Ogutu, Bernhards R; Baiden, Rita; Diallo, Diadier; Smith, Peter G; Binka, Fred N
The Malaria Clinical Trials Alliance (MCTA), a programme of INDEPTH network of demographic surveillance centres, was launched in 2006 with two broad objectives: to facilitate the timely development of a network of centres in Africa with the capacity to conduct clinical trials of malaria vaccines and drugs under conditions of good clinical practice (GCP); and to support, strengthen and mentor the centres in the network to facilitate their progression towards self-sustaining clinical research centres. Sixteen research centres in 10 African malaria-endemic countries were selected that were already working with the Malaria Vaccine Initiative (MVI) or the Medicines for Malaria Venture (MMV). All centres were visited to assess their requirements for research capacity development through infrastructure strengthening and training. Support provided by MCTA included: laboratory and facility refurbishment; workshops on GCP, malaria diagnosis, strategic management and media training; and training to support staff to undertake accreditation examinations of the Association of Clinical Research Professionals (ACRP). Short attachments to other network centres were also supported to facilitate sharing practices within the Alliance. MCTA also played a key role in the creation of the African Media & Malaria Research Network (AMMREN), which aims to promote interaction between researchers and the media for appropriate publicity and media reporting of research and developments on malaria, including drug and vaccine trials. In three years, MCTA strengthened 13 centres to perform GCP-compliant drug and vaccine trials, including 11 centres that form the backbone of a large phase III malaria vaccine trial. MCTA activities have demonstrated that centres can be brought up to GCP compliance on this time scale, but the costs are substantial and there is a need for further support of other centres to meet the growing demand for clinical trial capacity. The MCTA experience also indicates that
Murphy, S.C.; Hermsen, C.C.; Douglas, A.D.; Edwards, N.J.; Petersen, I.; Fahle, G.A.; Adams, M.; Berry, A.A.; Billman, Z.P.; Gilbert, S.C.; Laurens, M.B.; Leroy, O.; Lyke, K.E.; Plowe, C.V.; Seilie, A.M.; Strauss, K.A.; Teelen, K.; Hill, A.V.; Sauerwein, R.W.
Nucleic acid testing (NAT) for malaria parasites is an increasingly recommended diagnostic endpoint in clinical trials of vaccine and drug candidates and is also important in surveillance of malaria control and elimination efforts. A variety of reported NAT assays have been described, yet no formal
Murphy, Sean C; Hermsen, Cornelus C; Douglas, Alexander D; Edwards, Nick J; Petersen, Ines; Fahle, Gary A; Adams, Matthew; Berry, Andrea A; Billman, Zachary P; Gilbert, Sarah C; Laurens, Matthew B; Leroy, Odile; Lyke, Kristen E; Plowe, Christopher V; Seilie, Annette M; Strauss, Kathleen A; Teelen, Karina; Hill, Adrian V S; Sauerwein, Robert W
Nucleic acid testing (NAT) for malaria parasites is an increasingly recommended diagnostic endpoint in clinical trials of vaccine and drug candidates and is also important in surveillance of malaria control and elimination efforts. A variety of reported NAT assays have been described, yet no formal external quality assurance (EQA) program provides validation for the assays in use. Here, we report results of an EQA exercise for malaria NAT assays. Among five centers conducting controlled human malaria infection trials, all centers achieved 100% specificity and demonstrated limits of detection consistent with each laboratory's pre-stated expectations. Quantitative bias of reported results compared to expected results was generally Quality Assessment program that fulfills the need for EQA of malaria NAT assays worldwide.
Das, Debashish; Cheah, Phaik Yeong; Akter, Fateha; Paul, Dulal; Islam, Akhterul; Sayeed, Abdullah A; Samad, Rasheda; Rahman, Ridwanur; Hossain, Amir; Dondorp, Arjen; Day, Nicholas P; White, Nicholas J; Hasan, Mahtabuddin; Ghose, Aniruddha; Ashley, Elizabeth A
Background Existing evidence suggests that there is often limited understanding among participants in clinical trials about the informed consent process, resulting in their providing consent without really understanding the purpose of the study, specific procedures, and their rights. The objective of the study was to determine the subjects’ understanding of research, perceptions of voluntariness and motivations for participation in a malaria clinical trial. Methods In this study semi-structur...
Sean C Murphy
Full Text Available Nucleic acid testing (NAT for malaria parasites is an increasingly recommended diagnostic endpoint in clinical trials of vaccine and drug candidates and is also important in surveillance of malaria control and elimination efforts. A variety of reported NAT assays have been described, yet no formal external quality assurance (EQA program provides validation for the assays in use. Here, we report results of an EQA exercise for malaria NAT assays. Among five centers conducting controlled human malaria infection trials, all centers achieved 100% specificity and demonstrated limits of detection consistent with each laboratory's pre-stated expectations. Quantitative bias of reported results compared to expected results was generally <0.5 log10 parasites/mL except for one laboratory where the EQA effort identified likely reasons for a general quantitative shift. The within-laboratory variation for all assays was low at <10% coefficient of variation across a range of parasite densities. Based on this study, we propose to create a Molecular Malaria Quality Assessment program that fulfills the need for EQA of malaria NAT assays worldwide.
Das, Debashish; Cheah, Phaik Yeong; Akter, Fateha; Paul, Dulal; Islam, Akhterul; Sayeed, Abdullah A; Samad, Rasheda; Rahman, Ridwanur; Hossain, Amir; Dondorp, Arjen; Day, Nicholas P; White, Nicholas J; Hasan, Mahtabuddin; Ghose, Aniruddha; Ashley, Elizabeth A; Faiz, Abul
Existing evidence suggests that there is often limited understanding among participants in clinical trials about the informed consent process, resulting in their providing consent without really understanding the purpose of the study, specific procedures, and their rights. The objective of the study was to determine the subjects' understanding of research, perceptions of voluntariness and motivations for participation in a malaria clinical trial. In this study semi-structured interviews of adult clinical trial participants with uncomplicated falciparum malaria were conducted in Ramu Upazila Health Complex, in Bangladesh. Of 16 participants, the vast majority (81%) were illiterate. All subjects had a 'therapeutic misconception' i.e. the trial was perceived to be conducted primarily for the benefit of individual patients when in fact the main objective was to provide information to inform public health policy. From the patients' perspective, getting well from their illness was their major concern. Poor actual understanding of trial specific procedures was reported despite participants' satisfaction with treatment and nursing care. There is frequently a degree of overlap between research and provision of clinical care in malaria research studies. Patients may be motivated to participate to research without a good understanding of the principal objectives of the study despite a lengthy consent process. The findings suggest that use of a standard consent form following the current ICH-GCP guidelines does not result in achieving fully informed consent and the process should be revised, simplified and adapted to individual trial settings.
Looareesuwan, S; Chulay, J D; Canfield, C J; Hutchinson, D B
The continuing spread of drug-resistant malaria emphasizes the need for new antimalarial drugs. Atovaquone is a broad-spectrum antiprotozoal drug with a novel mechanism of action, via inhibition of parasite mitochondrial electron transport, and a favorable safety profile. Early studies with atovaquone alone for treatment of malaria demonstrated good initial control of parasitemia but an unacceptable rate of recrudescent parasitemia. Parasites isolated during recrudescence after treatment with atovaquone alone were resistant to atovaquone in vitro. The combination of atovaquone and proguanil is synergistic in vitro, and clinical studies demonstrated enhanced efficacy of the combination compared to either drug alone for treatment of malaria. Malarone, a fixed-dose combination of 250 mg of atovaquone and 100 mg of proguanil hydrochloride, is available in many countries for treatment of acute, uncomplicated malaria caused by Plasmodium falciparum. At the recommended dose (in adults, four tablets once a day for three days), the overall cure rate was > 98% in more than 500 patients with falciparum malaria. In four randomized, controlled clinical trials, treatment with atovaquone and proguanil hydrochloride was significantly more effective than mefloquine (Thailand), amodiaquine (Gabon), chloroquine (Peru and the Philippines) or chloroquine plus pyrimethamine/sulfadoxine (Philippines). In clinical trials where the comparator drug was highly effective, treatment with atovaquone and proguanil hydrochloride was equally effective. Parasites isolated during recrudescence after treatment with the combination of atovaquone and proguanil were not resistant to atovaquone in vitro. The most commonly reported adverse events in clinical trials (abdominal pain, anorexia, nausea, vomiting, diarrhea and coughing) occurred with similar frequency in patients treated with a comparator drug. Malarone is a safe and effective new agent for treatment of malaria.
Esamai, F; Ayuo, P; Owino-Ongor, W; Rotich, J; Ngindu, A; Obala, A; Ogaro, F; Quoqiao, L; Xingbo, G; Guangqian, L
To compare the clinical efficacy and safety of rectal dihydroartemisinin (DATM--Cotecxin) and intravenous quinine in the treatment of severe malaria in children and adults. Moi Teaching and Referral Hospital, Eldoret, Kenya between July and November 1998. A total of sixty seven patients aged two to sixty years with severe malaria were studied. This was an open randomised comparative clinical trial. These were parasite clearance time, fever clearance time, efficacy and the side effect profile of the two drugs. The two groups were comparable on admission on the clinical and laboratory parameters. The parasite clearance time was shorter in the rectal DATM group than quinine group. There was no statistical difference on the fever clearance time and cure rates in the two groups. The adverse reaction profile was better with rectal DATM than with quinine, tinnitus observed more in the quinine group. Rectal DATM is faster in parasite clearance than quinine and is a safe and convenient alternative to quinine in the treatment of severe malaria.
Full Text Available Exposing healthy human volunteers to Plasmodium falciparum-infected mosquitoes is an accepted tool to evaluate preliminary efficacy of malaria vaccines. To accommodate the demand of the malaria vaccine pipeline, controlled infections are carried out in an increasing number of centers worldwide. We assessed their safety and reproducibility.We reviewed safety and parasitological data from 128 malaria-naïve subjects participating in controlled malaria infection trials conducted at the University of Oxford, UK, and the Radboud University Nijmegen Medical Center, The Netherlands. Results were compared to a report from the US Military Malaria Vaccine Program.We show that controlled human malaria infection trials are safe and demonstrate a consistent safety profile with minor differences in the frequencies of arthralgia, fatigue, chills and fever between institutions. But prepatent periods show significant variation. Detailed analysis of Q-PCR data reveals highly synchronous blood stage parasite growth and multiplication rates.Procedural differences can lead to some variation in safety profile and parasite kinetics between institutions. Further harmonization and standardization of protocols will be useful for wider adoption of these cost-effective small-scale efficacy trials. Nevertheless, parasite growth rates are highly reproducible, illustrating the robustness of controlled infections as a valid tool for malaria vaccine development.
Yeka, Adoke; Banek, Kristin; Bakyaita, Nathan; Staedke, Sarah G; Kamya, Moses R; Talisuna, Ambrose; Kironde, Fred; Nsobya, Samuel L; Kilian, Albert; Slater, Madeline; Reingold, Arthur; Rosenthal, Philip J; Wabwire-Mangen, Fred; Dorsey, Grant
Background Drug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination antimalarial therapy including artemisinins has been advocated recently to improve efficacy and limit the spread of resistance, but artemisinins are expensive and relatively untested in highly endemic areas. We compared artemisinin-based and other combination therapies in four districts in Uganda with varying transmission intensity. Methods and Findings We enrolled 2,160 patients aged 6 mo or greater with uncomplicated falciparum malaria. Patients were randomized to receive chloroquine (CQ) + sulfadoxine-pyrimethamine (SP); amodiaquine (AQ) + SP; or AQ + artesunate (AS). Primary endpoints were the 28-d risks of parasitological failure either unadjusted or adjusted by genotyping to distinguish recrudescence from new infections. A total of 2,081 patients completed follow-up, of which 1,749 (84%) were under the age of 5 y. The risk of recrudescence after treatment with CQ + SP was high, ranging from 22% to 46% at the four sites. This risk was significantly lower (p AQ + SP or AQ + AS (7%–18% and 4%–12%, respectively). Compared to AQ + SP, AQ + AS was associated with a lower risk of recrudescence but a higher risk of new infection. The overall risk of repeat therapy due to any recurrent infection (recrudescence or new infection) was similar at two sites and significantly higher for AQ + AS at the two highest transmission sites (risk differences = 15% and 16%, pAQ + AS was the most efficacious regimen for preventing recrudescence, but this benefit was outweighed by an increased risk of new infection. Considering all recurrent infections, the efficacy of AQ + SP was at least as efficacious at all sites and superior to AQ + AS at the highest transmission sites. The high endemicity of malaria in Africa may impact on the efficacy of artemisinin-based combination therapy. The registration number for this trial is ISRCTN67520427 (http://www.controlled-trials.com/isrctn/trial
Byakika-Kibwika, Pauline; Achan, Jane; Lamorde, Mohammed; Karera-Gonahasa, Carine; Kiragga, Agnes N; Mayanja-Kizza, Harriet; Kiwanuka, Noah; Nsobya, Sam; Talisuna, Ambrose O; Merry, Concepta
Severe malaria is a medical emergency associated with high mortality. Adequate treatment requires initial parenteral therapy for fast parasite clearance followed by longer acting oral antimalarial drugs for cure and prevention of recrudescence. In a randomized controlled clinical trial, we evaluated the 42-day parasitological outcomes of severe malaria treatment with intravenous artesunate (AS) or intravenous quinine (QNN) followed by oral artemisinin based combination therapy (ACT) in children living in a high malaria transmission setting in Eastern Uganda. We enrolled 300 participants and all were included in the intention to treat analysis. Baseline characteristics were similar across treatment arms. The median and interquartile range for number of days from baseline to parasite clearance was significantly lower among participants who received intravenous AS (2 (1-2) vs 3 (2-3), P malaria symptoms. In this high transmission setting, we observed adequate initial treatment outcomes followed by very high rates of malaria re-infection post severe malaria treatment. The impact of recurrent antimalarial treatment on the long term efficacy of antimalarial regimens needs to be investigated and surveillance mechanisms for resistance markers established since recurrent malaria infections are likely to be exposed to sub-therapeutic drug concentrations. More strategies for prevention of recurrent malaria infections in the most at risk populations are needed. The study was registered with the Pan African Clinical Trial Registry ( PACTR201110000321348 ).
Full Text Available BACKGROUND: Drug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination antimalarial therapy including artemisinins has been advocated recently to improve efficacy and limit the spread of resistance, but artemisinins are expensive and relatively untested in highly endemic areas. We compared artemisinin-based and other combination therapies in four districts in Uganda with varying transmission intensity. METHODS AND FINDINGS: We enrolled 2,160 patients aged 6 mo or greater with uncomplicated falciparum malaria. Patients were randomized to receive chloroquine (CQ + sulfadoxine-pyrimethamine (SP; amodiaquine (AQ + SP; or AQ + artesunate (AS. Primary endpoints were the 28-d risks of parasitological failure either unadjusted or adjusted by genotyping to distinguish recrudescence from new infections. A total of 2,081 patients completed follow-up, of which 1,749 (84% were under the age of 5 y. The risk of recrudescence after treatment with CQ + SP was high, ranging from 22% to 46% at the four sites. This risk was significantly lower (p < 0.01 after AQ + SP or AQ + AS (7%-18% and 4%-12%, respectively. Compared to AQ + SP, AQ + AS was associated with a lower risk of recrudescence but a higher risk of new infection. The overall risk of repeat therapy due to any recurrent infection (recrudescence or new infection was similar at two sites and significantly higher for AQ + AS at the two highest transmission sites (risk differences = 15% and 16%, p < 0.003. CONCLUSION: AQ + AS was the most efficacious regimen for preventing recrudescence, but this benefit was outweighed by an increased risk of new infection. Considering all recurrent infections, the efficacy of AQ + SP was at least as efficacious at all sites and superior to AQ + AS at the highest transmission sites. The high endemicity of malaria in Africa may impact on the efficacy of artemisinin-based combination therapy. The registration number for this trial is ISRCTN
Mtove, George; Kimani, Joshua; Kisinza, William; Makenga, Geofrey; Mangesho, Peter; Duparc, Stephan; Nakalembe, Miriam; Phiri, Kamija S; Orrico, Russell; Rojo, Ricardo; Vandenbroucke, Pol
Multinational clinical trials are logistically complex and require close coordination between various stakeholders. They must comply with global clinical standards and are accountable to multiple regulatory and ethical bodies. In resource-limited settings, it is challenging to understand how to apply global clinical standards to international, national, and local factors in clinical trials, making multiple-level stakeholder engagement an important element in the successful conduct of these clinical trials. During the planning and implementation of a large multinational clinical trial for intermittent preventive treatment of malaria in pregnancy in resource-limited areas of sub-Saharan Africa, we encountered numerous challenges, which required implementation of a range of engagement measures to ensure compliance with global clinical and regulatory standards. These challenges included coordination with ongoing global malaria efforts, heterogeneity in national regulatory structures, sub-optimal healthcare infrastructure, local practices and beliefs, and perspectives that view healthcare providers with undue trust or suspicion. In addition to engagement with international bodies, such as the World Health Organization, the Malaria in Pregnancy Consortium, the Steve Biko Centre for Bioethics, and the London School of Hygiene and Tropical Medicine, in order to address the challenges just described, Pfizer Inc. and Medicines for Malaria Venture (the "Sponsoring Entities" for these studies) and investigators liaised with national- and district-level stakeholders such as health ministers and regional/local community health workers. Community engagement measures undertaken by investigators included local meetings with community leaders to explain the research aims and answer questions and concerns voiced by the community. The investigators also engaged with family members of prospective trial participants in order to be sensitive to local practices and beliefs. Engagement
Full Text Available ... Clinical Trials About Clinical Trials Clinical trials are research studies that explore whether a medical strategy, treatment, or ... humans. What Are Clinical Trials? Clinical trials are research studies that explore whether a medical strategy, treatment, or ...
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Feb 2, 2000 ... randomisation produced comparable intervention and comparison groups with balanced characteristics. Specific results of the baseline studies are presented in the companion paper. ... strategies for protecting pregnant women against malaria. ..... from malaria vaccine trial conducted among Tanzanian.
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Charunwatthana, Prakaykaew; Faiz, M. Abul; Ruangveerayut, Ronnatrai; Maude, Richard; Rahman, M. Ridwanur; Roberts, L. Jackson; Moore, Kevin; Yunus, Emran Bin; Hoque, M. Gofranul; Hasan, Mahatab Uddin; Lee, Sue J.; Pukrittayakamee, Sasithon; Newton, Paul N.; White, Nicholas J.; Day, Nicholas P.J.; Dondorp, Arjen M.
Objective Markers of oxidative stress are reported to be increased in severe malaria. It has been suggested that the antioxidant N-acetylcysteine (NAC) may be beneficial in treatment. We studied the efficacy and safety of parenteral N-acetylcysteine as an adjunct to artesunate treatment of severe falciparum malaria. Design A randomized double-blind placebo controlled trial on the use of high dose intravenous NAC as adjunctive treatment to artesunate. Setting A provincial hospital in Western Thailand and a tertiary referral hospital in Chittagong, Bangladesh. Patients One hundred and eight adult patients with severe falciparum malaria. Interventions Patients were randomized to receive N-acetylcysteine or placebo as adjunctive treatment to intravenous artesunate. Measurements and main results A total of 56 patients were treated with NAC and 52 received placebo. NAC had no significant effect on mortality, lactate clearance times (p=0.74) or coma recovery times (p=0.46). Parasite clearance time was increased from 30h (range 6h to 144h) to 36h (range 6h to 120h) (p=0.03), but this could be explained by differences in admission parasitemia. Urinary F2-isoprostane metabolites, measured as a marker of oxidative stress, were increased in severe malaria compared to patients with uncomplicated malaria and healthy volunteers. Admission red cell rigidity correlated with mortality, but did not improve with NAC. Conclusion Systemic oxidative stress is increased in severe malaria. Treatment with N-acetylcysteine had no effect on outcome in patients with severe falciparum malaria in this setting. PMID:19114891
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To assess whether indoor residual spraying can provide additional protection against clinical malaria over current best practice of long-lasting insecticidal mosquito nets in The Gambia: study protocol for a two-armed cluster-randomised trial
Full Text Available Abstract Background Recently, there has been mounting interest in scaling-up vector control against malaria in Africa. It needs to be determined if indoor residual spraying (IRS with DDT will provide significant marginal protection against malaria over current best practice of long-lasting insecticidal nets (LLINs and prompt treatment in a controlled trial, given that DDT is currently the most persistent insecticide for IRS. Methods A 2 armed cluster-randomised controlled trial will be conducted to assess whether DDT IRS and LLINs combined provide better protection against clinical malaria in children than LLINs alone in rural Gambia. Each cluster will be a village, or a group of small adjacent villages; all clusters will receive LLINs and half will receive IRS in addition. Study children, aged 6 months to 13 years, will be enrolled from all clusters and followed for clinical malaria using passive case detection to estimate malaria incidence for 2 malaria transmission seasons in 2010 and 2011. This will be the primary endpoint. Exposure to malaria parasites will be assessed using light and exit traps followed by detection of Anopheles gambiae species and sporozoite infection. Study children will be surveyed at the end of each transmission season to estimate the prevalence of Plasmodium falciparum infection and the prevalence of anaemia. Discussion Practical issues concerning intervention implementation, as well as the potential benefits and risks of the study, are discussed. Trial Registration ISRCTN01738840 - Spraying And Nets Towards malaria Elimination (SANTE
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Full Text Available ... child to enroll. Also, children aged 7 and older often must agree (assent) to take part in clinical trials. Clinical trials for children have the same scientific safeguards as clinical trials for adults. For more information, go to "How Do Clinical ...
