their narrow therapeutic margin. Studies performed with acenocoumarol have shown the relationship between demographic, clinical and genotypic variants and the response to these drugs. Once the influence of these genetic and clinical factors on the dose of acenocoumarol needed to maintain a stable international normalized ratio (INR) has been demonstrated, new strategies need to be developed to predict the appropriate doses of this drug. Several pharmacogenetic algorithms have been developed for warfarin, but only three have been developed for acenocoumarol. After the development of a pharmacogenetic algorithm, the obvious next step is to demonstrate its effectiveness and utility by means of a randomized controlled trial. The aim of this study is to evaluate the effectiveness and efficiency of an acenocoumarol dosing algorithm developed by our group which includes demographic, clinical and pharmacogenetic variables (VKORC1, CYP2C9, CYP4F2 and ApoE) in patients with venous thromboembolism (VTE). This is a multicenter, single blind, randomized controlled clinical trial. The protocol has been approved by La Paz University Hospital Research Ethics Committee and by the Spanish Drug Agency. Two hundred and forty patients with VTE in which oral anticoagulant therapy is indicated will be included. Randomization (case/control 1:1) will be stratified by center. Acenocoumarol dose in the control group will be scheduled and adjusted following common clinical practice; in the experimental arm dosing will be following an individualized algorithm developed and validated by our group. Patients will be followed for three months. The main endpoints are: 1) Percentage of patients with INR within the therapeutic range on day seven after initiation of oral anticoagulant therapy; 2) Time from the start of oral anticoagulant treatment to achievement of a stable INR within the therapeutic

Weekly, low-dose docetaxel combined with estramustine for Japanese castration-resistant prostate cancer: its efficacy and safety profile compared with tri-weekly standard-dose treatment.

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Nakai, Yasutomo; Nishimura, Kazuo; Nakayama, Masashi; Uemura, Motohide; Takayama, Hitoshi; Nonomura, Norio; Tsujimura, Akira

2014-02-01

We retrospectively investigated the efficacy and safety profile of weekly low-dose docetaxel (DTX) with estramustine in comparison with triweekly standard-dose DTX treatment for Japanese patients with castration-resistant prostate cancer (CRPC). Between April 2002 and January 2011, 75 CRPC patients were treated with triweekly DTX (60-75 mg/m(2) every 3 weeks) (standard-dose group), and 76 CRPC patients were treated with weekly low-dose DTX (20-30 mg/m(2) on days 2 and 9 with estramustine 560 mg on days 1-3 and 8-10) every 3 weeks (low-dose group). Prostate-specific antigen (PSA) response and progression-free and overall survival were analyzed in each group. Median serum PSA level of the standard-dose group and low-dose group was 25.0 and 35.5 ng/ml, respectively. In the standard-dose and low-dose groups, 57.8 and 65.2 % of patients, respectively, achieved a PSA decline ≥ 50 %. There was no significant difference in either median time to progression between the standard-dose group (10.0 months) and low-dose group (7.1 months) or in median duration of survival between the standard-dose group (24.2 months) and low-dose group (30.6 months). Multivariate analysis with a Cox proportional hazards regression model showed that DTX treatment protocol did not influence the risk of death. Incidences of grade 3-4 neutropenia, febrile neutropenia, and thrombocytopenia were significantly higher in the standard-dose versus low-dose group (58.7 vs. 7.9 %, 16.0 vs. 3.9 %, and 8.0 vs. 0 %, respectively). For Japanese CRPC patients, weekly low-dose DTX combined with estramustine has similar efficacy to standard-dose DTX but with fewer adverse events.

Evaluation of the efficacy and safety of olanzapine as an adjunctive treatment for anorexia nervosa in adolescent females: a randomized, double-blind, placebo-controlled trial