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Full Text Available ... decisionmaking. The purpose of clinical trials is research, so the studies follow strict scientific standards. These standards ... otherwise. The purpose of clinical trials is research, so the studies follow strict scientific standards. These standards ...
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Full Text Available ... needed. For safety purposes, clinical trials start with small groups of patients to find out whether a ... phase I clinical trials test new treatments in small groups of people for safety and side effects. ...
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Full Text Available ... providers don't always cover all patient care costs for clinical trials. If you're thinking about ... clinical trial, find out ahead of time about costs and coverage. You should learn about the risks ...
Full Text Available ... and treatments that work best. How Clinical Trials Work If you take part in a clinical trial, ... your doctor about all of your treatment options. Together, you can make the best choice for you. ...
Full Text Available ... medical knowledge and practice. Why Clinical Trials Are Important Clinical trials are a key research tool for ... and Usage No FEAR Act Grants and Funding Customer Service/Center for Health Information Email Alerts Jobs ...
Full Text Available ... a Clinical Trial If you're interested in learning more about, or taking part in, clinical trials, ... Customer Service/Center for Health Information Email Alerts Jobs and Careers Site Index About NHLBI National Institute ...
Full Text Available ... give permission for their child to enroll. Also, children aged 7 and older often must agree (assent) to take part in clinical trials. Find a Clinical Trial If you're interested in learning more about, or taking part in, clinical trials, ...
Full Text Available ... more screening tests to see which test produces the best results. Some companies and groups sponsor clinical trials that test the ... and Drug Administration (FDA) oversees these clinical trials. The NIH may partner with these companies or groups to help sponsor some trials. All ...
Full Text Available ... you to explore NIH Clinical Center for patient recruitment and clinical trial information. For more information, please email the NIH Clinical Center Office of Patient Recruitment at email@example.com or call ...
Full Text Available ... the same scientific safeguards as clinical trials for adults. For more information, go to "How Do Clinical ... based on what is known to work in adults. To improve clinical care of children, more studies ...
Full Text Available ... groups, companies, and organizations also sponsor clinical trials. Examples include Government Agencies, such as the U.S. Departments ... sponsor trials that test principles or strategies. For example, one NHLBI study explored whether the benefits of ...
Full Text Available ... Departments of Defense and Veterans Affairs; private companies; universities; and nonprofit organizations. NIH Institutes and Centers (including ... our campus or trials NIH has sponsored at universities, medical centers, and hospitals. ClinicalTrials.gov View a ...
Full Text Available ... identified earlier than they would be in general medical practice. This is because late-phase trials have large ... supporting clinical trials that have not only shaped medical practice around the world, but have improved the health ...
Full Text Available ... the past, clinical trial participants often were White men. Researchers assumed that trial results were valid for ... different ethnic groups sometimes respond differently than White men to the same medical approach. As a result, ...
Full Text Available ... or strategies work best for certain illnesses or groups of people. Some clinical trials show a positive result. For example, the National Heart, Lung, and Blood Institute (NHLBI) sponsored a trial of two different ...
Full Text Available ... healthy people to test new approaches to prevention, diagnosis, or screening. In the past, clinical trial participants ... DSMBs for large trials comparing alternative strategies for diagnosis or treatment. In addition, the NIH requires DSMBs ...
Full Text Available ... well they work. The U.S. Food and Drug Administration (FDA) oversees these clinical trials. The NIH may partner with these companies or groups to help sponsor some trials. All ...
Full Text Available ... trials produce the best data available for health care decisionmaking. The purpose of clinical trials is research, ... they advance medical knowledge and help improve patient care. Sponsorship and Funding The National Heart, Lung, and ...
Full Text Available ... including the NHLBI) usually sponsor trials that test principles or strategies. For example, one NHLBI study explored ... risks. Other examples of clinical trials that test principles or strategies include studies that explore whether surgery ...
Pehrson, Caroline; Salanti, Ali; Theander, Thor G
the condition. Areas covered: Pub Med was searched using the broad terms 'malaria parasite placenta' to identify studies of interactions between parasite and host, 'prevention of placental malaria' to identify current strategies to prevent placental malaria, and 'placental malaria vaccine' to identify pre-clinical...... vaccine development. However, all papers from these searches were not systematically included. Expert commentary: The first phase I clinical trials of vaccines are well underway. Trials testing efficacy are more complicated to carry out as only women that are exposed to parasites during pregnancy...
Full Text Available ... benefits of lowering high blood pressure in the elderly outweighed the risks. Other examples of clinical trials ... child to enroll. Also, children aged 7 and older often must agree (assent) to ... as clinical trials for adults. For more information, go to "How Do Clinical ...
Full Text Available ... part. Randomization Most clinical trials that have comparison groups use randomization. This involves assigning patients to different comparison groups by chance, rather than choice. This ...
Chibueze Peter Ihekwereme
Full Text Available Malaria has a negative impact on health and social and economic life of residents of endemic countries. The ultimate goals of designing new treatment for malaria are to prevent clinical infection, reduce morbidity, and decrease mortality. There are great advances in the understanding of the parasite-host interaction through studies by various scientists. In some of these studies, attempts were made to evaluate the roles of malaria pigment or toxins in the pathogenesis of malaria. Hemozoin is a key metabolite associated with severe malaria anemia (SMA, immunosuppression, and cytokine dysfunction. Targeting of this pigment may be necessary in the design of new therapeutic products against malaria. In this review, the roles of hemozoin in the morbidity and mortality of malaria are highlighted as an essential target in the quest for effective control of clinical malaria.
Full Text Available ... Children and Clinical Studies Program has been successfully developed and evaluated to fill an important gap in ... Possible Benefits Taking part in a clinical trial can have many benefits. For example, you may gain ...
Full Text Available ... you may get tests or treatments in a hospital, clinic, or doctor's office. In some ways, taking ... people will need to travel or stay in hospitals to take part in clinical trials. For example, ...
Chêne, Arnaud; Houard, Sophie; Nielsen, Morten A
Placental malaria caused by Plasmodium falciparum infection constitutes a major health problem manifesting as severe disease and anaemia in the mother, impaired fetal development, low birth weight or spontaneous abortion. Prevention of placental malaria currently relies on two key strategies...... that are losing efficacy due to spread of resistance: long-lasting insecticide-treated nets and intermittent preventive treatment during pregnancy. A placental malaria vaccine would be an attractive, cost-effective complement to the existing control tools. Two placental malaria vaccine candidates are currently...... in Phase Ia/b clinical trials. During two workshops hosted by the European Vaccine Initiative, one in Paris in April 2014 and the other in Brussels in November 2014, the main actors in placental malaria vaccine research discussed the harmonization of clinical development plans and of the immunoassays...
Full Text Available ... the clinical trial you take part in, the information gathered can help others and add to scientific knowledge. People who take part in clinical trials are vital to the process of improving medical care. Many people volunteer because ...
Full Text Available ... from other clinical trials show what doesn't work or may cause harm. For example, the NHLBI Women's Health Initiative ... safe a treatment is or how well it works. Children (aged 18 and younger) get ... legal consent for their child to take part in a clinical trial. When ...
Full Text Available ... to Expect During a clinical trial, doctors, nurses, social workers, and other health care providers might be part of your treatment ... clinical trials are vital to the process of improving medical care. Many people ... participants, it may not work for you. A new treatment may have side ...
Full Text Available ... Expect During a clinical trial, doctors, nurses, social workers, and other health care providers might be part of your treatment ... phase II clinical trials. The risk of side effects might be even greater for ... treatments. Health insurance and health care providers don't always ...
Full Text Available ... a Clinical Trial If you're interested in learning more about, or taking part in, clinical trials, talk with your doctor. He or she may know about studies going on in your area. You can visit the following website to learn more about ...
Full Text Available ... products, such as medicines, and how well they work. The U.S. Food and Drug Administration (FDA) oversees these clinical trials. ... cancer also increased. As a result, the U.S. Food and Drug Administration now recommends never using HT ... Clinical Trials Work If you take ...
Howard, Natasha; Durrani, Naeem; Sanda, Sanda; Beshir, Khalid; Hallett, Rachel; Rowland, Mark
Falciparum malaria is a significant problem for Afghan refugees in Pakistan. Refugee treatment guidelines recommended standard three-day chloroquine treatment (25 mg/kg) for first episodes and extended five-day treatment (40 mg/kg) for recrudescent infections, based on the assumption that a five-day course would more likely achieve a cure. An in-vivo randomized controlled trial was conducted among refugees with uncomplicated falciparum malaria to determine whether five-day treatment (CQ40) was more effective than standard treatment (CQ25). 142 falciparum patients were recruited into CQ25 or CQ40 treatment arms and followed up to 60 days with regular blood smears. The primary outcome was parasitological cure without recrudescence. Treatment failures were retreated with CQ40. PCR genotyping of 270 samples, from the same and nearby sites, was used to support interpretation of outcomes. 84% of CQ25 versus 51% of CQ40 patients experienced parasite recrudescence during follow-up (adjusted odds ratio 0.17, 95%CI 0.08-0.38). Cure rates were significantly improved with CQ40, particularly among adults. Fever clearance time, parasite clearance time, and proportions gametocytaemic post-treatment were similar between treatment groups. Second-line CQ40 treatment resulted in higher failure rates than first-line CQ40 treatment. CQ-resistance marker pfcrt 76T was found in all isolates analysed, while pfmdr1 86Y and 184Y were found in 18% and 37% of isolates respectively. CQ is not suitable for first-line falciparum treatment in Afghan refugee communities. The extended-dose CQ regimen can overcome 39% of resistant infections that would recrudesce under the standard regimen, but the high failure rate after directly observed treatment demonstrates its use is inappropriate.
Agnandji, Selidji Todagbe; Lell, Bertrand; Fernandes, José Francisco
The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial....
Full Text Available ... trial found that one of the combinations worked much better than the other for moderate persistent asthma. The results provided important treatment information for doctors and patients. The results from other clinical trials show what doesn't work or may cause harm. For example, the NHLBI ...
Full Text Available ... other expenses (for example, travel and child care)? Who will be in charge of my care? What will happen after the trial? Taking part in a clinical trial is your decision. Talk with your doctor about all of your treatment ...
Full Text Available ... strict scientific standards. These standards protect patients and help produce reliable study results. Clinical trials are one ... are important because they advance medical knowledge and help improve patient care. Sponsorship and Funding The National ...
Full Text Available ... patients to find out whether a new approach causes any harm. In later phases of clinical trials, ... device improves patient outcomes; offers no benefit; or causes unexpected harm All of these results are important ...
Full Text Available ... and compare new treatments with other available treatments. Steps To Avoid Bias The researchers doing clinical trials take steps to avoid bias. "Bias" means that human choices ...
Full Text Available ... gathered can help others and add to scientific knowledge. People who take part in clinical trials are vital to the process of improving medical care. Many people volunteer because they want to help others. ...
Full Text Available ... materials, and offer advice on research-related issues. Data Safety Monitoring Board Every National Institutes of Health ( ... III clinical trial is required to have a Data and Safety Monitoring Board (DSMB). This board consists ...
... of Personal Stories Peers Celebrating Art Peers Celebrating Music Be Vocal Support Locator DBSA In-Person Support ... by participating in a clinical trial is to science first and to the patient second. More About ...
Full Text Available ... to Expect During a clinical trial, doctors, nurses, social workers, and other health care providers might be ... the new approach. You also will have the support of a team of health care providers, who ...
Full Text Available ... final stages of a long and careful research process. The process often begins in a laboratory (lab), where scientists ... part in clinical trials are vital to the process of improving medical care. Many people volunteer because ...
Full Text Available ... as gene therapy) or vulnerable patients (such as children). A DSMB's role is to review data from a clinical trial for safety problems or differences in results among different groups. The DSMB also reviews research results ...
Full Text Available ... medical centers and doctors' offices around the country. Benefits and Risks Possible Benefits Taking part in a clinical trial can have many benefits. For example, you may gain access to new ...
Full Text Available ... or treatment is having harmful effects. Food and Drug Administration In the United States, the Food and Drug Administration (FDA) provides oversight for clinical trials that ...
Full Text Available ... Usually, a computer program makes the group assignments. Masking The term "masking" refers to not telling the clinical trial participants which treatment they're getting. Masking, or "blinding," helps avoid bias. For this reason, ...
Full Text Available ... organizations also sponsor clinical trials. Examples include Government Agencies, such as the U.S. Departments of Defense and ... how you feel. Some people will need to travel or stay in hospitals to take part in ...
Full Text Available ... clinical trials are required to have an IRB. Office for Human Research Protections The U.S. Department of Health and Human Services’ (HHS’) Office for Human Research Protections (OHRP) oversees all research ...
Full Text Available ... clinical trial. IRB members are doctors, statisticians, and community members. The IRB's purpose is to ensure that ... lung, and blood disorders. By engaging the research community and a broad group of stakeholders and advisory ...
Full Text Available ... successfully developed and evaluated to fill an important gap in information and education for parents, clinicians, researchers, ... gathered can help others and add to scientific knowledge. People who take part in clinical trials are ...
Full Text Available ... studies. View funding information for clinical trials optimization . Building 31 31 Center Drive Bethesda, MD 20892 Learn ... and Usage No FEAR Act Grants and Funding Building 31 31 Center Drive Bethesda, MD 20892 Learn ...
Full Text Available Skip to main content U.S. Department of Health & Human Services Health Topics Health Topics A-Z Clinical Trials Publications and Resources Health Education and Awareness The Science Science Home Blood Disorders and ...
Full Text Available ... results. Clinical trials are one of the final stages of a long and careful research process. The ... a patient's age and gender, the type and stage of disease, and whether the patient has had ...
Full Text Available ... Clinical Trials Publications and Resources Health Education and Awareness The Science Science Home Blood Disorders and Blood ... of estrogen and progestin, the risk of breast cancer also increased. As a result, the U.S. Food ...
Full Text Available ... issues arise. Participation and Eligibility Each clinical trial defines who is eligible to take part in the ... the strategy or treatment is having harmful effects. Food and Drug Administration In the United States, the ...
Full Text Available Skip to main content U.S. Department of Health & Human Services Health Topics Health Topics A-Z Clinical Trials Publications and Resources Health Education and Awareness The Science Science Home Blood Disorders ...
Full Text Available ... A-Z Clinical Trials Publications and Resources Health Education and Awareness The Science Science Home Blood Disorders ... to fill an important gap in information and education for parents, clinicians, researchers, children, and the general ...
Full Text Available ... clinical care of children, more studies are needed focusing on children's health with the goal to develop ... study? How might this trial affect my daily life? Will I have to be in the hospital? ...
Full Text Available ... work best for certain illnesses or groups of people. Clinical trials produce the best data available for ... or animals doesn't always work well in people. Thus, research in humans is needed. For safety ...
Full Text Available ... sponsor clinical trials. Examples include Government Agencies, such as the U.S. Departments of Defense and Veterans Affairs; ... age and frequency for doing screening tests, such as mammography; and compare two or more screening tests ...
Full Text Available ... harm. In later phases of clinical trials, researchers learn more about the new approach's risks and benefits. ... explore whether surgery or other medical treatments produce better results for certain illnesses or groups of people; ...
Full Text Available ... offer a variety of funding mechanisms tailored to planning and conducting clinical trials at all phases, including ... Center for Health Information Email Alerts Jobs and Careers Site Index About NHLBI National Institute of Health ...
Full Text Available ... patients. Usually, a computer program makes the group assignments. Masking The term "masking" refers to not telling ... questions to ask your doctor and the research staff, go to "How Do Clinical Trials Protect Participants?" ...
Full Text Available ... study explored whether the benefits of lowering high blood pressure in the elderly outweighed the risks. Other examples of clinical trials that test principles or strategies include studies that explore whether ...
Full Text Available ... treatment is having harmful effects. Food and Drug Administration In the United States, the Food and Drug Administration (FDA) provides oversight for clinical trials that are ...
Full Text Available ... questions to ask your doctor and the research staff, go to "How Do Clinical Trials Protect Participants?" ... in Bethesda, Maryland. The physicians, nurses, scientists and staff of the NHLBI encourage you to explore NIH ...
Full Text Available ... Science Science Home Blood Disorders and Blood Safety Sleep Science and Sleep Disorders Lung Diseases Heart and Vascular Diseases Precision ... women and that are ethnically diverse. Children also need clinical trials that focus on them, as medical ...
Full Text Available ... and evaluated to fill an important gap in information and education for parents, clinicians, researchers, children, and the general public. What to Expect During a clinical trial, ...
Full Text Available ... small groups of people for safety and side effects. Phase II clinical trials look at how well ... confirm how well treatments work, further examine side effects, and compare new treatments with other available treatments. ...
Full Text Available ... Events About NHLBI About NHLBI Home Mission and Strategic Vision Leadership Scientific Divisions Operations and Administration Advisory ... offer a variety of funding mechanisms tailored to planning and conducting clinical trials at all phases, including ...
Full Text Available ... NHLBI About NHLBI Home Mission and Strategic Vision Leadership Scientific Divisions Operations and Administration Advisory Committees Budget ... always, parents must give legal consent for their child to take part in a clinical trial. When ...
Full Text Available ... and organizations also sponsor clinical trials. Examples include Government Agencies, such as the U.S. Departments of Defense and Veterans Affairs; private companies; universities; and nonprofit organizations. NIH Institutes and ...
Full Text Available ... records can quickly show this information if safety issues arise. Participation and Eligibility Each clinical trial defines ... and materials, and offer advice on research-related issues. Data Safety Monitoring Board Every National Institutes of ...
Full Text Available ... women and that are ethnically diverse. Children also need clinical trials that focus on them, as medical ... often differ for children. For example, children may need lower doses of certain medicines or smaller medical ...
Full Text Available ... care providers might be part of your treatment team. They will monitor your health closely. You may ... taking part in a clinical trial. Your treatment team also may ask you to do other tasks. ...
Full Text Available ... new treatments in small groups of people for safety and side effects. Phase II clinical trials look at how well treatments work and further review these treatments for safety. Phase ...
Full Text Available ... Clinical Trials Publications and Resources Health Education and Awareness The Science Science Home Blood Disorders and Blood ... these results are important because they advance medical knowledge and help improve patient care. Sponsorship and Funding ...
Full Text Available ... and organizations also sponsor clinical trials. Examples include Government Agencies, such as the U.S. Departments of Defense ... FOIA) Accessibility Copyright and Usage No FEAR Act Grants and Funding Building 31 31 Center Drive Bethesda, ...
Full Text Available ... as the U.S. Departments of Defense and Veterans Affairs; private companies; universities; and nonprofit organizations. NIH Institutes ... for parents, clinicians, researchers, children, and the general public. What to Expect During a clinical trial, doctors, ...
Full Text Available ... combination of estrogen and progestin, the risk of breast cancer also increased. As a result, the U.S. Food ... to test new approaches to prevention, diagnosis, or screening. In the past, clinical trial participants often were ...
Full Text Available ... from other clinical trials show what doesn't work or may cause harm. For example, the NHLBI Women's Health Initiative tested whether hormone therapy (HT) reduced the risk of heart disease in postmenopausal women. ( ...
Full Text Available ... always, parents must give legal consent for their child to take part in a clinical trial. When ... minimal, both parents must give permission for their child to enroll. Also, children aged 7 and older ...
Full Text Available ... Wide Range of Audiences The Children and Clinical Studies Program has been successfully developed and evaluated to fill an important gap in information and education for parents, clinicians, researchers, children, and the general public. What to Expect During a clinical trial, doctors, ...
Full Text Available ... an important gap in information and education for parents, clinicians, researchers, children, and the general public. What to Expect During a clinical trial, doctors, nurses, social workers, and other health care providers might be part of your treatment team. ...
Full Text Available Skip to main content U.S. Department of Health & Human Services Health Topics Health Topics A-Z Clinical Trials Publications and Resources Health Education and Awareness The Science Science Home Blood Disorders and Blood Safety Sleep ...