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Moher David

2008-01-01

Full Text Available Abstract Background Anorexia Nervosa (AN is a serious, debilitating condition that causes significant physical, emotional, and functional impairment. The condition is characterized by destructive weight loss behaviours and a refusal to maintain body weight at or above a minimally normal weight for age and height. AN often develops in adolescence and is a predominantly female disorder. Treatment for AN typically involves medical, nutritional and psychological interventions. Pharmacotherapy is also often used; however, the literature on the effectiveness of these drugs in a pediatric population is very limited. Olanzapine, which is an 'atypical' antipsychotic, is becoming more widespread in the treatment of AN. Olanzapine is hypothesized to facilitate weight gain, while decreasing levels of agitation and decreasing resistance to treatment in young women with AN. This randomized, double-blind placebo-controlled trial seeks to examine the effectiveness and safety of olanzapine in female youth with AN. Methods/Design Adolescent females between the ages of 12 and 17 diagnosed with AN (either restricting or binge/purge type or Eating Disorder Not Otherwise Specified with a Body Mass Index of less than or equal to 17.5, will be offered inclusion in the study. Patients will be randomly assigned to receive either olanzapine or placebo. Patients assigned to receive olanzapine will start at a low dose of 1.25 mg/day for three days, followed by 2.5 mg/day for four days, 5 mg/day for one week, then 7.5 mg/day (the target dose chosen for 10 weeks. After 10 weeks at 7.5 mg the medication will be tapered and discontinued over a period of two weeks. The effectiveness of olanzapine versus placebo will be determined by investigating the change from baseline on measures of eating attitudes and behaviors, depression and anxiety, and change in Body Mass Index at week 12, and after a follow-up period at week 40. It is anticipated that 67 participants will be recruited

Safety of Prasugrel Loading Doses in Patients Pre-Loaded With Clopidogrel in the Setting of Primary Percutaneous Coronary Intervention

DEFF Research Database (Denmark)

Räber, Lorenz; Klingenberg, Roland; Heg, Dik

2015-01-01

OBJECTIVES: The aim of this study was to assess the safety of the concurrent administration of a clopidogrel and prasugrel loading dose in patients undergoing primary percutaneous coronary intervention. BACKGROUND: Prasugrel is one of the preferred P2Y12 platelet receptor antagonists for ST-segment.......62, p = 0.36). CONCLUSIONS: This observational, nonrandomized study of ST-segment elevation myocardial infarction patients suggests that the administration of a loading dose of prasugrel in patients pre-treated with a loading dose of clopidogrel is not associated with an excess of major bleeding events...

Pharmacokinetics, Safety and Tolerability of Melissa officinalis Extract which Contained Rosmarinic Acid in Healthy Individuals: A Randomized Controlled Trial.

Directory of Open Access Journals (Sweden)

Moeko Noguchi-Shinohara

Full Text Available The aim of this study was to evaluate the safety, tolerability and pharmacokinetics of single dose of Melissa officinalis extract which contained rosmarinic acid, including food-effects in healthy individuals. A total of eleven healthy individuals were randomly assigned to treatment arms in the two studies [Study 1 (fasted state and Study 2 (fed state]. Rosmarinic acid in serum was measured by a coulometric detection method using High-Performance Liquid Chromatography electrochemical detector. The serum concentration of total rosmarinic acid peaked at 1 hour after administration of Melissa officinalis extract containing 500mg rosmarinic acid in fasted state, with a maximum serum concentration 162.20 nmol/ L. The area under the curve for intact rosmarinic acid was calculated from the serum concentration-time profile to be 832.13 nmol • hour/ L. Food intake increases area under the curve and delayed time at which the maximum serum concentration. Rosmarinic acid supplementation did not affect liver, kidney, or blood cell function parameters. No adverse event was reported by any of the participants due to the study treatment. Single dose of Melissa officinalis extract containing 500 mg rosmarinic acid appears to be safe and tolerable in healthy individuals. Food intake increased the exposure of rosmarinic acid and delayed absorption of rosmarinic acid in healthy individuals.

Efficacy and safety of oxcarbazepine in the treatment of children with epilepsy: a meta-analysis of randomized controlled trials

Directory of Open Access Journals (Sweden)

Geng H

2017-03-01

Full Text Available Hua Geng, Chengzhong Wang Department of Pediatrics, Maternal and Child Health Hospital of Yancheng, Yancheng City, People’s Republic of China Background: To assess the efficacy and safety of oxcarbazepine (OXC in the treatment of children with epilepsy.Methods: Randomized controlled trials (RCTs published in PubMed, Embase, Web of Science, Cochrane Library, Scopus, SinoMed (Chinese BioMedical Literature Service System, China, and Chinese National Knowledge Infrastructure (China database were systematically reviewed. Eligible studies were those that compared the efficacy and safety of OXC with other antiepileptic drugs in epilepsy. Risk ratio (RR with 95% confidence intervals (95% CIs was calculated using fixed-effects or random-effects model.Results: Eleven RCTs with a total of 1,241 patients met the inclusion criteria and were included in this meta-analysis. Compared with other antiepileptic drugs (sodium valproate, levetiracetam, phenytoin, and placebo, OXC was associated with similar seizure-free rate (RR =1.06, 95% CI: 0.94, 1.20; P=0.366 and percentage reduction from baseline in seizure frequency (for ≥75% reduction: RR =1.15, 95% CI: 0.88, 1.49; P=0.310; for 50%–75% reduction: RR =1.12, 95% CI: 0.90, 1.39; P=0.301; for <50% reduction: RR =0.79, 95% CI: 0.56, 1.12; P=0.179. Moreover, patients treated with OXC had a comparable incidence of adverse events compared with those treated with other antiepileptic drugs (RR =1.01, 95% CI: 0.92, 1.11; P=0.760.Conclusion: OXC showed similar effects and safety as other antiepileptic drugs in the treatment of children with epilepsy. Further well-conducted, large-scale RCTs are needed to validate these findings. Keywords: epilepsy, children, oxcarbazepine, meta-analysis