Full Text Available ... treatments produce better results for certain illnesses or groups of people; look at the best age and frequency for doing screening tests, such as mammography; and compare two or more screening tests to see which test ... Some companies and groups sponsor clinical trials that test the safety of ...
Full Text Available ... patient has had certain treatments or has other health problems. Eligibility criteria ensure that new approaches are tested ... public. What to Expect During a clinical trial, doctors, nurses, social workers, and other health care providers might be part of your treatment ...
Full Text Available ... This shows how the approach affects a living body and whether it's harmful. However, an approach that works well in the lab or animals doesn't always work well in people. Thus, research in humans is needed. For safety purposes, clinical trials start ...
Full Text Available ... to main content U.S. Department of Health & Human Services Health Topics Health Topics A-Z Clinical Trials Publications and Resources Health Education and Awareness The Science Science Home Blood Disorders and Blood Safety Sleep Science and ...
Full Text Available ... protect patients and help produce reliable study results. Clinical trials are one of the final stages of a long and careful research process. The process often begins in a laboratory (lab), where scientists first develop and test new ...
Full Text Available ... benefits of lowering high blood pressure in the elderly outweighed the risks. Other examples of clinical trials ... child to enroll. Also, children aged 7 and older often must agree (assent) to take part ... about how you feel. Some people will need to travel or stay in hospitals ...
Full Text Available ... safe a treatment is or how well it works. Children (aged 18 and younger) get special protection as research subjects. Almost always, parents must give legal consent for their child to take part in a clinical trial. When ...
Full Text Available ... As a result, the U.S. Food and Drug Administration now recommends never using HT to prevent heart disease. When HT is used for menopausal symptoms, it should be taken only at the smallest dose and for the shortest time possible. Clinical trials, like the two described above, ...
Full Text Available ... approach that works well in the lab or animals doesn't always work well in people. Thus, research in humans is needed. For safety purposes, clinical trials start with small groups of patients to find out whether a ...
Claudio J. Struchiner
Full Text Available Malaria vaccine candidates have already been tested and new trials are being carried out. We present a brief description of specific issues of validity that are relevant when assessing vaccine efficacy in the field and illustrate how the application of these principles might improve our interpretation of the data being gathered in actual malaria vaccine field trials. Our discussion assumes that vaccine evaluation shares the same general principles of validity with epidemiologic causal inference, i.e., the process of drawing inferences from epidemiologic data aiming at the identification of causes of diseases. Judicious exercise of these principles indicates that, for meaningful interpretation, measures of vaccine efficacy require definitions based upon arguments conditional on the amount of exposure to infection, and specification of the initial and final states in which one believes the effect of interest takes place.
Day, Simon; Machin, David; Green, Sylvan B
... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xix INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 The Development of Clinical Trials Simon...
Full Text Available ... criteria differ from trial to trial. They include factors such as a patient's age and gender, the ... bias. "Bias" means that human choices or other factors not related to the protocol affect the trial's ...
Full Text Available ... under way. For example, some trials are stopped early if benefits from a strategy or treatment are ... stop a trial, or part of a trial, early if the strategy or treatment is having harmful ...
Full Text Available ... people who fit the patient traits for that study (the eligibility criteria). Eligibility criteria differ from trial to trial. They include factors such as a patient's age and gender, the type and stage of disease, and whether ...
Full Text Available ... trials are research studies that explore whether a medical strategy, treatment, or device is safe and effective ... trials are research studies that explore whether a medical strategy, treatment, or device is safe and effective ...
Full Text Available ... trials show what doesn't work or may cause harm. For example, the NHLBI Women's Health Initiative tested whether hormone therapy (HT) reduced the risk of heart disease in postmenopausal women. (When the trial began, HT ...
Full Text Available ... for trials with cutting-edge approaches, such as gene therapy or new biological treatments. Health insurance and ... trials that involve high-risk procedures (such as gene therapy) or vulnerable patients (such as children). A ...
Full Text Available ... sponsored a trial of two different combinations of asthma treatments. The trial found that one of the ... much better than the other for moderate persistent asthma. The results provided important treatment information for doctors ...
Full Text Available ... Sponsors also may stop a trial, or part of a trial, early if the strategy or treatment is having harmful effects. Food and Drug Administration In the United States, the Food and Drug Administration (FDA) provides oversight ...
Grigg, M J; William, T; Dhanaraj, P; Menon, J; Barber, B E; von Seidlein, L; Rajahram, G; Price, R N; Anstey, N M; Yeo, T W
Introduction Malaria due to Plasmodium knowlesi is reported throughout South-East Asia, and is the commonest cause of it in Malaysia. P. knowlesi replicates every 24 h and can cause severe disease and death. Current 2010 WHO Malaria Treatment Guidelines have no recommendations for the optimal treatment of non-severe knowlesi malaria. Artemisinin-combination therapies (ACT) and chloroquine have each been successfully used to treat knowlesi malaria; however, the rapidity of parasite clearance has not been prospectively compared. Malaysia's national policy for malaria pre-elimination involves mandatory hospital admission for confirmed malaria cases with discharge only after two negative blood films; use of a more rapidly acting antimalarial agent would have health cost benefits. P. knowlesi is commonly microscopically misreported as P. malariae, P. falciparum or P. vivax, with a high proportion of the latter two species being chloroquine-resistant in Malaysia. A unified ACT-treatment protocol would provide effective blood stage malaria treatment for all Plasmodium species. Methods and analysis ACT KNOW, the first randomised controlled trial ever performed in knowlesi malaria, is a two-arm open-label trial with enrolments over a 2-year period at three district sites in Sabah, powered to show a difference in proportion of patients negative for malaria by microscopy at 24 h between treatment arms (clinicaltrials.gov #NCT01708876). Enrolments started in December 2012, with completion expected by September 2014. A total sample size of 228 is required to give 90% power (α 0.05) to determine the primary end point using intention-to-treat analysis. Secondary end points include parasite clearance time, rates of recurrent infection/treatment failure to day 42, gametocyte carriage throughout follow-up and rates of anaemia at day 28, as determined by survival analysis. Ethics and dissemination This study has been approved by relevant institutional ethics committees in
Grigg, M J; William, T; Dhanaraj, P; Menon, J; Barber, B E; von Seidlein, L; Rajahram, G; Price, R N; Anstey, N M; Yeo, T W
Malaria due to Plasmodium knowlesi is reported throughout South-East Asia, and is the commonest cause of it in Malaysia. P. knowlesi replicates every 24 h and can cause severe disease and death. Current 2010 WHO Malaria Treatment Guidelines have no recommendations for the optimal treatment of non-severe knowlesi malaria. Artemisinin-combination therapies (ACT) and chloroquine have each been successfully used to treat knowlesi malaria; however, the rapidity of parasite clearance has not been prospectively compared. Malaysia's national policy for malaria pre-elimination involves mandatory hospital admission for confirmed malaria cases with discharge only after two negative blood films; use of a more rapidly acting antimalarial agent would have health cost benefits. P. knowlesi is commonly microscopically misreported as P. malariae, P. falciparum or P. vivax, with a high proportion of the latter two species being chloroquine-resistant in Malaysia. A unified ACT-treatment protocol would provide effective blood stage malaria treatment for all Plasmodium species. ACT KNOW, the first randomised controlled trial ever performed in knowlesi malaria, is a two-arm open-label trial with enrolments over a 2-year period at three district sites in Sabah, powered to show a difference in proportion of patients negative for malaria by microscopy at 24 h between treatment arms (clinicaltrials.gov #NCT01708876). Enrolments started in December 2012, with completion expected by September 2014. A total sample size of 228 is required to give 90% power (α 0.05) to determine the primary end point using intention-to-treat analysis. Secondary end points include parasite clearance time, rates of recurrent infection/treatment failure to day 42, gametocyte carriage throughout follow-up and rates of anaemia at day 28, as determined by survival analysis. This study has been approved by relevant institutional ethics committees in Malaysia and Australia. Results will be disseminated to inform
Full Text Available ... the NHLBI's Children and Clinical Studies Web page. Children and Clinical Studies Learn more about Children and Clinical Studies Importance of Children in Clinical Studies Children have often had to ...
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Full Text Available ... for trials with cutting-edge approaches, such as gene therapy or new biological treatments. Health insurance and health ... trials that involve high-risk procedures (such as gene therapy) or vulnerable patients (such as children). A DSMB's ...
Objective: With paucity of documentation of congenital clinical malaria in the world literature, we therefore aimed to review its rates, presentation, management and out come of this problem in neonates at the Usmanu Danfodiyo University Teaching Hospital, Sokoto. Methodology: This prospective study was carried out in ...
Full Text Available ... include factors such as a patient's age and gender, the type and stage of disease, and whether ... How long will the trial last? Who will pay for the tests and treatments I receive? Will ...
Full Text Available ... medicines, and how well they work. The U.S. Food and Drug Administration (FDA) oversees these ... trials are a key research tool for advancing medical knowledge and patient care. ...
Full Text Available ... Masking, or "blinding," helps avoid bias. For this reason, researchers also may not be told which treatments ... from a study at any time, for any reason. Also, during the trial, you have the right ...
Full Text Available ... get special protection as research subjects. Almost always, parents must give legal consent for their child to ... trial's potential risks are greater than minimal, both parents must give permission for their child to enroll. ...
Full Text Available ... risk of heart disease in the first few years, and HT also increased the risk of stroke ... a safety measure. They ensure a trial excludes any people for whom the protocol has known risks ...
Full Text Available ... Initiative tested whether hormone therapy (HT) reduced the risk of heart disease in postmenopausal women. (When the trial began, HT was already in common use for the treatment of menopausal symptoms. It also ...
Full Text Available ... risk of heart disease in the first few years, and HT also increased the risk of stroke ... master plan called a protocol (PRO-to-kol). This plan explains how the trial will work. The ...
Full Text Available ... treatment is having harmful effects. Food and Drug Administration In the United States, the Food and Drug ... life? Will I have to be in the hospital? How long will the trial last? Who will ...
Full Text Available ... procedures painful? What are the possible risks, side effects, and benefits of taking part in the study? How might this trial affect my daily life? Will I have to be in the hospital? ...
Full Text Available ... Blood Safety Sleep Science and Sleep Disorders Lung Diseases Heart and Vascular Diseases Precision Medicine Activities Obesity, Nutrition, ... whether hormone therapy (HT) reduced the risk of heart disease in postmenopausal women. (When the trial began, HT ...
Full Text Available ... are ethical and that the participants' rights are protected. The IRB reviews the trial's protocol before the ... may know about studies going on in your area. You can visit the following website to learn ...
Full Text Available ... a laboratory (lab), where scientists first develop and test new ideas. If an approach seems promising, the ... Centers (including the NHLBI) usually sponsor trials that test principles or strategies. For example, one NHLBI study ...
Full Text Available ... whether hormone therapy (HT) reduced the risk of heart disease in postmenopausal women. (When the trial began, HT ... also was increasingly being used for prevention of heart disease.) The study found that HT increased the risk ...
Full Text Available ... trials optimization . Building 31 31 Center Drive Bethesda, MD 20892 Learn more about getting to NIH Get ... and Funding Building 31 31 Center Drive Bethesda, MD 20892 Learn more about getting to NIH Connect ...
Full Text Available ... that the participants' rights are protected. The IRB reviews the trial's protocol before the study begins. An IRB will only approve research that deals with medically important questions ...
Full Text Available ... to preexisting differences between the patients. Usually, a computer program makes the group assignments. Masking The term " ... under way. For example, some trials are stopped early if benefits from a strategy or treatment are ...
Full Text Available ... treatment of menopausal symptoms. It also was increasingly being used for prevention of heart disease.) The study ... a trial are due to the different strategies being used, not to preexisting differences between the patients. ...
Full Text Available ... Precision Medicine Activities Obesity, Nutrition, and Physical Activity Population and Epidemiology Studies Women’s Health All Science A- ... assumed that trial results were valid for other populations as well. Researchers now realize that women and ...
Watch these videos to learn about some basic aspects of cancer clinical trials such as the different phases of clinical trials, methods used to protect patient safety, and how the costs of clinical trials are covered.
Full Text Available ... Diseases Heart and Vascular Diseases Precision Medicine Activities Obesity, Nutrition, and Physical Activity Population and Epidemiology Studies ... the NHLBI's Children and Clinical Studies Web page. Children and Clinical Studies Learn more about Children and ...
Full Text Available ... go to the NHLBI's Children and Clinical Studies Web page. Children and Clinical Studies Learn more about ... Protections The U.S. Department of Health and Human Services’ (HHS’) Office for Human Research Protections (OHRP) oversees ...
Full Text Available ... Studies Learn more about Children and Clinical Studies Importance of Children in Clinical Studies Children have often ... rights that help protect them. Scientific Oversight Institutional Review Board Institutional review boards (IRBs) help provide scientific ...
Full Text Available ... taking the same treatment the same way. These patients are closely watched by Data and Safety Monitoring Boards. Even if you don't directly ... risk procedures (such as gene therapy) or vulnerable patients (such as ... trial for safety problems or differences in results among different groups. ...
Full Text Available ... edge approaches, such as gene therapy or new biological treatments. Health insurance and health care providers don't ... of a trial, early if the strategy or treatment is having harmful effects. Food and Drug Administration In the United States, the Food and ...
Full Text Available ... U.S. Departments of Defense and Veterans Affairs; private companies; universities; and nonprofit organizations. NIH Institutes and Centers (including the NHLBI) usually sponsor trials that test principles or strategies. For example, one NHLBI study explored whether the ...
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Full Text Available ... Diseases Heart and Vascular Diseases Precision Medicine Activities Obesity, Nutrition, and Physical Activity Population and Epidemiology Studies ... include factors such as a patient's age and gender, the type and stage of disease, ... helps ensure that any differences observed during a trial are due to the ...
Full Text Available ... an important gap in information and education for parents, clinicians, researchers, children, and the general public. What to Expect During ... trial's potential risks are greater than minimal, both parents must give permission for their child to enroll. Also, children aged 7 and older ...
Full Text Available ... and devices specific to children. Resources for a Wide Range of Audiences The Children and Clinical Studies ... have not only shaped medical practice around the world, but have improved the health of millions of ...
Full Text Available ... the strategy or treatment is having harmful effects. Food and Drug Administration In the United States, the Food and Drug Administration (FDA) provides oversight for clinical ...
Full Text Available ... harmful effects. Food and Drug Administration In the United States, the Food and Drug Administration (FDA) provides oversight ... of research studies at the NIH Clinical Center, America's research hospital, located on the NIH campus in ...
Full Text Available ... seems promising, the next step may involve animal testing. This shows how the approach affects a living body and whether it's harmful. However, an approach that works well in the lab or animals doesn't always work well in people. Thus, research in humans is needed. For safety purposes, clinical ...
Full Text Available ... the final stages of a long and careful research process. The process often begins in a laboratory (lab), where scientists first develop and test new ideas. If an approach seems ... Thus, research in humans is needed. For safety purposes, clinical ...
Peace, Karl E; Chen, Ding-Geng
... in the pharmaceutical industry, Clinical trial methodology emphasizes the importance of statistical thinking in clinical research and presents the methodology as a key component of clinical research...
Bélard, Sabine; Issifou, Saadou; Hounkpatin, Aurore B
GMZ2 is a fusion protein of Plasmodium falciparum merozoite surface protein 3 (MSP3) and glutamate rich protein (GLURP) that mediates an immune response against the blood stage of the parasite. Two previous phase I clinical trials, one in naïve European adults and one in malaria-exposed Gabonese ...... adults showed that GMZ2 was well tolerated and immunogenic. Here, we present data on safety and immunogenicity of GMZ2 in one to five year old Gabonese children, a target population for future malaria vaccine efficacy trials....
Vekemans, Johan; Marsh, Kevin; Greenwood, Brian; Leach, Amanda; Kabore, William; Soulanoudjingar, Solange; Asante, Kwaku Poku; Ansong, Daniel; Evans, Jennifer; Sacarlal, Jahit; Bejon, Philip; Kamthunzi, Portia; Salim, Nahya; Njuguna, Patricia; Hamel, Mary J; Otieno, Walter; Gesase, Samwel; Schellenberg, David
An effective malaria vaccine, deployed in conjunction with other malaria interventions, is likely to substantially reduce the malaria burden. Efficacy against severe malaria will be a key driver for decisions on implementation. An initial study of an RTS, S vaccine candidate showed promising efficacy against severe malaria in children in Mozambique. Further evidence of its protective efficacy will be gained in a pivotal, multi-centre, phase III study. This paper describes the case definitions of severe malaria used in this study and the programme for standardized assessment of severe malaria according to the case definition. Case definitions of severe malaria were developed from a literature review and a consensus meeting of expert consultants and the RTS, S Clinical Trial Partnership Committee, in collaboration with the World Health Organization and the Malaria Clinical Trials Alliance. The same groups, with input from an Independent Data Monitoring Committee, developed and implemented a programme for standardized data collection.The case definitions developed reflect the typical presentations of severe malaria in African hospitals. Markers of disease severity were chosen on the basis of their association with poor outcome, occurrence in a significant proportion of cases and on an ability to standardize their measurement across research centres. For the primary case definition, one or more clinical and/or laboratory markers of disease severity have to be present, four major co-morbidities (pneumonia, meningitis, bacteraemia or gastroenteritis with severe dehydration) are excluded, and a Plasmodium falciparum parasite density threshold is introduced, in order to maximize the specificity of the case definition. Secondary case definitions allow inclusion of co-morbidities and/or allow for the presence of parasitaemia at any density. The programmatic implementation of standardized case assessment included a clinical algorithm for evaluating seriously sick children
Afrane, Yaw A; Zhou, Guofa; Githeko, Andrew K; Yan, Guiyun
In African highland areas where endemicity of malaria varies greatly according to altitude and topography, parasitaemia accompanied by fever may not be sufficient to define an episode of clinical malaria in endemic areas. To evaluate the effectiveness of malaria interventions, age-specific case definitions of clinical malaria needs to be determined. Cases of clinical malaria through active case surveillance were quantified in a highland area in Kenya and defined clinical malaria for different age groups. A cohort of over 1,800 participants from all age groups was selected randomly from over 350 houses in 10 villages stratified by topography and followed for two-and-a-half years. Participants were visited every two weeks and screened for clinical malaria, defined as an individual with malaria-related symptoms (fever [axillary temperature≥37.5°C], chills, severe malaise, headache or vomiting) at the time of examination or 1-2 days prior to the examination in the presence of a Plasmodium falciparum positive blood smear. Individuals in the same cohort were screened for asymptomatic malaria infection during the low and high malaria transmission seasons. Parasite densities and temperature were used to define clinical malaria by age in the population. The proportion of fevers attributable to malaria was calculated using logistic regression models. Incidence of clinical malaria was highest in valley bottom population (5.0% cases per 1,000 population per year) compared to mid-hill (2.2% cases per 1,000 population per year) and up-hill (1.1% cases per 1,000 population per year) populations. The optimum cut-off parasite densities through the determination of the sensitivity and specificity showed that in children less than five years of age, 500 parasites per μl of blood could be used to define the malaria attributable fever cases for this age group. In children between the ages of 5-14, a parasite density of 1,000 parasites per μl of blood could be used to define the
Information about NCI programs and initiatives that sponsor, conduct, develop, or support clinical trials, including NCI’s Clinical Trial Network (NCTN) and NCI Community Oncology Research Program (NCORP) initiatives.
Peace, Karl E; Chen, Ding-Geng
"Now viewed as its own scientific discipline, clinical trial methodology encompasses the methods required for the protection of participants in a clinical trial and the methods necessary to provide...
Lavery James V
Full Text Available Abstract Background Severe malaria remains a major cause of global morbidity and mortality. Despite the use of potent anti-parasitic agents, the mortality rate in severe malaria remains high. Adjunctive therapies that target the underlying pathophysiology of severe malaria may further reduce morbidity and mortality. Endothelial activation plays a central role in the pathogenesis of severe malaria, of which angiopoietin-2 (Ang-2 has recently been shown to function as a key regulator. Nitric oxide (NO is a major inhibitor of Ang-2 release from endothelium and has been shown to decrease endothelial inflammation and reduce the adhesion of parasitized erythrocytes. Low-flow inhaled nitric oxide (iNO gas is a US FDA-approved treatment for hypoxic respiratory failure in neonates. Methods/Design This prospective, parallel arm, randomized, placebo-controlled, blinded clinical trial compares adjunctive continuous inhaled nitric oxide at 80 ppm to placebo (both arms receiving standard anti-malarial therapy, among Ugandan children aged 1-10 years of age with severe malaria. The primary endpoint is the longitudinal change in Ang-2, an objective and quantitative biomarker of malaria severity, which will be analysed using a mixed-effects linear model. Secondary endpoints include mortality, recovery time, parasite clearance and neurocognitive sequelae. Discussion Noteworthy aspects of this trial design include its efficient sample size supported by a computer simulation study to evaluate statistical power, meticulous attention to complex ethical issues in a cross-cultural setting, and innovative strategies for safety monitoring and blinding to treatment allocation in a resource-constrained setting in sub-Saharan Africa. Trial Registration ClinicalTrials.gov Identifier: NCT01255215
... and Public Home » Hepatitis C » Treatment Decisions Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... can I find out about participating in a hepatitis C clinical trial? Many trials are being conducted ...
van der Hoek, W; Premasiri, D A; Wickremasinghe, A R
To assess the possibility of developing a protocol for the clinical diagnosis of malaria, a study was done at the regional laboratory of the Anti-Malaria Campaign in Puttalam, Sri Lanka. Of a group of 502 patients, who suspected they were suffering from malaria, 97 had a positive blood film for malaria parasites (71 Plasmodium vivax and 26 P. falciparum). There were no important differences in signs and symptoms between those with positive and those with negative blood films. It is argued that it is unlikely that health workers can improve on the diagnosis of malaria made by the patients themselves, if laboratory facilities are not available. For Sri Lanka the best option is to expand the number of facilities where microscopic examination for malaria parasites can take place.
Full Text Available Abstract Managing clinical trials, of whatever size and complexity, requires efficient trial management. Trials fail because tried and tested systems handed down through apprenticeships have not been documented, evaluated or published to guide new trialists starting out in this important field. For the past three decades, trialists have invented and reinvented the trial management wheel. We suggest that to improve the successful, timely delivery of important clinical trials for patient benefit, it is time to produce standard trial management guidelines and develop robust methods of evaluation.
evaluate statistical models that integrate environmental and clinical data to .... was to identify and assess forecasting methods used to forecast malaria, and ...... 3Children's Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and ...... Sachs J, Malaney P. The economic and social burden of malaria.
Features to distinguish Malaria from Typhoid fever. These can be discerned from a good and detailed clinical history, in addition to a thorough physical examination. The following would help. The paroxysms of malaria fever as against the step ladder pattern fever of typhoid fever. The prominence of headaches in typhoid ...
Information about the several types of cancer clinical trials, including treatment trials, prevention trials, screening trials, supportive and palliative care trials. Each type of trial is designed to answer different research questions.
Banchongaksorn, T; Prajakwong, S; Rooney, W; Vickers, P
The rapid manual ParaSight-F test of Plasmodium falciparum malaria, an antigen capture test for detecting trophozoite-derived histidine rich protein-2 (PF HRP-2), is simple to perform and provides a definite diagnosis within 10 minutes. During an operational trial at health centers and mobile malaria units where microscopical diagnosis is not available and using defined symptom screening criteria, 3,361 subjects were tested yielding 618 positives (18.4%) for PF-HRP-2 by ParaSight-F. Microscopic examination of the same subjects by thick blood film examined 7 days later at a malaria clinic showed 578 falciparum, and 349 vivax and mixed infection (F+V) 41. The technology proved highly effective in detecting falciparum malaria at the peripheral levels where access to malaria laboratory services are difficult, thus allowing immediate administration of a complete course of treatment in the absence of a microscopic examination.
children who presented with malaria symptoms at the same clinic and tested positive or ... phagocytes immunity and induce anti-inflammatory immune response ...... treatment gap, Malawi will be ready to submit a validation request for virtual .... Conclusions. Vaccination and quarantine are the important disease preventive.
Ballou, W. R; Arevalo-Herrera, Myriam; Carucci, Daniel; Richie, Thomas L; Corradin, Giampietro; Diggs, Carter; Druilhe, Pierre; Giersing, Birgitte K; Saul, Allan; Heppner, D. G
... powerful driver for stimulating clinical development of candidate vaccines for malaria. This new way forward promises to greatly increase the likelihood of bringing a safe and effective vaccine to licensure...
Kleijnen, J; Knipschild, P; ter Riet, G
OBJECTIVE--To establish whether there is evidence of the efficacy of homoeopathy from controlled trials in humans. DESIGN--Criteria based meta-analysis. Assessment of the methodological quality of 107 controlled trials in 96 published reports found after an extensive search. Trials were scored using a list of predefined criteria of good methodology, and the outcome of the trials was interpreted in relation to their quality. SETTING--Controlled trials published world wide. MAIN OUTCOME MEASURES--Results of the trials with the best methodological quality. Trials of classical homoeopathy and several modern varieties were considered separately. RESULTS--In 14 trials some form of classical homoeopathy was tested and in 58 trials the same single homoeopathic treatment was given to patients with comparable conventional diagnosis. Combinations of several homoeopathic treatments were tested in 26 trials; isopathy was tested in nine trials. Most trials seemed to be of very low quality, but there were many exceptions. The results showed a positive trend regardless of the quality of the trial or the variety of homeopathy used. Overall, of the 105 trials with interpretable results, 81 trials indicated positive results whereas in 24 trials no positive effects of homoeopathy were found. The results of the review may be complicated by publication bias, especially in such a controversial subject as homoeopathy. CONCLUSIONS--At the moment the evidence of clinical trials is positive but not sufficient to draw definitive conclusions because most trials are of low methodological quality and because of the unknown role of publication bias. This indicates that there is a legitimate case for further evaluation of homoeopathy, but only by means of well performed trials. PMID:1825800
Friedman, Lawrence M; DeMets, David L; Reboussin, David M; Granger, Christopher B
This is the fifth edition of a very successful textbook on clinical trials methodology, written by recognized leaders who have long and extensive experience in all areas of clinical trials. The three authors of the first four editions have been joined by two others who add great expertise. Most chapters have been revised considerably from the fourth edition. A chapter on regulatory issues has been included and the chapter on data monitoring has been split into two and expanded. Many contemporary clinical trial examples have been added. There is much new material on adverse events, adherence, issues in analysis, electronic data, data sharing, and international trials. This book is intended for the clinical researcher who is interested in designing a clinical trial and developing a protocol. It is also of value to researchers and practitioners who must critically evaluate the literature of published clinical trials and assess the merits of each trial and the implications for the care and treatment of ...
U.S. Department of Health & Human Services — Provides patients, family members, health care professionals, and members of the public easy access to information on clinical trials for a wide range of diseases...
Scheurlen, A.; Kay, R.; Baum, M.
This book contains the proceedings on Cancer clinical trials: A critical appraisal. Topics covered include: Scientific fundamentals; Heterogeneous treatment effects; On combining information: Historical controls, overviews, and comprehensive cohort studies; and assessment of quality of life
Senn, S J
The relevance of the philosophy of Sir Karl Popper to the planning, conduct and analysis of clinical trials is examined. It is shown that blinding and randomization can only be regarded as valuable for the purpose of refuting universal hypotheses. The purpose of inclusion criteria is also examined. It is concluded that a misplaced belief in induction is responsible for many false notions regarding clinical trials.
Webb Emily L
Full Text Available Abstract Background Individual malaria interventions provide only partial protection in most epidemiological situations. Thus, there is a need to investigate whether combining interventions provides added benefit in reducing mortality and morbidity from malaria. The potential benefits of combining IPT in children (IPTc with home management of malaria (HMM was investigated. Methods During the 2008 malaria transmission season, 1,277 children under five years of age resident in villages within the rural Farafenni demographic surveillance system (DSS in North Bank Region, The Gambia were randomized to receive monthly IPTc with a single dose of sulphadoxine/pyrimethamine (SP plus three doses of amodiaquine (AQ or SP and AQ placebos given by village health workers (VHWs on three occasions during the months of September, October and November, in a double-blind trial. Children in all study villages who developed an acute febrile illness suggestive of malaria were treated by VHWs who had been taught how to manage malaria with artemether-lumefantrine (Coartem™. The primary aims of the project were to determine whether IPTc added significant benefit to HMM and whether VHWs could effectively combine the delivery of both interventions. Results The incidence of clinical attacks of malaria was very low in both study groups. The incidence rate of malaria in children who received IPTc was 0.44 clinical attacks per 1,000 child months at risk while that for control children was 1.32 per 1,000 child months at risk, a protective efficacy of 66% (95% CI -23% to 96%; p = 0.35. The mean (standard deviation haemoglobin concentration at the end of the malaria transmission season was similar in the two treatment groups: 10.2 (1.6 g/dL in the IPTc group compared to 10.3 (1.5 g/dL in the placebo group. Coverage with IPTc was high, with 94% of children receiving all three treatments during the study period. Conclusion Due to the very low incidence of malaria, no firm
Sabchareon, A; Attanath, P; Chanthavanich, P; Phanuaksook, P; Prarinyanupharb, V; Poonpanich, Y; Mookmanee, D; Teja-Isavadharm, P; Heppner, D G; Brewer, T G; Chongsuphajaisiddhi, T
A randomized pilot study to compare the safety and efficacy of artesunate suppositories (15 mg/kg/day for three days) versus oral artesunate (6 mg/kg/day for three days), both in combination with mefloquine (25 mg/kg), was conducted in 52 Thai children with uncomplicated multidrug-resistant falciparum malaria. Forty-five patients (87%) had a full 28-day follow-up in the hospital to assess efficacy and exclude reinfection. Mean [range] times to fever clearance of the two groups were similar (42 hr [15-104] versus 42 hr [6-119]). Artesunate suppositories resulted in significantly longer times to achieve 50% and 90% reductions of the initial parasite counts (17 and 26 hr versus 9 and 15 hr; P suppositories group (42 hr [14-93] versus 35 hr [16-69]), but the difference was not significant. The cure rates by days 28 were not significantly different, 92% for artesunate suppository-treated patients and 100% for oral artesunate-treated patients. Both drug regimens are safe and effective. Further studies are needed to characterize the pharmacokinetic properties and the optimum regimen of artesunate suppositories for the treatment of severe malaria.
Opoka, Robert O; Ndugwa, Christopher M; Latham, Teresa S; Lane, Adam; Hume, Heather A; Kasirye, Phillip; Hodges, James S; Ware, Russell E; John, Chandy C
Hydroxyurea treatment is recommended for children with sickle cell anemia (SCA) living in high-resource malaria-free regions, but its safety and efficacy in malaria-endemic sub-Saharan Africa, where the greatest sickle-cell burden exists, remain unknown. In vitro studies suggest hydroxyurea could increase malaria severity, and hydroxyurea-associated neutropenia could worsen infections. NOHARM (Novel use Of Hydroxyurea in an African Region with Malaria) was a randomized, double-blinded, placebo-controlled trial conducted in malaria-endemic Uganda, comparing hydroxyurea to placebo at 20 ± 2.5 mg/kg per day for 12 months. The primary outcome was incidence of clinical malaria. Secondary outcomes included SCA-related adverse events (AEs), clinical and laboratory effects, and hematological toxicities. Children received either hydroxyurea (N = 104) or placebo (N = 103). Malaria incidence did not differ between children on hydroxyurea (0.05 episodes per child per year; 95% confidence interval [0.02, 0.13]) vs placebo (0.07 episodes per child per year [0.03, 0.16]); the hydroxyurea/placebo malaria incidence rate ratio was 0.7 ([0.2, 2.7]; P = .61). Time to infection also did not differ significantly between treatment arms. A composite SCA-related clinical outcome (vaso-occlusive painful crisis, dactylitis, acute chest syndrome, splenic sequestration, or blood transfusion) was less frequent with hydroxyurea (45%) than placebo (69%; P = .001). Children receiving hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, with decreased leukocytes and reticulocytes. Serious AEs, sepsis episodes, and dose-limiting toxicities were similar between treatment arms. Three deaths occurred (2 hydroxyurea, 1 placebo, and none from malaria). Hydroxyurea treatment appears safe for children with SCA living in malaria-endemic sub-Saharan Africa, without increased severe malaria, infections, or AEs. Hydroxyurea provides SCA-related laboratory and clinical
Woo, K T
All clinical trials in Singapore will now have to conform to the Medicines (Clinical Trials) Amended Regulations 1998 and the Singapore Good Clinical Practice (GCP) Guidelines 1998. The Medical Clinical Research Committee (MCRC) has been established to oversee the conduct of clinical drug trials in Singapore and together with the legislations in place, these will ensure that clinical trials conducted in Singapore are properly controlled and the well-being of trial subjects are safe guarded. All clinical drug trials require a Clinical Trial Certificate from the MCRC before the trial can proceed. The hospital ethics committee (EC) vets the application for a trial certificate before it is sent to MCRC. The drug company sponsoring the trial has to indemnify the trial investigators and the hospital for negligence arising from the trial. The MCRC, apart from ensuring the safety of trial subjects, has to provide continuing review of the clinical trial and monitors adverse events in the course of the trial. The EC will conduct continuing review of clinical trials. When a non-drug clinical trial is carried out, the EC will ensure that the proposed protocol addresses ethical concerns and meets regulatory requirements for such trials. There is great potential for pharmaceutical Research & Development (R&D) in Singapore. We must develop our skills and infrastructure in clinical trials to enable Singapore to be a regional hub for R&D of drugs in Asia.
Leslie, Toby; Rowland, Mark; Mikhail, Amy; Cundill, Bonnie; Willey, Barbara; Alokozai, Asif; Mayan, Ismail; Hasanzai, Anwar; Baktash, Sayed Habibullah; Mohammed, Nader; Wood, Molly; Rahimi, Habib-U-Rahman; Laurent, Baptiste; Buhler, Cyril; Whitty, Christopher J M
The World Health Organisation (WHO) recommends parasitological diagnosis of malaria before treatment, but use of malaria rapid diagnostic tests (mRDTs) by community health workers (CHWs) has not been fully tested within health services in south and central Asia. mRDTs could allow CHWs to diagnose malaria accurately, improving treatment of febrile illness. A cluster randomised trial in community health services was undertaken in Afghanistan. The primary outcome was the proportion of suspected malaria cases correctly treated for polymerase chain reaction (PCR)-confirmed malaria and PCR negative cases receiving no antimalarial drugs measured at the level of the patient. CHWs from 22 clusters (clinics) received standard training on clinical diagnosis and treatment of malaria; 11 clusters randomised to the intervention arm received additional training and were provided with mRDTs. CHWs enrolled cases of suspected malaria, and the mRDT results and treatments were compared to blind-read PCR diagnosis. In total, 256 CHWs enrolled 2400 patients with 2154 (89.8%) evaluated. In the intervention arm, 75.3% (828/1099) were treated appropriately vs. 17.5% (185/1055) in the control arm (cluster adjusted risk ratio: 3.72, 95% confidence interval 2.40-5.77; p < 0.001). In the control arm, 85.9% (164/191) with confirmed Plasmodium vivax received chloroquine compared to 45.1% (70/155) in the intervention arm (p < 0.001). Overuse of chloroquine in the control arm resulted in 87.6% (813/928) of those with no malaria (PCR negative) being treated vs. 10.0% (95/947) in the intervention arm, p < 0.001. In the intervention arm, 71.4% (30/42) of patients with P. falciparum did not receive artemisinin-based combination therapy, partly because operational sensitivity of the RDTs was low (53.2%, 38.1-67.9). There was high concordance between recorded RDT result and CHW prescription decisions: 826/950 (87.0%) with a negative test were not prescribed an antimalarial. Co
Abdulla, S.; Adam, I.; Adjei, G. O.
values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs). Methods: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled...... trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting...... early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data. Results: In total, 29,493 patients from 84 clinical trials were included...
Full Text Available BACKGROUND: Protection from malaria with insecticide-treated bednets (ITNs during pregnancy is widely advocated, but evidence of benefit has been inconsistent. We undertook a systematic review of randomised trials. METHODS AND FINDINGS: Three cluster-randomised and two individually randomised trials met the inclusion criteria; four from Africa (n = 6,418 and one from Thailand (n = 223. In Africa, ITNs compared to no nets increased mean birth weight by 55 g (95% confidence interval [CI] 21-88, reduced low birth weight by 23% (relative risk [RR] 0.77, 95% CI 0.61-0.98, and reduced miscarriages/stillbirths by 33% (RR 0.67, 0.47-0.97 in the first few pregnancies. Placental parasitaemia was reduced by 23% in all gravidae (RR 0.77, 0.66-0.90. The effects were apparent in the cluster-randomised trials and the one individually randomised trial in Africa. The trial in Thailand, which randomised individuals to ITNs or untreated nets, showed reductions in anaemia and fetal loss in all gravidae, but not reductions in clinical malaria or low birth weight. CONCLUSIONS: ITNs used throughout pregnancy or from mid-pregnancy onwards have a beneficial impact on pregnancy outcome in malaria-endemic Africa in the first few pregnancies. The potential impact of ITNs in pregnant women and their newborns in malaria regions outside Africa requires further research.
Jakobsen, P H; McKay, V; N'Jie, R
Healthy Gambian children, children with clinical Plasmodium falciparum malaria, and children with asymptomatic P. falciparum infections were studied to investigate whether antitoxic activities may contribute to protection against malarial symptoms. Markers of inflammatory reactions, soluble tumor...... necrosis factor receptor I, and C-reactive protein were found in high concentrations in children with symptomatic P. falciparum malaria compared with levels in children with asymptomatic P. falciparum infections or in healthy children, indicating that inflammatory reactions are induced only in children...... decreased capacity to block induction of LAL activation by P. falciparum exoantigen. The decreased blocking activity was restored in the following dry season, when the children had no clinical malaria. Symptomatic children also had the highest immunoglobulin G (IgG) reactivities to conserved P. falciparum...
Kraus, V B; Blanco, F J; Englund, M
The objective of this work was to describe requirements for inclusion of soluble biomarkers in osteoarthritis (OA) clinical trials and progress toward OA-related biomarker qualification. The Guidelines for Biomarkers Working Group, representing experts in the field of OA biomarker research from...
McAlindon, T. E.; Driban, J. B.; Henrotin, Y.
The goal of this document is to update the original OARSI recommendations specifically for the design, conduct, and reporting of clinical trials that target symptom or structure modification among individuals with knee osteoarthritis (OA). To develop recommendations for the design, conduct...
Palter, S F
The modern clinical trial is a form of human experimentation. There is a long history of disregard for individual rights of the patient in this context, and special attention must be paid to ethical guidelines for these studies. Clinical trials differ in basic ways from clinical practice. Foremost is the introduction of outside interests, beyond those of the patient's health, into the doctor-patient therapeutic alliance. Steps must be taken to protect the interests of the patient when such outside influence exists. Kantian moral theory and the Hippocratic oath dictate that the physician must respect the individual patient's rights and hold such interests paramount. These principles are the basis for informed consent. Randomization of patients is justified when a condition of equipoise exists. The changing nature of health care delivery in the United States introduces new outside interests into the doctor-patient relationship.
This study was carried out to investigate the prevalence of malaria parasitamiae and its clinical features in children aged 0-5 years in parts of Delta State of Nigeria. Blood samples were randomly collected from the thumb of each child using the finger prick method. A total of 600 blood samples (360 males and 240 females) ...
Malaria, the greatest pandemia in the world, claims an estimated one million lives each year in Africa alone. While it may still be said that for the most part malaria is found in what is known as the world's poverty belt, cases are now frequently diagnosed in western countries. Due to resistant strains of malaria which have developed because of…
Katherine E Halliday
the younger class at 9 and 24 months and on arithmetic scores at 24 months.In this setting in Kenya, IST as implemented in this study is not effective in improving the health or education of school children. Possible reasons for the absence of an impact are the marked geographical heterogeneity in transmission, the rapid rate of reinfection following AL treatment, the variable reliability of RDTs, and the relative contribution of malaria to the aetiology of anaemia in this setting.www.ClinicalTrials.gov NCT00878007.