Efficacy and safety of fixed dose combination of atorvastatin and hydroxychloroquine: a randomized, double-blind comparison with atorvastatin alone among Indian patients with dyslipidemia.

Science.gov (United States)

Pareek, Anil; Chandurkar, Nitin; Thulaseedharan, N K; Legha, R; Agarwal, Manish; Mathur, S L; Salkar, H R; Pednekar, Sangeeta; Pai, Vikas; Sriram, Usha; Khyalappa, Rajesh; Parmar, Mahendra; Agrawal, Navneet; Dhruv, Urman; Saxena, Subhash

2015-11-01

To evaluate the efficacy and safety of atorvastatin + hydroxychloroquine fixed-dose combination tablets in comparison with atorvastatin alone in treatment of dyslipidemia. This double-blind, randomized, out-patient study was conducted in 328 patients with primary dyslipidemia having low-density lipoprotein cholesterol (LDL-C) ≥ 130 mg/dL (3.37 mmol/L) to ≤ 250 mg/dL (6.48 mmol/L) and triglycerides ≤ 400 mg/dL (4.52 mmol/L). Eligible patients were randomized to receive either atorvastatin 10 mg (n = 167) or atorvastatin 10 mg + hydroxychloroquine 200 mg (n = 161) for 24 weeks. CTRI/2010/091/006138. To compare percentage change in LDL-C, total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) from baseline to Week 12 and Week 24 between groups. To compare mean change in glycated hemoglobin (HbA1c), fasting blood glucose (FBG), high-sensitivity C-reactive protein (Hs-CRP), and percentage of patients achieving lipid goals at Week 12 and Week 24. At Week 24, percentage reduction in LDL-C (-32.52 [-36.13 to -28.91] vs -39.54 [-43.25 to -35.83]; p = 0.008), TC (-24.41 [-27.10 to -21.72] vs -29.30 [-32.07 to -26.54]; p = 0.013), and non-HDL-C (-30.37 [-33.71 to -27.04] vs -36.76 [-40.18 to -33.33]; p = 0.009) was significantly greater in combination treated patients. Both the treatments showed a significant reduction in triglycerides at Week 24 from baseline, however, this reduction was not statistically significantly different between treatment groups. No significant change in HDL-C was observed in patients from both the treatment groups. At Week 24, change in HbA1c (0.22 [0.07 to 0.37] vs -0.13 [-0.28 to 0.03]; p = 0.002) and FBG was also statistically significant in favor of combination therapy (0.37 [0.07 to 0.67] vs -0.29 [-0.59 to 0.03]; p = 0.003), whereas no statistically significant difference was observed in change in Hs-CRP (p = 0.310). Significantly more patients from the

Phase I/II dose-finding study of nanoparticle albumin-bound paclitaxel (nab®-Paclitaxel) plus Cisplatin as Treatment for Metastatic Nasopharyngeal Carcinoma

International Nuclear Information System (INIS)

Huang, Yan; Liang, Wenhua; Yang, Yunpeng; Zhao, Liping; Zhao, Hongyun; Wu, Xuan; Zhao, Yuanyuan; Zhang, Yang; Zhang, Li