Bayés, M; Rabasseda, X; Prous, J R
Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Intergrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 249553, 2-Methoxyestradiol; Abatacept, Adalimumab, Adefovir dipivoxil, Agalsidase beta, Albinterferon alfa-2b, Aliskiren fumarate, Alovudine, Amdoxovir, Amlodipine besylate/atorvastatin calcium, Amrubicin hydrochloride, Anakinra, AQ-13, Aripiprazole, AS-1404, Asoprisnil, Atacicept, Atrasentan; Belimumab, Bevacizumab, Bortezomib, Bosentan, Botulinum toxin type B, Brivaracetam; Catumaxomab, Cediranib, Cetuximab, cG250, Ciclesonide, Cinacalcet hydrochloride, Curcumin, Cypher; Darbepoetin alfa, Denosumab, Dihydrexidine; Eicosapentaenoic acid/docosahexaenoic acid, Entecavir, Erlotinib hydrochloride, Escitalopram oxalate, Etoricoxib, Everolimus, Ezetimibe; Febuxostat, Fenspiride hydrochloride, Fondaparinux sodium; Gefitinib, Ghrelin (human), GSK-1562902A; HSV-tk/GCV; Iclaprim, Imatinib mesylate, Imexon, Indacaterol, Insulinotropin, ISIS-112989; L-Alanosine, Lapatinib ditosylate, Laropiprant; Methoxy polyethylene glycol-epoetin-beta, Mipomersen sodium, Motexafin gadolinium; Natalizumab, Nimotuzumab; OSC, Ozarelix; PACAP-38, Paclitaxel nanoparticles, Parathyroid Hormone-Related Protein-(1-36), Pasireotide, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pertuzumab, Picoplatin, Pimecrolimus, Pitavastatin calcium, Plitidepsin; Ranelic acid distrontium salt, Ranolazine, Recombinant human relaxin H2, Regadenoson, RFB4(dsFv)-PE38, RO-3300074, Rosuvastatin calcium; SIR-Spheres, Solifenacin succinate, Sorafenib, Sunitinib malate; Tadalafil, Talabostat, Taribavirin hydrochloride, Taxus, Temsirolimus, Teriparatide, Tiotropium bromide, Tipifarnib, Tirapazamine, Tocilizumab; UCN-01, Ularitide
Bayés, M; Rabasseda, X; Prous, J R
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity. prous.com. This issue focuses on the following selection of drugs: ABX-IL-8, Acclaim, adalimumab, AGI-1067, alagebrium chloride, alemtuzumab, Alequel, Androgel, anti-IL-12 MAb, AOD-9604, aripiprazole, atomoxetine hydrochloride; Biphasic insulin aspart, bosentan, botulinum toxin type B, bovine lactoferrin, brivudine; Cantuzumab mertansine, CB-1954, CDB-4124, CEA-TRICOM, choriogonadotropin alfa, cilansetron, CpG-10101, CpG-7909, CTL-102, CTL-102/CB-1954; DAC:GRF, darbepoetin alfa, davanat-1, decitabine, del-1 Genemedicine, dexanabinol, dextofisopam, dnaJP1, dronedarone hydrochloride, dutasteride; Ecogramostim, eletriptan, emtricitabine, EPI-hNE-4, eplerenone, eplivanserin fumarate, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, esomeprazole magnesium, etoricoxib, ezetimibe; Falecalcitriol, fingolimod hydrochloride; Gepirone hydrochloride; HBV-ISS, HSV-2 theracine, human insulin; Imatinib mesylate, Indiplon, insulin glargine, ISAtx-247; L612 HuMAb, levodopa/carbidopa/entacapone, lidocaine/prilocaine, LL-2113AD, lucinactant, LY-156735; Meclinertant, metelimumab, morphine hydrochloride, morphine-6-glucuronide; Natalizumab, nimotuzumab, NX-1207, NYVAC-HIV C; Omalizumab, onercept, osanetant; PABA, palosuran sulfate, parathyroid hormone (human recombinant), parecoxib sodium, PBI-1402, PCK-3145, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pemetrexed disodium, pimecrolimus, PINC, pregabalin; Ramelteon, rasagiline mesilate, rasburicase, rimonabant hydrochloride, RO-0098557, rofecoxib, rosiglitazone maleate/metformin hydrochloride; Safinamide mesilate, SHL-749, sitaxsentan sodium, sparfosic acid, SprayGel, squalamine, St. John's Wort
Howard, Natasha; Enayatullah, Sayed; Mohammad, Nader; Mayan, Ismail; Shamszai, Zohra; Rowland, Mark; Leslie, Toby
Afghanistan has some of the worst maternal and infant mortality indicators in the world and malaria is a significant public health concern. Study objectives were to assess prevalence of malaria and anaemia, related knowledge and practices, and malaria prevention barriers among pregnant women in eastern Afghanistan. Three studies were conducted: (1) a clinical survey of maternal malaria, maternal anaemia, and neonatal birthweight in a rural district hospital delivery-ward; (2) a case-control study of malaria risk among reproductive-age women attending primary-level clinics; and (3) community surveys of malaria and anaemia prevalence, socioeconomic status, malaria knowledge and reported behaviour among pregnant women. Among 517 delivery-ward participants (1), one malaria case (prevalence 1.9/1000), 179 anaemia cases (prevalence 346/1000), and 59 low-birthweight deliveries (prevalence 107/1000) were detected. Anaemia was not associated with age, gravidity, intestinal parasite prevalence, or low-birthweight at delivery. Among 141 malaria cases and 1010 controls (2), no association was found between malaria infection and pregnancy (AOR 0.89; 95 % CI 0.57-1.39), parity (AOR 0.95; 95 % CI 0.85-1.05), age (AOR 1.02; 95 % CI 1.00-1.04), or anaemia (AOR 1.00; 95 % CI 0.65-1.54). Those reporting insecticide-treated net usage had 40 % reduced odds of malaria infection (AOR 0.60; 95 % CI 0.40-0.91). Among 530 community survey participants (3), malaria and anaemia prevalence were 3.9/1000 and 277/1000 respectively, with 34/1000 experiencing severe anaemia. Despite most women having no formal education, malaria knowledge was high. Most expressed reluctance to take malaria preventive medication during pregnancy, deeming it potentially unsafe. Given the low malaria risk and reported avoidance of medication during pregnancy, intermittent preventive treatment is hard to justify or implement. Preventive strategy should instead focus on long-lasting insecticidal nets for all pregnant
Rodriguez-Barraquer, Isabel; Arinaitwe, Emmanuel; Jagannathan, Prasanna; Boyle, Michelle J.; Tappero, Jordan; Muhindo, Mary; Kamya, Moses R.; Dorsey, Grant; Drakeley, Chris; Ssewanyana, Isaac; Smith, David L.; Greenhouse, Bryan
Background. Plasmodium falciparum malaria remains a leading cause of childhood morbidity and mortality. There are important gaps in our understanding of the factors driving the development of antimalaria immunity as a function of age and exposure. Methods. We used data from a cohort of 93 children participating in a clinical trial in Tororo, Uganda, an area of very high exposure to P. falciparum. We jointly quantified individual heterogeneity in the risk of infection and the development of immunity against infection and clinical disease. Results. Results showed significant heterogeneity in the hazard of infection and independent effects of age and cumulative number of infections on the risk of infection and disease. The risk of developing clinical malaria upon infection decreased on average by 6% (95% confidence interval [CI], 0%–12%) for each additional year of age and by 2% (95% CI, 1%–3%) for each additional prior infection. Children randomly assigned to receive dihydroartemisinin-piperaquine for treatment appeared to develop immunity more slowly than those receiving artemether-lumefantrine. Conclusions. Heterogeneity in P. falciparum exposure and immunity can be independently evaluated using detailed longitudinal studies. Improved understanding of the factors driving immunity will provide key information to anticipate the impact of malaria-control interventions and to understand the mechanisms of clinical immunity. PMID:27481862
Maiti, Rituparna; M, Raghavendra
The concept of outsourcing for the development and global studies on new drugs has become widely accepted in the pharmaceutical industry due to its cost and uncertainty. India is going to be the most preferred location for contract pharma research and development due to its huge treatment naïve population, human resources, technical skills, adoption/amendment/implementation of rules/laws by regulatory authorities, and changing economic environment. But still 'miles to go' to fulfill the pre-requisites to ensure India's success. In spite of all the pitfalls, the country is ambitious and optimist to attract multinational pharmaceutical companies to conduct their clinical trials in India.
Hänscheid, Thomas; Melo-Cristino, José; Grobusch, Martin P.; Pinto, Bernardino G.
BACKGROUND: Misdiagnosis of imported malaria is not uncommon and even abnormal routine laboratory tests may not trigger malaria smears. However, blind screening of all thrombocytopenic samples might be a possible way to detect clinically unsuspected malaria cases in the accident and emergency
Ouma, Peter; van Eijk, Anna M.; Hamel, Mary J.; Parise, Monica; Ayisi, John G.; Otieno, Kephas; Kager, Piet A.; Slutsker, Laurence
OBJECTIVE: To determine the prevalence of malaria and anaemia among urban and peri-urban women attending their first antenatal clinic (ANC) in an area of perennial malaria transmission. METHODS: Between November 2003 and May 2004 we screened first ANC attenders for malaria and anaemia in a large
Chidiac, C; Katlama, C; Yeni, P
Just over a decade after identification of chemokine receptors CCR5 and CXCR4 as coreceptors for HIV, maraviroc (Celsentri), the first CCR5 antagonist, has recently obtained its Marketing Authorization in the United States and Europe, for treatment of treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable. CCR5 antagonists, after fusion inhibitor enfuvirtide available since 2003, also belong to entry inhibitors. These molecules, unlike previous antiretrovirals, do not target the virus but its target cell by blocking viral penetration. Maraviroc has shown its clinical efficacy in patients failing other antiretroviral classes. Its safety profile was similar to placebo in two large phase III trials. However, careful assessment of both hepatic and immunologic safety of this new therapeutic class is needed. Viral tropism testing has to be investigated before using maraviroc in the clinic, because CCR5 antagonists are not active against CXCR4 viruses. For the moment indicated for the treatment-experienced patient population, maraviroc could in the future benefit to other types of patients, depending on ongoing trials results.
Full Text Available Objective: To identify a new, safe and effective source to combat and prevent drug resistant malaria therapeutically and to make it as a home-made bio-medicine which is called as OMARIA (Orissa malaria research indigenous attempt and use it on long term basis (decade in mono clinical station and in field. Methods: The rind of a lesser known Indian indigenous fruit dalimba/ Punica granatum (P. granatum is taken. Manual process to make a hand-made or home-made bio-medicine is done. Hand-filled into gelatin capsules and administered as an internal medicine. Therapy to 532 clinical cases is given at the Govt Red Cross Clinic, and Prophylaxis at site is administered to 401 cases by adopting 3 villages. Results: Hydrophyllic, ellagitannins viz., punicalagin (C 48H28O 30; mw 1 1 00~1 1 25, punicalin (C 34H22O 22; mw 780~785, ellagic acid (C14H6O8; mw 302 and K+ co-exists as the only drug moieties. OMARIA has no other confounding or confabulating compounds. There is non alkaloid. Conclusions: OMARIA delivers therapeutics and prophylaxis to drug resistant Plasmodium falciparum (P. falciparum cases. There are no side effects and no contradictions. Non-toxic at bolus/loading doses. No case progressed to cerebral malaria. OMARIA is a first time work. Original report on pan global basis.
Deepa; Alwar, Vanamala A; Rameshkumar, Karuna; Ross, Cecil
The study was undertaken to correlate the blood groups and clinical presentations in malaria patients and to understand the differential host susceptibility in malaria. From October 2007 to September 2008, malaria positive patients' samples were evaluated in this study. Hemoglobin, total leukocyte count, and platelet count of each patient were done on an automated cell counter. After determining the blood groups, malarial species and the severity of clinical course were correlated. A total of 100 patients were included in the study, of which 63 cases were positive for Plasmodium falciparum and 37 cases were positive for P. vivax infection and 11 patients had mixed infection. The results of the blood groups showed 22 - 'A' group, 42 - 'B' group, 35 - 'O' group and 1 was 'AB' group. When the clinical courses between different groups were compared using the following parameters for severe infection--a parasitic load of >10/1000 RBCs, severe anemia with hemoglobin 101°F and other organ involvement, it was observed that 'O' group had an advantage over other the groups. The difference in rosetting ability between red blood cells of different 'ABO' blood groups with a diminished rosetting potential in blood group 'O' red blood cells was due to the differential host susceptibility. 'O' group had an advantage over the other three blood groups. Based on literature and the results of this study, the diminished rosetting potential in blood group 'O' red blood cells is suggested as the basis for the differential host susceptibility.
Di Giulio, Paola; Campagna, Sara; Dimonte, Valerio
Clinical trials are pivotal for the development of nursing knowledge. To describe the clinical trials published in nursing journals in the last two years and propose some general reflections on nursing research. A search with the key-word trial was done on PubMed (2009-2013) on Cancer Nursing, European Journal of Oncology Nursing, International Journal of Nursing Studies, Journal of Advanced Nursing, Journal of Clinical Nursing and Nursing Research. Of 228 trials identified, 104 (45.8%) were published in the last 2 years. Nurses from Asian countries published the larger number of trials. Educational and supportive interventions were the most studied (61/104 trials), followed by clinical interventions (33/104). Samples were limited and most trials are monocentric. A growing number of trials is published, on issues relevant for the nursing profession, however larger samples and multicentric studies would be necessary.
Bayés, M; Rabasseda, X; Prous, J R
Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issues focuses on the following selection of drugs: (-)-Epigallocatechin gallate, (-)-gossypol, 2-deoxyglucose, 3,4-DAP, 7-monohydroxyethylrutoside; Ad5CMV-p53, adalimumab, adefovir dipivoxil, ADH-1, alemtuzumab, aliskiren fumarate, alvocidib hydrochloride, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, amrubicin hydrochloride, AN-152, anakinra, anecortave acetate, antiasthma herbal medicine intervention, AP-12009, AP-23573, apaziquone, aprinocarsen sodium, AR-C126532, AR-H065522, aripiprazole, armodafinil, arzoxifene hydrochloride, atazanavir sulfate, atilmotin, atomoxetine hydrochloride, atorvastatin, avanafil, azimilide hydrochloride; Bevacizumab, biphasic insulin aspart, BMS-214662, BN-83495, bortezomib, bosentan, botulinum toxin type B; Caspofungin acetate, cetuximab, chrysin, ciclesonide, clevudine, clofarabine, clopidogrel, CNF-1010, CNTO-328, CP-751871, CX-717, Cypher; Dapoxetine hydrochloride, darifenacin hydrobromide, dasatinib, deferasirox, dextofisopam, dextromethorphan/quinidine sulfate, diclofenac, dronedarone hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Edaravone, efaproxiral sodium, emtricitabine, entecavir, eplerenone, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, etoricoxib, ezetimibe, ezetimibe/simvastatin; Finrozole, fipamezole hydrochloride, fondaparinux sodium, fulvestrant; Gabapentin enacarbil, gaboxadol, gefitinib, gestodene, ghrelin (human); Human insulin, human papillomavirus vaccine; Imatinib mesylate, immunoglobulin intravenous (human), indiplon, insulin detemir, insulin glargine, insulin glulisine, intranasal insulin, istradefylline, i.v. gamma
Mahamadou A Thera
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].
Mbonye, Anthony K.; Magnussen, Pascal; Lal, Sham; Hansen, Kristian S.; Cundill, Bonnie; Chandler, Clare; Clarke, Siân E.
treatment of malaria with ACT. Trial Registration ClinicalTrials.gov NCT01194557. PMID:26200467
Miriam K Laufer
Full Text Available The predominance of chloroquine-susceptible falciparum malaria in Malawi more than a decade after chloroquine's withdrawal permits contemplation of re-introducing chloroquine for targeted uses. We aimed to compare the ability of different partner drugs to preserve chloroquine efficacy and prevent the re-emergence of resistance.Children with uncomplicated malaria were enrolled at a government health center in Blantyre, Malawi. Participants were randomized to receive chloroquine alone or combined with artesunate, azithromycin or atovaquone-proguanil for all episodes of uncomplicated malaria for one year. The primary outcome was incidence of clinical malaria. Secondary endpoints included treatment efficacy, and incidence of the chloroquine resistance marker pfcrt T76 and of anemia. Of the 640 children enrolled, 628 were included in the intention-to-treat analysis. Malaria incidence (95% confidence interval was 0.59 (.46-.74, .61 (.49-.76, .63 (.50-.79 and .68 (.54-.86 episodes/person-year for group randomized to receive chloroquine alone or in combination with artesunate, azithromycin or atovaquone-proguanil respectively and the differences were not statistically significant. Treatment efficacy for first episodes was 100% for chloroquine monotherapy and 97.9% for subsequent episodes of malaria. Similar results were seen in each of the chloroquine combination groups. The incidence of pfcrt T76 in pure form was 0%; mixed infections with both K76 and T76 were found in two out of 911 infections. Young children treated with chloroquine-azithromycin had higher hemoglobin concentrations at the study's end than did those in the chloroquine monotherapy group.Sustained chloroquine efficacy with repeated treatment supports the eventual re-introduction of chloroquine combinations for targeted uses such as intermittent preventive treatment.ClinicalTrials.gov NCT00379821.
Laufer, Miriam K; Thesing, Phillip C; Dzinjalamala, Fraction K; Nyirenda, Osward M; Masonga, Rhoda; Laurens, Matthew B; Stokes-Riner, Abbie; Taylor, Terrie E; Plowe, Christopher V
The predominance of chloroquine-susceptible falciparum malaria in Malawi more than a decade after chloroquine's withdrawal permits contemplation of re-introducing chloroquine for targeted uses. We aimed to compare the ability of different partner drugs to preserve chloroquine efficacy and prevent the re-emergence of resistance. Children with uncomplicated malaria were enrolled at a government health center in Blantyre, Malawi. Participants were randomized to receive chloroquine alone or combined with artesunate, azithromycin or atovaquone-proguanil for all episodes of uncomplicated malaria for one year. The primary outcome was incidence of clinical malaria. Secondary endpoints included treatment efficacy, and incidence of the chloroquine resistance marker pfcrt T76 and of anemia. Of the 640 children enrolled, 628 were included in the intention-to-treat analysis. Malaria incidence (95% confidence interval) was 0.59 (.46-.74), .61 (.49-.76), .63 (.50-.79) and .68 (.54-.86) episodes/person-year for group randomized to receive chloroquine alone or in combination with artesunate, azithromycin or atovaquone-proguanil respectively and the differences were not statistically significant. Treatment efficacy for first episodes was 100% for chloroquine monotherapy and 97.9% for subsequent episodes of malaria. Similar results were seen in each of the chloroquine combination groups. The incidence of pfcrt T76 in pure form was 0%; mixed infections with both K76 and T76 were found in two out of 911 infections. Young children treated with chloroquine-azithromycin had higher hemoglobin concentrations at the study's end than did those in the chloroquine monotherapy group. Sustained chloroquine efficacy with repeated treatment supports the eventual re-introduction of chloroquine combinations for targeted uses such as intermittent preventive treatment. ClinicalTrials.gov NCT00379821.
... less than the risk of catching this infection. Chloroquine has been the drug of choice for protecting against malaria. But because of resistance, it is now only suggested for use in areas where Plasmodium vivax , P. oval , and ...
... bites you, the parasite can get into your blood. The parasite lays eggs, which develop into more parasites. They ... cells until you get very sick. Because the parasites live in the blood, malaria can also be spread through other ways. ...
Sullivan, Richard T; Ssewanyana, Isaac; Wamala, Samuel; Nankya, Felistas; Jagannathan, Prasanna; Tappero, Jordan W; Mayanja-Kizza, Harriet; Muhindo, Mary K; Arinaitwe, Emmanuel; Kamya, Moses; Dorsey, Grant; Feeney, Margaret E; Riley, Eleanor M; Drakeley, Chris J; Greenhouse, Bryan; Sullivan, Richard
Repeated exposure to Plasmodium falciparum is associated with perturbations in B cell sub-set homeostasis, including expansion atypical memory B cells. However, B cell perturbations immediately following acute malaria infection have been poorly characterized, especially with regard to their relationship with immunity to malaria. To better understand the kinetics of B cell sub-sets following malaria, the proportions of six B cell sub-sets were assessed at five time points following acute malaria in four to 5 years old children living in a high transmission region of Uganda. B cell sub-set kinetics were compared with measures of clinical immunity to malaria-lower parasite density at the time of malaria diagnosis and recent asymptomatic parasitaemia. Atypical memory B cell and transitional B cell proportions increased following malaria. In contrast, plasmablast proportions were highest at the time of malaria diagnosis and rapidly declined following treatment. Increased proportions of atypical memory B cells were associated with greater immunity to malaria, whereas increased proportions of transitional B cells were associated with evidence of less immunity to malaria. These findings highlight the dynamic changes in multiple B cell sub-sets following acute, uncomplicated malaria, and how these sub-sets are associated with developing immunity to malaria.
Full Text Available Abstract Cross-Over Clinical Trials in comparison with Parallel groups clinical trials have some advantages such as control of confounding variables, small sample size, and short time to implement the research project. But this type of research has few essential limitations that discusses in this monogram.
Ndibazza, Juliet; Webb, Emily L; Lule, Swaib
Background. Helminth and malaria coinfections are common in the tropics. We investigated the hypothesis that prenatal exposure to these parasites might influence susceptibility to infections such as malaria in childhood.Methods. In a birth cohort of 2,345 mother-child pairs in Uganda, maternal...... helminth and malaria infection status was determined during pregnancy, and childhood malaria episodes recorded from birth to age five years. We examined associations between maternal infections and malaria in the offspring.Results. Common maternal infections were hookworm (45%), Mansonella perstans (21......%), Schistosoma mansoni (18%), and Plasmodium falciparum (11%). At age 5 years, 69% of the children were still under follow-up. The incidence of malaria was 34 episodes per 100 child-years, and the mean prevalence of asymptomatic malaria at annual visits was 5.4%. Maternal hookworm and M. perstans infections were...
Mmbando, Bruno P; Lusingu, John P; Vestergaard, Lasse S
BACKGROUND: In Sub-Sahara Africa, malaria due to Plasmodium falciparum is the main cause of ill health. Evaluation of malaria interventions, such as drugs and vaccines depends on clinical definition of the disease, which is still a challenge due to lack of distinct malaria specific clinical...... features. Parasite threshold is used in definition of clinical malaria in evaluation of interventions. This however, is likely to be influenced by other factors such as transmission intensity as well as individual level of immunity against malaria. METHODS: This paper describes step function and dose...... response model with threshold parameter as a tool for estimation of parasite threshold for onset of malaria fever in highlands (low transmission) and lowlands (high transmission intensity) strata. These models were fitted using logistic regression stratified by strata and age groups (0-1, 2-3, 4-5, 6...
Full Text Available The World Health Organization recommends that malaria be confirmed by parasitological diagnosis before treatment using Artemisinin-based Combination Therapy (ACT. Despite this, many health workers in malaria endemic countries continue to diagnose malaria based on symptoms alone. This study evaluates interventions to help bridge this gap between guidelines and provider practice. A stratified cluster-randomized trial in 42 communities in Enugu state compared 3 scenarios: Rapid Diagnostic Tests (RDTs with basic instruction (control; RDTs with provider training (provider arm; and RDTs with provider training plus a school-based community intervention (provider-school arm. The primary outcome was the proportion of patients treated according to guidelines, a composite indicator requiring patients to be tested for malaria and given treatment consistent with the test result. The primary outcome was evaluated among 4946 (93% of the 5311 patients invited to participate. A total of 40 communities (12 in control, 14 per intervention arm were included in the analysis. There was no evidence of differences between the three arms in terms of our composite indicator (p = 0.36: stratified risk difference was 14% (95% CI -8.3%, 35.8%; p = 0.26 in the provider arm and 1% (95% CI -21.1%, 22.9%; p = 0.19 in the provider-school arm, compared with control. The level of testing was low across all arms (34% in control; 48% provider arm; 37% provider-school arm; p = 0.47. Presumptive treatment of uncomplicated malaria remains an ingrained behaviour that is difficult to change. With or without extensive supporting interventions, levels of testing in this study remained critically low. Governments and researchers must continue to explore alternative ways of encouraging providers to deliver appropriate treatment and avoid the misuse of valuable medicines.ClinicalTrials.gov NCT01350752.
Background- Severe Plasmodium falciparum malaria remains one of the major causes of childhood morbidity and mortality in Africa. Severe malaria manifests itself as three main clinical syndromes-impaired consciousness (cerebral malaria), respiratory distress and severe malarial anaemia. Cerebral malaria and respiratory distress are major contributors to malaria mortality but their pathophysiology remains unclear. Motivation/Objectives- Most children with severe malaria die within the first 24 hours of admission to a hospital because of their pathophysiological conditions. Thus, along with anti-malarial drugs, various adjuvant therapies such as fluid bolus (for hypovolaemia) and anticonvulsants (for seizures) are given to alleviate the sick child’s condition. But these therapies can sometimes have adverse effects. Hence, a clear understanding of severe malaria pathophysiology is essential for making an informed decision regarding adjuvant therapies. Methodology- We used mass spectrometry-based shotgun proteomics to study plasma samples from Gambian children with severe malaria. We compared the proteomic profiles of different severe malaria syndromes and generated hypotheses regarding the underlying disease mechanisms. Results/Conclusions- The main challenges of studying the severe malaria syndromes using proteomics were the high complexity and variability among the samples. We hypothesized that hepatic injury and nitric oxide play roles in the pathophysiology of cerebral malaria and respiratory distress.
Thompson, Michael A
Social media has potential in clinical trials for pointing out trial issues, addressing barriers, educating, and engaging multiple groups involved in cancer clinical research. Social media is being used in clinical trials to highlight issues such as poor accrual and barriers; educate potential participants and physicians about clinical trial options; and is a potential indirect or direct method to improve accrual. We are moving from a passive "push" of information to patients to a "pull" of patients requesting information. Patients and advocates are often driving an otherwise reluctant health care system into communication. Online patient communities are creating new information repositories. Potential clinical trial participants are using the Twittersphere and other sources to learn about potential clinical trial options. We are seeing more organized patient-centric and patient-engaged forums with the potential to crowd source to improve clinical trial accrual and design. This is an evolving process that will meet many individual, institutional, and regulatory obstacles as we move forward in a changed research landscape.
Katz, J N; Losina, E; Lohmander, L S
To highlight methodological challenges in the design and conduct of randomized trials of surgical interventions and to propose strategies for addressing these challenges. This paper focuses on three broad areas: enrollment; intervention; and assessment including implications for analysis. For eac...
Ibbott, Geoffrey S.; Haworth, Annette; Followill, David S.
Cooperative groups, of which the Radiation Therapy Oncology Group is one example, conduct national clinical trials that often involve the use of radiation therapy. In preparation for such a trial, the cooperative group prepares a protocol to define the goals of the trial, the rationale for its design, and the details of the treatment procedure to be followed. The Radiological Physics Center (RPC) is one of several quality assurance (QA) offices that is charged with assuring that participating institutions deliver doses that are clinically consistent and comparable. The RPC does this by conducting a variety of independent audits and credentialing processes. The RPC has compiled data showing that credentialing can help institutions comply with the requirements of a cooperative group clinical protocol. Phantom irradiations have been demonstrated to exercise an institution’s procedures for planning and delivering advanced external beam techniques (1–3). Similarly, RPC data indicate that a rapid review of patient treatment records or planning procedures can improve compliance with clinical trials (4). The experiences of the RPC are presented as examples of the contributions that a national clinical trials QA center can make to cooperative group trials. These experiences illustrate the critical need for comprehensive QA to assure that clinical trials are successful and cost-effective. The RPC is supported by grants CA 10953 and CA 81647 from the National Cancer Institute, NIH, DHHS. PMID:24392352
Ngo Duc Thang
Full Text Available In Vietnam, malaria remains a problem in some remote areas located along its international borders and in the central highlands, partly due to the bionomics of the local vector, mainly found in forested areas and less vulnerable to standard control measures. Long Lasting Insecticidal Hammocks (LLIH, a tailored and user-friendly tool for forest workers, may further contribute in reducing the malaria burden. Their effectiveness was tested in a large community-based intervention trial carried out in Ninh Thuan province in Central Vietnam.Thirty villages (population 18,646 were assembled in 20 clusters (1,000 individuals per cluster that were randomly allocated to either the intervention or control group (no LLIH after stratification according to the pre-intervention P. falciparum antibody prevalence ( or =30%. LLIH were distributed to the intervention group in December 2004. For the following 2 years, the incidence of clinical malaria and the prevalence of infection were determined by passive case detection at community level and by bi-annual malariometric surveys. A 2-fold larger effect on malaria incidence in the intervention as compared to the control group was observed. Similarly, malaria prevalence decreased more substantially in the intervention (1.6-fold greater reduction than in the control group. Both for incidence and prevalence, a stronger and earlier effect of the intervention was observed in the high endemicity stratum. The number of malaria cases and infections averted by the intervention overall was estimated at 10.5 per 1,000 persons and 5.6/100 individuals, respectively, for the last half of 2006. In the high endemicity stratum, the impact was much higher, i.e. 29/1000 malaria cases and 15.7 infections/100 individuals averted.LLIH reduced malaria incidence and prevalence in this remote and forested area of Central Vietnam. As the targets of the newly-launched Global Malaria Action Plan include the 75% reduction of the global
Reimer, C; Lødrup, A; Smith, G
of an alginate (Gaviscon Advance, Reckitt Benckiser, Slough, UK) on reflux symptoms in patients with persistent symptoms despite once daily PPI. MethodsThis was a multicentre, randomised, placebo-controlled, 7-day double-blind trial preceded by a 7-day run-in period. Reflux symptoms were assessed using...
Adu, Bright; Dodoo, Daniel; Adukpo, Selorme
Plasmodium falciparum malaria kills nearly a million people annually. Over 90% of these deaths occur in children under five years of age in sub-Saharan Africa. A neutrophil mediated mechanism, the antibody dependent respiratory burst (ADRB), was recently shown to correlate with protection from...... by allele specific restriction enzyme digestion. FCGR3B-exon 3 was sequenced in 585 children, aged 1 to 12 years living in a malaria endemic region of Ghana. Multivariate logistic regression analysis found no association between Fc¿RIIA-166H/R polymorphism and clinical malaria. The A-allele of FCGR3B-c.233C...... malaria vaccines....
dividing and are far more noticeable than the small amount of clear cyto- plasm surrounding them (Figs 10.6a & 10.6b). Mature schizonts contain 8...edema Same as P. vivax 16 10 • Topics on The paThology of proTozoan and invasive arThropod diseases Figure 10.38 Transmission electron micrograph of...mesangiopathic glo- merulonephropathy caused by quartan malaria, deposition of immune complexes may be demonstrated by electron or immunofluorescence microscopy
Kirsten E Lyke
Full Text Available Experimental infection of malaria-naïve volunteers by the bite of Plasmodium falciparum-infected mosquitoes is a preferred means to test the protective effect of malaria vaccines and drugs. The standard model relies on the bite of five infected mosquitoes to induce malaria. We examined the efficacy of malaria transmission using mosquitoes raised aseptically in compliance with current Good Manufacturing Practices (cGMPs.Eighteen adults aged 18-40 years were randomized to receive 1, 3 or 5 bites of Anopheles stephensi mosquitoes infected with the chloroquine-sensitive NF54 strain of P. falciparum. Seventeen participants developed malaria; fourteen occurring on Day 11. The mean prepatent period was 10.9 days (9-12 days. The geometric mean parasitemia was 15.7 parasites/µL (range: 4-70 by microscopy. Polymerase chain reaction (PCR detected parasites 3.1 (range: 0-4 days prior to microscopy. The geometric mean sporozoite load was 16,753 sporozoites per infected mosquito (range: 1,000-57,500. A 1-bite participant withdrew from the study on Day 13 post-challenge and was PCR and smear negative.The use of aseptic, cGMP-compliant P. falciparum-infected mosquitoes is safe, is associated with a precise prepatent period compared to the standard model and appears more efficient than the standard approach, as it led to infection in 100% (6/6 of volunteers exposed to three mosquito bites and 83% (5/6 of volunteers exposed to one mosquito bite.ClinicalTrials.gov NCT00744133.
Full Text Available The pre-erythrocytic malaria vaccine RTS,S/AS02A has shown to confer protection against clinical malaria for at least 21 months in a trial in Mozambican children. Efficacy varied between different endpoints, such as parasitaemia or clinical malaria; however the underlying mechanisms that determine efficacy and its duration remain unknown. We performed a new, exploratory analysis to explore differences in the duration of protection among participants to better understand the protection afforded by RTS,S.The study was a Phase IIb double-blind, randomized controlled trial in 2022 children aged 1 to 4 years. The trial was designed with two cohorts to estimate vaccine efficacy against two different endpoints: clinical malaria (cohort 1 and infection (cohort 2. Participants were randomly allocated to receive three doses of RTS,S/AS02A or control vaccines. We did a retrospective, unplanned sub-analysis of cohort 2 data using information collected for safety through the health facility-based passive case detection system. Vaccine efficacy against clinical malaria was estimated over the first six-month surveillance period (double-blind phase and over the following 12 months (single-blind phase, and analysis was per-protocol. Adjusted vaccine efficacy against first clinical malaria episodes in cohort 2 was of 35.4% (95% CI 4.5-56.3; p = 0.029 over the double-blind phase and of 9.0% (-30.6-36.6; p = 0.609 during the single-blind phase.Contrary to observations in cohort 1, where efficacy against clinical malaria did not wane over time, in cohort 2 the efficacy decreases with time. We hypothesize that this reduced duration of protection is a result of the early diagnosis and treatment of infections in cohort 2 participants, preventing sufficient exposure to asexual-stage antigens. On the other hand, the long-term protection against clinical disease observed in cohort 1 may be a consequence of a prolonged exposure to low-dose blood-stage asexual parasitaemia.ClinicalTrials
Jency Maria Koshy
Full Text Available Introduction: Cerebral malaria (CM is one of the most common causes for non-traumatic encephalopathy in the world. It affects both the urban and rural population. It is a challenge to treat these patients in a resource limited setting; where majority of these cases present. Materials and Methods: This was a prospective study carried out from September 2005 to December 2006 at Jiwan Jyoti Christian Hospital in Eastern Uttar Pradesh in India. This is a secondary level care with limited resources. We studied the clinical profile, treatment and outcome of all the patients above the age of 14 years diagnosed with CM. Results: There were a total of 53 patients with CM of which 38 (71.7% of them were females. Among them, 35 (66% patients were less than 30 years of age. The clinical features noted were seizure (39.62%, anemia (84.9%, icterus (16.98%, hypotension (13.2%, bleeding (3.7%, hepatomegaly (5.66%, splenomegaly (5.66%, non-cardiogenic pulmonary edema (16.98% and renal dysfunction (37.36%. Co-infection with Plasmodium vivax was present in 13 (24.53% of them. Treatment received included artesunin compounds or quinine. Median time of defervescence was 2 (interquartile range1-3. Complete recovery was achieved in 43 (81% of them. Two (3.7% of them died. Conclusion: CM, once considered to be a fatal disease has shown remarkable improvement in the outcome with the wide availability of artesunin and quinine components. To combat the malaria burden, physicians in resource limited setting should be well trained to manage these patients especially in the endemic areas. The key to management is early diagnosis and initiation of treatment based on a high index of suspicion. Anticipation and early recognition of the various complications are crucial.
Gil-Extremera, B; Jiménez-López, P; Mediavilla-García, J D
Clinical trials are essential tools for the progress of clinical medicine in its diagnostic and therapeutic aspects. Since the first trial in 1948, which related tobacco use with lung cancer, there have been more than 150,000 clinical trials to date in various areas (paediatrics, cardiology, oncology, endocrinology, etc.). This article highlights the importance for all physicians to participate, over the course of their professional career, in a clinical trial, due to the inherent benefits for patients, the progress of medicine and for curricular prestige. The authors have created a synthesis of their experience with clinical trials on hypertension, diabetes, dyslipidaemia and ischaemic heart disease over the course of almost 3 decades. Furthermore, a brief reference has been made to the characteristics of a phase I unit, as well as to a number of research studies currently underway. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.
Full Text Available BACKGROUND: The long terminal half life of piperaquine makes it suitable for intermittent preventive treatment for malaria but no studies of its use for prevention have been done in Africa. We did a cluster randomized trial to determine whether piperaquine in combination with either dihydroartemisin (DHA or sulfadoxine-pyrimethamine (SP is as effective, and better tolerated, than SP plus amodiaquine (AQ, when used for intermittent preventive treatment in children delivered by community health workers in a rural area of Senegal. METHODS: Treatments were delivered to children 3-59 months of age in their homes once per month during the transmission season by community health workers. 33 health workers, each covering about 60 children, were randomized to deliver either SP+AQ, DHA+PQ or SP+PQ. Primary endpoints were the incidence of attacks of clinical malaria, and the incidence of adverse events. RESULTS: 1893 children were enrolled. Coverage of monthly rounds and compliance with daily doses was similar in all groups; 90% of children received at least 2 monthly doses. Piperaquine combinations were better tolerated than SP+AQ with a significantly lower risk of common, mild adverse events. 103 episodes of clinical malaria were recorded during the course of the trial. 68 children had malaria with parasitaemia >3000/microL, 29/671 (4.3% in the SP+AQ group, compared with 22/604 (3.6% in the DHA+PQ group (risk difference 0.47%, 95%CI -2.3%,+3.3%, and 17/618 (2.8% in the SP+PQ group (risk difference 1.2%, 95%CI -1.3%,+3.6%. Prevalences of parasitaemia and the proportion of children carrying Pfdhfr and Pfdhps mutations associated with resistance to SP were very low in all groups at the end of the transmission season. CONCLUSIONS: Seasonal IPT with SP+PQ in children is highly effective and well tolerated; the combination of two long-acting drugs is likely to impede the emergence of resistant parasites. TRIAL REGISTRATION: ClinicalTrials.gov NCT00529620.
Full Text Available Malaria pathogenesis may be influenced by IgE responses and cytokine cross-regulation. Several mutations in the IL-4/STAT6 signaling pathway can alter cytokine cross-regulation and IgE responses during a Plasmodium falciparum malarial infection. This study investigated the relationship between a STAT6 intronic single-nucleotide polymorphism (rs3024974, total IgE, cytokines, and malaria severity in 238 Ghanaian children aged between 0.5 and 13 years. Total IgE and cytokine levels were measured by ELISA, while genotyping was done by polymerase chain reaction-restriction fragment length polymorphism (RFLP. Compared with healthy controls, heterozygosity protected against clinical malaria: uncomplicated malaria (odds ratios [OR] = 0.13, P < 0.001, severe malarial anemia (OR = 0.18, P < 0.001, and cerebral malaria (OR = 0.39, P = 0.022. Levels of total IgE significantly differed among malaria phenotypes (P = 0.044 and rs3024974 genotypes (P = 0.037. Neither cytokine levels nor IL-6/IL-10 ratios were associated with malaria phenotypes or rs3024974 genotypes. This study suggests a role for rs3024974 in malaria pathogenesis and offers further insights into an IL-4/STAT6 pathway mutation in malaria pathogenesis.
Emery, C. A.; Roos, Ewa M.; Verhagen, E.
The risk of post-traumatic osteoarthritis (PTOA) substantially increases following joint injury. Research efforts should focus on investigating the efficacy of preventative strategies in high quality randomized controlled trials (RCT). The objective of these OARSI RCT recommendations is to inform...... the design, conduct and analytical approaches to RCTs evaluating the preventative effect of joint injury prevention strategies. Recommendations regarding the design, conduct, and reporting of RCTs evaluating injury prevention interventions were established based on the consensus of nine researchers...... internationally with expertise in epidemiology, injury prevention and/or osteoarthritis (OA). Input and resultant consensus was established through teleconference, face to face and email correspondence over a 1 year period. Recommendations for injury prevention RCTs include context specific considerations...
Acquah Patrick A
Full Text Available Abstract Background Plasmodium falciparum can be detected by microscopy, histidine-rich-protein-2 (HRP2 capture test or PCR but the respective clinical relevance of the thereby diagnosed infections in pregnant women is not well established. Methods In a cross-sectional, year-round study among 839 delivering women in Agogo, Ghana, P. falciparum was screened for in both, peripheral and placental blood samples, and associations with maternal anaemia, low birth weight (LBW and preterm delivery (PD were analysed. Results In peripheral blood, P. falciparum was observed in 19%, 34%, and 53% by microscopy, HRP2 test, and PCR, respectively. For placental samples, these figures were 35%, 41%, and 59%. Irrespective of diagnostic tool, P. falciparum infection increased the risk of anaemia. Positive peripheral blood results of microscopy and PCR were not associated with LBW or PD. In contrast, the HRP2 test performed well in identifying women at increased risk of poor pregnancy outcome, particularly in case of a negative peripheral blood film. Adjusting for age, parity, and antenatal visits, placental HRP2 was the only marker of infection associated with LBW (adjusted odds ratio (aOR, 1.5 (95%CI, 1.0–2.2 and, at borderline statistical significance, PD (aOR, 1.4 (1.0–2.1 in addition to anaemia (aOR, 2.3 (1.7–3.2. Likewise, HRP2 in peripheral blood of seemingly aparasitaemic women was associated with PD (aOR, 1.7 (1.0–2.7 and anaemia (aOR, 2.1 (1.4–3.2. Conclusion Peripheral blood film microscopy not only underestimates placental malaria. In this highly endemic setting, it also fails to identify malaria as a cause of foetal impairment. Sub-microscopic infections detected by a HRP2 test in seemingly aparasitaemic women increase the risks of anaemia and PD. These findings indicate that the burden of malaria in pregnancy may be even larger than thought and accentuate the need for effective anti-malarial interventions in pregnancy.