2016-01-01

This phase I/II study aimed to determine the maximum tolerated dose (MTD) of nanoparticle albumin-bound paclitaxel (nab ® -paclitaxel) plus cisplatin as treatment for metastatic nasopharyngeal carcinoma (NPC). Patients were enrolled into 1 of 3 dose cohorts, each with 21-day treatment cycles: 1) intravenous (IV) nab-paclitaxel 260 mg/m 2 on day 1; 2) IV nab-paclitaxel 140 mg/m 2 on days 1 and 8; 3) IV nab-paclitaxel 100 mg/m 2 on days 1, 8, and 15. All patients received IV cisplatin 75 mg/m 2 on day 1. Treatment continued for 4–6 cycles, or until progression or unacceptable toxicity. If more than one-third of the patients in a cohort experienced a dose-limiting toxicity (DLT), the dose used in the previous cohort would be designated the MTD. Secreted protein acidic and rich in cysteine (SPARC) expression was detected by immunohistochemistry staining. Sixty-nine patients were enrolled, of whom 64 and 67 were eligible for efficacy and safety analysis, respectively. Two DLTs occurred in cohort 1 (grade 4 febrile neutropenia, grade 3 myalgia), none occurred in cohort 2, and 2 occurred in cohort 3 (both grade 3 fatigue). The MTD was not reached. Partial responses were achieved by 42 patients, 15 had stable disease, and 7 had progressive disease, giving an overall response rate of 66 %. Median progression-free survival was 9 months (95 % CI, 6–12 months). Grade ≥ 3 adverse events were mainly hematologic. There was no significant difference between the 3 cohorts with respect to efficacy or safety. Biomarker analyses indicated that stromal, rather than tumoral, SPARC may predict the response to nab-paclitaxel in NPC. Our findings suggest that nab-paclitaxel plus cisplatin is a highly active regimen with moderate toxicity for the treatment of metastatic NPC, which warrants further investigation in a phase III study. ClinicalTrials.gov ID: NCT01735409. The trial was registered on November 20th, 2012. The online version of this article (doi:10.1186/s12885

Maintaining occupational dose ALARA through work management

International Nuclear Information System (INIS)

Khan, A. H.

1999-01-01

Canadian philosophy in keeping occupational dose ALARA has been to train staff in radiation safety so that they can be fully responsible for participating in minimizing the risks associated with the hazardous work. Senior managers actively promote high standards of performance in dose reduction techniques as a means for integrating ALARA into the operation and maintenance of the station by all personnel. Minimizing radiation dose is accomplished by applying cost effective work management techniques such as Job Safety Analysis, pre-job briefings and establishing and achieving radiation dose goals. Radiation dose goals are used as a management tool for involving all work groups in reducing doses as well as providing a means of assessing the effectiveness of dose reduction actions. ALARA, along with conventional safety, is used as a lever to raise the standard of quality of work and to overall build a safety culture. (author). 4 figs

Efficacy and Safety of Sarecycline, a Novel, Once-Daily, Narrow Spectrum Antibiotic for the Treatment of Moderate to Severe Facial Acne Vulgaris: Results of a Phase 2, Dose-Ranging Study.

Science.gov (United States)

Leyden, James J; Sniukiene, Vilma; Berk, David R; Kaoukhov, Alexandre

2018-03-01

There is a need for new oral antibiotics for acne with improved safety profiles and targeted antibacterial spectra. Sarecycline is a novel, tetracycline-class antibiotic specifically designed for acne, offering a narrow spectrum of activity compared with currently available tetracyclines, including less activity against enteric Gram-negative bacteria. This phase 2 study evaluated the efficacy and safety of three doses of sarecycline for moderate to severe facial acne vulgaris. In this multicenter, double-blind, placebo-controlled study, patients aged 12 to 45 years were randomized to once-daily sarecycline 0.75 mg/kg, 1.5 mg/kg, 3.0 mg/kg, or placebo. Efficacy analyses included change from baseline in inflammatory and noninflammatory lesion counts at week 12, with between-group comparisons using analysis of covariance. Safety assessments included adverse events (AEs), clinical laboratories, vital signs, electrocardiograms, and physical examinations. Overall, 285 randomized patients received at least one dose of study drug. At week 12, sarecycline 1.5 mg/kg and 3.0 mg/kg groups demonstrated significantly reduced inflammatory lesions from baseline (52.7% and 51.8%, respectively) versus placebo (38.3%; P=0.02 and P=0.03, respectively). Sarecycline was safe and well tolerated, with similar gastrointestinal AE rates in sarecycline and placebo groups. Vertigo and photosensitivity AEs occurred in less than 1% of patients when pooling sarecycline groups; no vulvovaginal candidiasis AEs occurred. Discontinuation rates due to AEs were low. No serious AEs occurred. Once-daily sarecycline 1.5 mg/kg significantly reduced inflammatory lesions versus placebo and was safe and well tolerated with low rates of AEs, including gastrointestinal AEs. Sarecycline 3.0 mg/kg did not result in additional efficacy versus 1.5 mg/kg. Sarecycline may represent a novel, once-daily treatment for patients with moderate to severe acne. It offers a narrow antibacterial spectrum relative to other