Full Text Available Number of malaria cases in Kabupaten Trenggalek in 2014 is 89 cases, and 83 cases are import malaria from migrant workers. Import malaria is transmitted across two areas and affects the clinical medication seeking. This research wants to describe the pattern of clinical medication seeking for import malaria by migrant workers in Puskesmas Pandean working area. This was cross sectional study with descriptive quantitative approach. Research’s sample is 26 import malaria sufferers in 2013–2015 who has chosen purposively with inclusion criteria. Interview had used to get information about characteristics, place felt the symptom, first clinical medication seeking (place and time, clinical diagnosis, medication follow up, and recovery status. The result of the research shows 100% respondent is man and the age about 20-30 years old (53,8 who is working as agricultural laborers outside Java. Mostly of respondent feel the malaria symptoms in their working place (53,8%. The day seeks clinical medication at day three after symptom (34, 6%. Respondents that feel the symptom in Puskesmas Pandean working area chose Puskesmas as clinical medication place (42,3%, and hospital (19,2% for them whose experience the malaria symptom in their working area. Puskesmas is chosen as clinical diagnosis place (69% and only 11,5% respondent got medication follow up. Puskesmas is chosen as intermediate clinical medication place (60% for 19,2% respondent that is not recovered well, although 20% go to Dukun. All of respondent chose the clinical medication as their prime medication. Need to make medication follow up visitation well complete. Keyword: pattern, clinical medication, import malaria, migrant worker
Full Text Available In addition to the expensive and lengthy process of developing a new medicine, the attrition rate in clinical research was on the rise, resulting in stagnation in the development of new compounds. As a consequence to this, the US Food and Drug Administration released a critical path initiative document in 2004, highlighting the need for developing innovative trial designs. One of the innovations suggested the use of adaptive designs for clinical trials. Thus, post critical path initiative, there is a growing interest in using adaptive designs for the development of pharmaceutical products. Adaptive designs are expected to have great potential to reduce the number of patients and duration of trial and to have relatively less exposure to new drug. Adaptive designs are not new in the sense that the task of interim analysis (IA/review of the accumulated data used in adaptive designs existed in the past too. However, such reviews/analyses of accumulated data were not necessarily planned at the stage of planning clinical trial and the methods used were not necessarily compliant with clinical trial process. The Bayesian approach commonly used in adaptive designs was developed by Thomas Bayes in the 18th century, about hundred years prior to the development of modern statistical methods by the father of modern statistics, Sir Ronald A. Fisher, but the complexity involved in Bayesian approach prevented its use in real life practice. The advances in the field of computer and information technology over the last three to four decades has changed the scenario and the Bayesian techniques are being used in adaptive designs in addition to other sequential methods used in IA. This paper attempts to describe the various adaptive designs in clinical trial and views of stakeholders about feasibility of using them, without going into mathematical complexities.
In addition to the expensive and lengthy process of developing a new medicine, the attrition rate in clinical research was on the rise, resulting in stagnation in the development of new compounds. As a consequence to this, the US Food and Drug Administration released a critical path initiative document in 2004, highlighting the need for developing innovative trial designs. One of the innovations suggested the use of adaptive designs for clinical trials. Thus, post critical path initiative, there is a growing interest in using adaptive designs for the development of pharmaceutical products. Adaptive designs are expected to have great potential to reduce the number of patients and duration of trial and to have relatively less exposure to new drug. Adaptive designs are not new in the sense that the task of interim analysis (IA)/review of the accumulated data used in adaptive designs existed in the past too. However, such reviews/analyses of accumulated data were not necessarily planned at the stage of planning clinical trial and the methods used were not necessarily compliant with clinical trial process. The Bayesian approach commonly used in adaptive designs was developed by Thomas Bayes in the 18th century, about hundred years prior to the development of modern statistical methods by the father of modern statistics, Sir Ronald A. Fisher, but the complexity involved in Bayesian approach prevented its use in real life practice. The advances in the field of computer and information technology over the last three to four decades has changed the scenario and the Bayesian techniques are being used in adaptive designs in addition to other sequential methods used in IA. This paper attempts to describe the various adaptive designs in clinical trial and views of stakeholders about feasibility of using them, without going into mathematical complexities.
Nyunt, Myat Htut; Soe, Myat Thu; Myint, Hla Win; Oo, Htet Wai; Aye, Moe Moe; Han, Soe Soe; Zaw, Ni Ni; Cho, Cho; Aung, Phyo Zaw; Kyaw, Khin Thiri; Aye, Thin Thin; San, Naychi Aung; Ortega, Leonard; Thimasarn, Krongthong; Bustos, Maria Dorina G; Galit, Sherwin; Hoque, Mohammad Rafiul; Ringwald, Pascal; Han, Eun-Taek; Kyaw, Myat Phone
Emergence of artemisinin-resistant malaria in Southeast Asian countries threatens the global control of malaria. Although K13 kelch propeller has been assessed for artemisinin resistance molecular marker, most of the mutations need to be validated. In this study, artemisinin resistance was assessed by clinical and molecular analysis, including k13 and recently reported markers, pfarps10, pffd and pfmdr2. A prospective cohort study in 1160 uncomplicated falciparum patients was conducted after treatment with artemisinin-based combination therapy (ACT), in 6 sentinel sites in Myanmar from 2009 to 2013. Therapeutic efficacy of ACT was assessed by longitudinal follow ups. Molecular markers analysis was done on all available day 0 samples. True recrudescence treatment failures cases and day 3 parasite positivity were detected at only the southern Myanmar sites. Day 3 positive and k13 mutants with higher prevalence of underlying genetic foci predisposing to become k13 mutant were detected only in southern Myanmar since 2009 and comparatively fewer mutations of pfarps10, pffd, and pfmdr2 were observed in western Myanmar. K13 mutations, V127M of pfarps10, D193Y of pffd, and T448I of pfmdr2 were significantly associated with day 3 positivity (OR: 6.48, 3.88, 2.88, and 2.52, respectively). Apart from k13, pfarps10, pffd and pfmdr2 are also useful for molecular surveillance of artemisinin resistance especially where k13 mutation has not been reported. Appropriate action to eliminate the resistant parasites and surveillance on artemisinin resistance should be strengthened in Myanmar. Trial registration This study was registered with ClinicalTrials.gov, identifier NCT02792816.
Crompton, Peter D; Pierce, Susan K; Miller, Louis H
Malaria caused by Plasmodium falciparum remains a major public health threat, especially among children and pregnant women in Africa. An effective malaria vaccine would be a valuable tool to reduce the disease burden and could contribute to elimination of malaria in some regions of the world. Current malaria vaccine candidates are directed against human and mosquito stages of the parasite life cycle, but thus far, relatively few proteins have been studied for potential vaccine development. The most advanced vaccine candidate, RTS,S, conferred partial protection against malaria in phase II clinical trials and is currently being evaluated in a phase III trial in Africa. New vaccine targets need to be identified to improve the chances of developing a highly effective malaria vaccine. A better understanding of the mechanisms of naturally acquired immunity to malaria may lead to insights for vaccine development.
Plasmodium falciparum malaria in pregnancy: prevalence of peripheral parasitaemia, anaemia and malaria care-seeking behaviour among pregnant women attending two antenatal clinics in Edo State, Nigeria
Enato, E. F. O.; Mens, P. F.; Okhamafe, A. O.; Okpere, E. E.; Pogoson, E.; Schallig, H. D. F. H.
SUMMARY: This study evaluated malaria care-seeking behaviour, as well as the prevalence of parasitaemia and anaemia among pregnant women attending antenatal clinics of two tertiary healthcare facilities in Edo State, Nigeria. Malaria was highly prevalent in the study group (20% by microscopy and
Chan, C. M. C.; Scheinman, J. I.; Roth, K. S.
As the powerful tools of molecular biology continue to delineate new concepts of pathogenesis of diseases, new molecular-level therapeutic modalities are certain to emerge. In order to design and execute clinical trials to evaluate outcomes of these new treatment modalities, we will soon need a new supply of investigators with training and experience in clinical research. The slowly-progressive nature of chronic pediatric kidney disease often results in diagnosis being made at a time remote from initial result, and the inherently slow rate of progression makes changes difficult to measure. Thus, development of molecular markers for both diagnosis and rate of progression will be critical to studies of new therapeutic modalities. We will review general aspects of clinical trials and will use current and past studies as examples to illustrate specific points, especially as these apply to chronic kidney disease associated with obstructive uropathy in children. (author)
Mbonye, Anthony K; Magnussen, Pascal; Chandler, Clare I R; Hansen, Kristian S; Lal, Sham; Cundill, Bonnie; Lynch, Caroline A; Clarke, Siân E
An intervention was designed to introduce rapid diagnostics tests for malaria (mRDTs) into registered drug shops in Uganda to encourage rational and appropriate treatment of malaria with artemisinin-based combination therapy (ACT). We conducted participatory training of drug shop vendors and implemented supporting interventions to orientate local communities (patients) and the public sector (health facility staff and district officials) to the behavioral changes in diagnosis, treatment and referral being introduced in drug shops. The intervention was designed to be evaluated through a cluster randomized trial. In this paper, we present detailed design, implementation and evaluation experiences in order to help inform future studies of a complex nature. Three preparatory studies (formative, baseline and willingness-to-pay) were conducted to explore perceptions on diagnosis and treatment of malaria at drug shops, and affordable prices for mRDTs and ACTs in order to inform the design of the intervention and implementation modalities. The intervention required careful design with the intention to be acceptable, sustainable and effective. Critical components of intervention were: community sensitization and creating awareness, training of drug shop vendors to diagnose malaria with mRDTs, treat and refer customers to formal health facilities, giving pre-referral rectal artesunate and improved record-keeping. The primary outcome was the proportion of patients receiving appropriately-targeted treatment with ACT, evaluated against microscopy on a research blood slide. Introducing mRDTs in drug shops may seem simple, but our experience of intervention design, conduct and evaluation showed this to be a complex process requiring multiple interventions and evaluation components drawing from a combination of epidemiological, social science and health economics methodologies. The trial was conducted in phases sequenced such that each benefited from the other. The main challenges
suggest that in an area of moderately high malaria transmission, IST with SP or AS+AQ may be a safe and effective strategy for the control of malaria in pregnancy. However, it is important that these encouraging findings are confirmed in other geographical areas and that the impact of IST on placental malaria is investigated.ClinicalTrials.gov NCT00432367 [NCT00432367].
Simon I Hay
Full Text Available The epidemiology of malaria makes surveillance-based methods of estimating its disease burden problematic. Cartographic approaches have provided alternative malaria burden estimates, but there remains widespread misunderstanding about their derivation and fidelity. The aims of this study are to present a new cartographic technique and its application for deriving global clinical burden estimates of Plasmodium falciparum malaria for 2007, and to compare these estimates and their likely precision with those derived under existing surveillance-based approaches.In seven of the 87 countries endemic for P. falciparum malaria, the health reporting infrastructure was deemed sufficiently rigorous for case reports to be used verbatim. In the remaining countries, the mapped extent of unstable and stable P. falciparum malaria transmission was first determined. Estimates of the plausible incidence range of clinical cases were then calculated within the spatial limits of unstable transmission. A modelled relationship between clinical incidence and prevalence was used, together with new maps of P. falciparum malaria endemicity, to estimate incidence in areas of stable transmission, and geostatistical joint simulation was used to quantify uncertainty in these estimates at national, regional, and global scales. Combining these estimates for all areas of transmission risk resulted in 451 million (95% credible interval 349-552 million clinical cases of P. falciparum malaria in 2007. Almost all of this burden of morbidity occurred in areas of stable transmission. More than half of all estimated P. falciparum clinical cases and associated uncertainty occurred in India, Nigeria, the Democratic Republic of the Congo (DRC, and Myanmar (Burma, where 1.405 billion people are at risk. Recent surveillance-based methods of burden estimation were then reviewed and discrepancies in national estimates explored. When these cartographically derived national estimates were ranked
Asma, Umm-e; Taufiq, Farha; Khan, Wajihullah
Malaria is one of the most widespread infectious diseases of tropical countries with an estimated 207 million cases globally. In India, there are endemic pockets of this disease, including Aligarh. Hundreds of Plasmodium falciparum and P. vivax cases with severe pathological conditions are recorded every year in this district. The aim of this study is to find out changes in liver enzymes and kidney markers. Specific diagnosis for P. falciparum and P. vivax was made by microscopic examination of Giemsa stained slides. Clinical symptoms were observed in both of these infections. Liver enzymes, such as AST, ALT, and ALP, and kidney function markers, such as creatinine and urea, were estimated by standard biochemical techniques. In Aligarh district, P. vivax, P. falciparum, and mixed infections were 64%, 34%, and 2%, respectively. In case of P. falciparum infection, the incidences of anemia, splenomegaly, renal failure, jaundice, and neurological sequelae were higher compared to those in P. vivax infection. Recrudescence and relapse rates were 18% and 20% in P. falciparum and P. vivax infections, respectively. Liver dysfunctions and renal failures were more common in P. falciparum patients, particularly in elderly patients. Artesunate derivatives must, therefore, be introduced for the treatment of P. falciparum as they resist to chloroquine as well as sulfadoxine-pyrimethamine combinations.
A randomized open label clinical trial to compare the efficacy and safety of intravenous quinine followed by oral malarone vs. intravenous quinine followed by oral quinine in the treatment of severe malaria.
Esamai, F; Tenge, C N; Ayuo, P O; Ong'or, W Owino; Obala, A; Jakait, B
The treatment of patients with severe malaria in sub-Saharan Africa has become a challenge to clinicians due to poor compliance to quinine and the increasing multidrug resistance to antimalarials by the P. falciparum parasite. The aim of this study was to compare the efficacy and safety profile of two truncated antimalarial regimens of intravenous quinine followed by oral Malarone (Malarone arm) with intravenous quinine followed by oral quinine (quinine arm) in the treatment of severe P. falciparum malaria. The outcome measures were parasite clearance time, fever clearance time, efficacy, and adverse events profile. Consecutive patients aged 1-60 years, with a diagnosis of severe malaria with positive blood smears for P. falciparum parasites and admitted to the Moi Teaching and Referral Hospital were randomized into the two study arms. Of the 360 patients studied 167 and 193 cases were randomized into the Malarone and quinine arms, respectively. Of the five (1.4 per cent) patients who died, three came from the quinine arm. The frequency of adverse reactions was higher in the oral quinine group (31.6 per cent) than in the Malarone group (25.7 per cent). The mean parasite clearance time was 120 h and 108 h for the quinine and Malarone arms of the study, respectively, and the mean fever clearance times were 84 h and 72 h for the quinine and Malarone arms, respectively (p=0.1). Truncated therapeutic regimen using malarone after intravenous quinine is safer and as effective as conventional intravenous quinine followed by oral quinine in the treatment of severe malaria. The P. falciparum recrudescence rate was lower with the use of Malarone than for quinine.
Bradley, John; Knight, Philip; Stone, William; Osoti, Victor; Makori, Euniah; Owaga, Chrispin; Odongo, Wycliffe; China, Pauline; Shagari, Shehu; Doumbo, Ogobara K.; Sauerwein, Robert W.; Kariuki, Simon; Drakeley, Chris; Stevenson, Jennifer; Cox, Jonathan
-intervention that was statistically significant after adjustment for covariates (p = 0.024), but not 16 wk post-intervention (p = 0.265). We observed no statistically significant trend in the effect of the intervention on nPCR parasite prevalence in the evaluation zone in relation to distance from the hotspot boundary 8 wk (p = 0.27) or 16 wk post-intervention (p = 0.75). Thirty-six patients with clinical malaria confirmed by rapid diagnostic test could be located to intervention or control clusters, with no apparent difference between the study arms. In intervention clusters we caught an average of 1.14 female anophelines inside hotspots and 0.47 in evaluation zones; in control clusters we caught an average of 0.90 female anophelines inside hotspots and 0.50 in evaluation zones, with no apparent difference between study arms. Our trial was not powered to detect subtle effects of hotspot-targeted interventions nor designed to detect effects of interventions over multiple transmission seasons. Conclusions Despite high coverage, the impact of interventions targeting malaria vectors and human infections on nPCR parasite prevalence was modest, transient, and restricted to the targeted hotspot areas. Our findings suggest that transmission may not primarily occur from hotspots to the surrounding areas and that areas with highly heterogeneous but widespread malaria transmission may currently benefit most from an untargeted community-wide approach. Hotspot-targeted approaches may have more validity in settings where human settlement is more nuclear. Trial registration ClinicalTrials.gov NCT01575613 PMID:27071072
Kim, Jane S.; Knickelbein, Jared E.; Nussenblatt, Robert B.; Sen, H. Nida
The treatment of noninfectious uveitis continues to remain a challenge for many ophthalmologists. Historically, clinical trials in uveitis have been sparse, and thus, most treatment decisions have largely been based on clinical experience and consensus guidelines. The current treatment paradigm favors initiation then tapering of corticosteroids with addition of steroid-sparing immunosuppressive agents for persistence or recurrence of disease. Unfortunately, in spite of a multitude of highly unfavorable systemic effects, corticosteroids are still regarded as the mainstay of treatment for many patients with chronic and refractory noninfectious uveitis. However, with the success of other conventional and biologic immunomodulatory agents in treating systemic inflammatory and autoimmune conditions, interest in targeted treatment strategies for uveitis has been renewed. Multiple clinical trials on steroid-sparing immunosuppressive agents, biologic agents, intraocular corticosteroid implants, and topical ophthalmic solutions have already been completed, and many more are ongoing. This review discusses the results and implications of these clinical trials investigating both alternative and novel treatment options for noninfectious uveitis. PMID:26035763
Manoj Ku Mohapatra
Full Text Available Objective: To study the profile of convulsion in adult severe falciparum malaria and efficacy of phenytoin sodium for its control. Methods: It comprised of two sub studies. Study-1 evaluated the pattern and risk factors of seizure in severe malaria and Study-2 investigated the efficacy of phenytoin sodium to control seizure in an open label trial. Patients of severe malaria were diagnosed as per WHO guideline. Clinical type and duration of convulsion were determined. Biochemical and haematological investigations including EEG and CT scan of brain were performed in all cases. All patients were treated with injection artesunate along with other supportive measures and patients with convulsions were treated with injection phenytoin sodium. Results: Out of 408 patients of severe malaria 118 (28.9% patients had seizure. Generalized tonic clonic seizure, partial seizure with secondary generalization, and status epilepticus was present in 89(75.4%, 25(21.2%, and 4(3.4% cases respectively. CT scan was abnormal in 16 (13.6% cases. EEG was abnormal in 108 (91.5% cases showing generalized seizure activity. Patients with convulsion (n=118 were treated with phenytoin sodium injection and convulsion was controlled within 12 hours [mean (6.2依2.1 hours] of treatment in 107 (90.6% patients. Recurrence of seizure occurred in 2 (1.7% patients and 11 (9.3% patients did not respond. The mortality and sequelae were more among patients with than without convulsion. Conclusions: Seizure is common in adult falciparum malaria and phenytoin is an effective drug for seizure control.
Full Text Available Abstract Background In the rural areas of sub-Saharan Africa, the majority of young children affected by malaria have no access to formal health services. Home treatment through mothers of febrile children supported by mother groups and local health workers has the potential to reduce malaria morbidity and mortality. Methods A cluster-randomized controlled effectiveness trial was implemented from 2002–2004 in a malaria endemic area of rural Burkina Faso. Six and seven villages were randomly assigned to the intervention and control arms respectively. Febrile children from intervention villages were treated with chloroquine (CQ by their mothers, supported by local women group leaders. CQ was regularly supplied through a revolving fund from local health centres. The trial was evaluated through two cross-sectional surveys at baseline and after two years of intervention. The primary endpoint of the study was the proportion of moderate to severe anaemia in children aged 6–59 months. For assessment of the development of drug efficacy over time, an in vivo CQ efficacy study was nested into the trial. The study is registered under http://www.controlled-trials.com (ISRCTN 34104704. Results The intervention was shown to be feasible under program conditions and a total of 1.076 children and 999 children were evaluated at baseline and follow-up time points respectively. Self-reported CQ treatment of fever episodes at home as well as referrals to health centres increased over the study period. At follow-up, CQ was detected in the blood of high proportions of intervention and control children. Compared to baseline findings, the prevalence of anaemia (29% vs 16%, p P. falciparum parasitaemia, fever and palpable spleens was lower at follow-up but there were no differences between the intervention and control group. CQ efficacy decreased over the study period but this was not associated with the intervention. Discussion The decreasing prevalence of malaria
Whicher, Danielle M; Miller, Jennifer E; Dunham, Kelly M; Joffe, Steven
To successfully implement a pragmatic clinical trial, investigators need access to numerous resources, including financial support, institutional infrastructure (e.g. clinics, facilities, staff), eligible patients, and patient data. Gatekeepers are people or entities who have the ability to allow or deny access to the resources required to support the conduct of clinical research. Based on this definition, gatekeepers relevant to the US clinical research enterprise include research sponsors, regulatory agencies, payers, health system and other organizational leadership, research team leadership, human research protections programs, advocacy and community groups, and clinicians. This article provides a framework to help guide gatekeepers' decision-making related to the use of resources for pragmatic clinical trials. Relevant ethical considerations for gatekeepers include (1) concern for the interests of individuals, groups, and communities affected by the gatekeepers' decisions, including protection from harm and maximization of benefits; (2) advancement of organizational mission and values; and (3) stewardship of financial, human, and other organizational resources. Separate from these ethical considerations, gatekeepers' actions will be guided by relevant federal, state, and local regulations. This framework also suggests that to further enhance the legitimacy of their decision-making, gatekeepers should adopt transparent processes that engage relevant stakeholders when feasible and appropriate. We apply this framework to the set of gatekeepers responsible for making decisions about resources necessary for pragmatic clinical trials in the United States, describing the relevance of the criteria in different situations and pointing out where conflicts among the criteria and relevant regulations may affect decision-making. Recognition of the complex set of considerations that should inform decision-making will guide gatekeepers in making justifiable choices regarding
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Peter G Kremsner
.m. regimen, showing non-inferiority of the simplified three-dose regimen to the conventional five-dose regimen (95% CI -7, 5; p = 0.02. In the three-dose i.v. arm, 246/333 (74% children had ≥ 99% reduction in parasitemia at 24 h; hence, non-inferiority of this regimen to the five-dose control regimen was not shown (95% CI -12, 1; p = 0.24. Delayed parasite clearance was associated with the N86YPfmdr1 genotype. In a post hoc analysis, 192/885 (22% children developed delayed anemia, an adverse event associated with increased leukocyte counts. There was no observed difference in delayed anemia between treatment arms. A potential limitation of the study is its open-label design, although the primary outcome measures were assessed in a blinded manner.A simplified three-dose i.m. regimen for severe malaria in African children is non-inferior to the more complex WHO-recommended regimen. Parenteral ARS is associated with a risk of delayed anemia in African children.Pan African Clinical Trials Registry PACTR201102000277177.
Full Text Available Abstract Background The accuracy of malaria case reporting is challenging due to restricted human and material resources in many countries. The reporting often depends on the clinical diagnosis because of the scarcity of microscopic examinations. Particularly, clinical malaria case reporting by primary health care facilities (local clinics, which constitutes the baseline data of surveillance, has never previously been sufficiently evaluated. In order to improve the malaria reporting system to the level required to eventually eliminate this disease, this study estimates the gaps between the records of clinics and government statistics regarding the incidence of clinical malaria, and then also examines some factors that might explain the data discrepancy, including such variables as clinic staffing and record keeping. Methods All medical records for outpatients in 2007, handwritten by nurses, were collected from local clinics in Honiara, the capital of the Solomon Islands. The all-monthly clinical malaria cases were then recalculated. The corresponding monthly data in official statistics were provided by the government. Next, in order to estimate any data discrepancy, the ratio of the cases recorded at clinics to the cases reported to the government was determined on the monthly basis. Finally, the associations between the monthly discrepancy and other variables were evaluated by a multiple regression analysis. Results The mean data discrepancy between the records of clinics and government statistics was 21.2% (n = 96. Significant associations were observed between the discrepancy and the average number of patients (coefficient: 0.05, 95%CI: 0.31, 0.07, illegible handwriting (coefficient: 0.09, 95%CI: 0.04, 0.15, the use of tally sheets (coefficient:-0.38, 95%CI: -0.54, -0.22, and the clinic level (coefficient:-0.48, 95%CI:-0.89,-0.06. Conclusion The findings of this study demonstrate the huge data discrepancy between the records of clinics and
Madhubhai M. Patel
Full Text Available Malaria is endemic in Gujarat and the adjoining areas like many other parts of theIndia. Depending upon the environmental conditions different species of malarial parasiteare found in different areas. The present study was planned to see the pattern of malarialinfection diagnosed at B.J. Desai Trust Hospital, Kheda, Gujarat. Methods: Giemsastained thick and thin blood films of indoor and outdoor febrile patients sent to thelaboratory of B.J. Desai Trust Hospital, Kheda, Gujarat with a suspicion of malaria, wereexamined. Thick film was examined for the diagnosis of malaria while thin films wereseen to know the species. Results: Out of 1994 patients screened, 145 (7.2% were foundinfected. Plasmodium vivax was seen in the majority (72.47.2%. Plasmodium falciparumwas the second common species detected in 24.1 % cases. Mixed infection was seen in3.44% cases while Plasmodium malariae and ovale was not seen in any patient.Conclusion: Plasmodium vivax was the commonest type of malaria diagnosed at KhedaDistrict in Gujarat, during 2008- 2009.
The recovery of the patient should be facilitated as the result of therapeutic research. The basic rule for every therapeutic-clinical trial mist involve a comparison of therapeutic approaches. In acute conditions, such as acute infectious diseases, infarcts, etc., comparisons should be made between two or more groups: the collective therapeutic comparison = the between patients trial. The formation of groups, to be compared one with the other can be justified only if one is reasonably sure that a pathogenic condition indeed exists. In chronic diseases, which extend essentially unchanged over a lengthy period but are nevertheless reversible, therapeutic comparisons may be made between two or more time intervals within the course of the disease in the same individual. This type of therapeutic trial rests primarily upon a (refined!) type of specious reasoning and secondarily, upon modified statistics: the individual therapeutic comparison = the within patient trial. The collective therapeutic comparison, on the one hand, and the individual therapeutic comparison on the other, overlap somewhat in scope. The immediate therapeutic effect is not always an indication of its true value, which may become evident only upon long-term treatment. The short-term trials of therapeutic regimens in an individual must, therefore, be frequently supplemented by long-term trials which can only be carried out by comparing two groups. For many clinical investigations, therefore, the joint efforts of numerous hospitals are absolutely necessary. The second basic rule of therapeutic research is the elimination of secondary causes. The difficulties introduced by these secondary considerations are far greater in therapeutic trials carried out on ambulatory patients than has been hitherto realized. In order to remove subjective secondary causes, the author demanded, in 1931, the use of hidden or illusory media (placebos, dummies) that is, unconscious causative agents. The double blind
Accrual to cancer clinical trials (CCT) is imperative to safeguard continued improvement in cancer outcomes. A retrospective chart review was performed of patients (n=140) starting a new anti-cancer agent in a north Dublin cancer centre. This review was performed over a four-month period, beginning in November 2015. Only 29% (n=41) had a CCT option. The overall accrual rate to CCT was 5% (n=7), which is comparable to internationally reported figures. The main reasons for failure to recruit to CCT included the lack of a CCT option for cancer type (n=30, 23%), stage (n=25, 19%), and line of treatment (n=23, 17%). Over the last decade, the rate of accrual to CCTs has in fact doubled and the number of trials open to recruitment has tripled. Ongoing governmental and philanthropic support is necessary to continue this trend to further expand CCT patient options with a target accrual rate of 10%.
Patrick Georges Cech
Full Text Available This trial was conducted to evaluate the safety and immunogenicity of two virosome formulated malaria peptidomimetics derived from Plasmodium falciparum AMA-1 and CSP in malaria semi-immune adults and children.The design was a prospective randomized, double-blind, controlled, age-deescalating study with two immunizations. 10 adults and 40 children (aged 5-9 years living in a malaria endemic area were immunized with PEV3B or virosomal influenza vaccine Inflexal®V on day 0 and 90.No serious or severe adverse events (AEs related to the vaccines were observed. The only local solicited AE reported was pain at injection site, which affected more children in the Inflexal®V group compared to the PEV3B group (p = 0.014. In the PEV3B group, IgG ELISA endpoint titers specific for the AMA-1 and CSP peptide antigens were significantly higher for most time points compared to the Inflexal®V control group. Across all time points after first immunization the average ratio of endpoint titers to baseline values in PEV3B subjects ranged from 4 to 15 in adults and from 4 to 66 in children. As an exploratory outcome, we found that the incidence rate of clinical malaria episodes in children vaccinees was half the rate of the control children between study days 30 and 365 (0.0035 episodes per day at risk for PEV3B vs. 0.0069 for Inflexal®V; RR = 0.50 [95%-CI: 0.29-0.88], p = 0.02.These findings provide a strong basis for the further development of multivalent virosomal malaria peptide vaccines.ClinicalTrials.gov NCT00513669.
Ng'ang'a Zipporah W
Full Text Available Abstract Background The effects of Plasmodium falciparum on B-cell homeostasis have not been well characterized. This study investigated whether an episode of acute malaria in young children results in changes in the peripheral B cell phenotype. Methods Using flow-cytofluorimetric analysis, the B cell phenotypes found in the peripheral blood of children aged 2–5 years were characterized during an episode of acute uncomplicated clinical malaria and four weeks post-recovery and in healthy age-matched controls. Results There was a significant decrease in CD19+ B lymphocytes during acute malaria. Characterization of the CD19+ B cell subsets in the peripheral blood based on expression of IgD and CD38 revealed a significant decrease in the numbers of naive 1 CD38-IgD+ B cells while there was an increase in CD38+IgD- memory 3 B cells during acute malaria. Further analysis of the peripheral B cell phenotype also identified an expansion of transitional CD10+CD19+ B cells in children following an episode of acute malaria with up to 25% of total CD19+ B cell pool residing in this subset. Conclusion Children experiencing an episode of acute uncomplicated clinical malaria experienced profound disturbances in B cell homeostasis.
Kangoye, David Tiga; Noor, Abdisalan; Midega, Janet; Mwongeli, Joyce; Mkabili, Dora; Mogeni, Polycarp; Kerubo, Christine; Akoo, Pauline; Mwangangi, Joseph; Drakeley, Chris; Marsh, Kevin; Bejon, Philip; Njuguna, Patricia
Targeted malaria control interventions are expected to be cost-effective. Clinical, parasitological and serological markers of malaria transmission have been used to detect malaria transmission hotspots, but few studies have examined the relationship between the different potential markers in low transmission areas. The present study reports on the relationships between clinical, parasitological, serological and entomological markers of malaria transmission in an area of low transmission intensity in Coastal Kenya. Longitudinal data collected from 831 children aged 5-17 months, cross-sectional survey data from 800 older children and adults, and entomological survey data collected in Ganze on the Kenyan Coast were used in the present study. The spatial scan statistic test used to detect malaria transmission hotspots was based on incidence of clinical malaria episodes, prevalence of asymptomatic asexual parasites carriage detected by microscopy and polymerase chain reaction (PCR), seroprevalence of antibodies to two Plasmodium falciparum merozoite antigens (AMA1 and MSP1-19) and densities of Anopheles mosquitoes in CDC light-trap catches. There was considerable overlapping of hotspots by these different markers, but only weak to moderate correlation between parasitological and serological markers. PCR prevalence and seroprevalence of antibodies to AMA1 or MSP1-19 appeared to be more sensitive markers of hotspots at very low transmission intensity. These findings may support the choice of either serology or PCR as markers in the detection of malaria transmission hotspots for targeted interventions.
Heppner, D.G.; Schwenk, R.J.; Arnot, D.; Sauerwein, R.W.; Luty, A.J.F.
To date, the only pre-blood stage vaccine to confer protection against malaria in field trials elicits both antigen-specific antibody and T-cell responses. Recent clinical trials of new heterologous prime-boost malaria vaccine regimens using DNA, fowlpox or MVA, have chiefly elicited T-cell
Clinical trials now increasingly impinge on society at large. First there is growing emphasis from health organizations on the need for unbiased evidence about the effectiveness of promoted remedies. Second, as most novel treatments accrue increased costs to society, these need to be evaluated in terms of value for money. Third, there has been confusion and concern about the resolution of conflicting evidence, especially the role of advertising and commercial pressures from a powerful pharmaceutical industry motivated by profit. Fourth, there is concern about research fraud and the ethics of clinical trials. Fifth, there is increasing suspicion of political advice, which sometimes has sought to reassure an anxious public on the basis of complex and possibly inadequate scientific information. Some of these issues are addressed by truly independent and properly constituted data and safety monitoring committees, which are of particular importance when academic investigators or universities have a large financial conflict of interest. This is now more problematic with the current encouragement of investigator-led spin-off companies. These issues are best resolved by independent financial support (from government or other institutions) rather than relying on the commercial sponsor.
Followill, David S.; Urie, Marcia; Galvin, James M.; Ulin, Kenneth; Xiao, Ying; FitzGerald, Thomas J.
The National Cancer Institute (NCI) clinical cooperative groups have been instrumental over the past 50 years in developing clinical trials and evidence-based clinical trial processes for improvements in patient care. The cooperative groups are undergoing a transformation process to launch, conduct, and publish clinical trials more rapidly. Institutional participation in clinical trials can be made more efficient and include the expansion of relationships with international partners. This paper reviews the current processes that are in use in radiation therapy trials and the importance of maintaining effective credentialing strategies to assure the quality of the outcomes of clinical trials. The paper offers strategies to streamline and harmonize credentialing tools and processes moving forward as the NCI undergoes transformative change in the conduct of clinical trials.
Followill, David S. [Radiological Physics Center, Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, TX (United States); Urie, Marcia [Quality Assurance Review Center, Department of Radiation Oncology, University of Massachusetts Medical School, Lincoln, RI (United States); Galvin, James M. [Department of Radiation Oncology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA (United States); Radiation Therapy Oncology Group, Philadelphia, PA (United States); Ulin, Kenneth [Quality Assurance Review Center, Department of Radiation Oncology, University of Massachusetts Medical School, Lincoln, RI (United States); Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, MA (United States); Xiao, Ying [Department of Radiation Oncology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA (United States); Radiation Therapy Oncology Group, Philadelphia, PA (United States); FitzGerald, Thomas J., E-mail: firstname.lastname@example.org [Quality Assurance Review Center, Department of Radiation Oncology, University of Massachusetts Medical School, Lincoln, RI (United States); Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, MA (United States)
The National Cancer Institute (NCI) clinical cooperative groups have been instrumental over the past 50 years in developing clinical trials and evidence-based clinical trial processes for improvements in patient care. The cooperative groups are undergoing a transformation process to launch, conduct, and publish clinical trials more rapidly. Institutional participation in clinical trials can be made more efficient and include the expansion of relationships with international partners. This paper reviews the current processes that are in use in radiation therapy trials and the importance of maintaining effective credentialing strategies to assure the quality of the outcomes of clinical trials. The paper offers strategies to streamline and harmonize credentialing tools and processes moving forward as the NCI undergoes transformative change in the conduct of clinical trials.
admitted children with severe malaria there is a need for health providers to deploy strategic management of fatal prognostic factors. In conclusion ..... Umulisa, N., Uwimana, A., Mokuolu, O.A., Adedoyin, O.T., Johnson, W.B.R.,. Tshefu, A.K. ...
Maude, Richard J; Nguon, Chea; Ly, Po; Bunkea, Tol; Ngor, Pengby; Canavati de la Torre, Sara E; White, Nicholas J; Dondorp, Arjen M; Day, Nicholas P J; White, Lisa J; Chuor, Char Meng
Artemisinin-resistant Plasmodium falciparum malaria has recently been identified on the Thailand-Cambodia border and more recently in parts of Thailand, Myanmar and Vietnam. There is concern that if this resistance were to spread, it would severely hamper malaria control and elimination efforts worldwide. Efforts are currently underway to intensify malaria control activities and ultimately eliminate malaria from Cambodia. To support these efforts, it is crucial to have a detailed picture of disease burden and its major determinants over time. An analysis of spatial and temporal data on clinical malaria in Cambodia collected by the National Centre for Parasitology, Entomology and Malaria Control (CNM) and the Department of Planning and Health Information, Ministry of Health Cambodia from 2004 to 2013 is presented. There has been a marked decrease of 81% in annual cases due to P. falciparum since 2009 coinciding with a rapid scale-up in village malaria workers (VMWs) and insecticide-treated bed nets (ITNs). Concurrently, the number of cases with Plasmodium vivax has greatly increased. It is estimated that there were around 112,000 total cases in 2012, 2.8 times greater than the WHO estimate for that year, and 68,000 in 2013 (an annual parasite incidence (API) of 4.6/1000). With the scale-up of VMWs, numbers of patients presenting to government facilities did not fall and it appears likely that those who saw VMWs had previously accessed healthcare in the private sector. Malaria mortality has decreased, particularly in areas with VMWs. There has been a marked decrease in cases in parts of western Cambodia, especially in Pailin and Battambang Provinces. In the northeast, the fall in malaria burden has been more modest, this area having the highest API in 2013. The clinical burden of falciparum malaria in most areas of Cambodia has greatly decreased from 2009 to 2013, associated with roll-out of ITNs and VMWs. Numbers of cases with P. vivax have increased. Possible
Cassese, Mariarita; Zuber, Veronica
Women use more medicines than men because they fall ill more often and suffer more from chronic diseases, but also because women pay more attention to their health and have more consciousness and care about themselves. Although medicines can have different effects on women and men, women still represent a small percentage in the first phases of trials (22%) which are essential to verify drugs dosage, side effects, and safety. Even though women are more present in trials, studies results are not presented with a gender approach. This situation is due to educational, social, ethical and economical factors. The scientific research must increase feminine presence in clinical trials in order to be equal and correct, and all the key stakeholder should be involved in this process. We still have a long way to cover and it doesn't concern only women but also children and old people. The aim is to have a medicine not only illness-focused but patient-focused: a medicine able to take into consideration all the patient characteristics and so to produce a really personalized therapy. What above described is part of the reasons why in 2005 was founded the National Observatory for Women's Health (Osservatorio Nazionale sulla Salute della Donna, ONDa) which promotes a gender health awareness and culture in Italy, at all the levels of the civil and scientific society.
Full Text Available Women use more medicines than men because they fall ill more often and suffer more from chronic diseases, but also because women pay more attention to their health and have more consciousness and care about themselves. Although medicines can have different effects on women and men, women still represent a small percentage in the first phases of trials (22% which are essential to verify drugs dosage, side effects, and safety. Even though women are more present in trials, studies results are not presented with a gender approach. This situation is due to educational, social, ethical and economical factors. The scientific research must increase feminine presence in clinical trials in order to be equal and correct, and all the key stakeholder should be involved in this process. We still have a long way to cover and it doesn't concern only women but also children and old people. The aim is to have a medicine not only illness-focused but patient-focused: a medicine able to take into consideration all the patient characteristics and so to produce a really personalized therapy. What above described is part of the reasons why in 2005 was founded the National Observatory for Women's Health (Osservatorio Nazionale sulla Salute della Donna, ONDa which promotes a gender health awareness and culture in Italy, at all the levels of the civil and scientific society.
Full Text Available Pfs25 and Pvs25, surface proteins of mosquito stage of the malaria parasites P. falciparum and P. vivax, respectively, are leading candidates for vaccines preventing malaria transmission by mosquitoes. This single blinded, dose escalating, controlled Phase 1 study assessed the safety and immunogenicity of recombinant Pfs25 and Pvs25 formulated with Montanide ISA 51, a water-in-oil emulsion.The trial was conducted at The Johns Hopkins Center for Immunization Research, Washington DC, USA, between May 16, 2005-April 30, 2007. The trial was designed to enroll 72 healthy male and non-pregnant female volunteers into 1 group to receive adjuvant control and 6 groups to receive escalating doses of the vaccines. Due to unexpected reactogenicity, the vaccination was halted and only 36 volunteers were enrolled into 4 groups: 3 groups of 10 volunteers each were immunized with 5 microg of Pfs25/ISA 51, 5 microg of Pvs25/ISA 51, or 20 microg of Pvs25/ISA 51, respectively. A fourth group of 6 volunteers received adjuvant control (PBS/ISA 51. Frequent local reactogenicity was observed. Systemic adverse events included two cases of erythema nodosum considered to be probably related to the combination of the antigen and the adjuvant. Significant antibody responses were detected in volunteers who completed the lowest scheduled doses of Pfs25/ISA 51. Serum anti-Pfs25 levels correlated with transmission blocking activity.It is feasible to induce transmission blocking immunity in humans using the Pfs25/ISA 51 vaccine, but these vaccines are unexpectedly reactogenic for further development. This is the first report that the formulation is associated with systemic adverse events including erythema nodosum.ClinicalTrials.gov NCT00295581.
Gustafsson, Finn; Atar, Dan; Pitt, Bertram
Trialists have an ethical and financial responsibility to plan and conduct clinical trials in a manner that will maximize the scientific knowledge gained from the trial. However, the amount of scientific information generated by randomized clinical trials in cardiovascular medicine is highly vari...
Abanyie Francisca A
Full Text Available Abstract Background The diagnosis of malaria can be difficult in non-endemic areas, such as the United States, and delays in diagnosis and errors in treatment occur too often. Methods A nationwide survey of laboratories in the United States and its nine dependent territories was conducted in 2010 to determine factors that may contribute to shortcomings in the diagnosis of malaria. This survey explored the availability of malaria diagnostic tests, techniques used, and reporting practices. Results The survey was completed by 201 participants. Ninety percent reported that their laboratories had at least one type of malaria diagnostic test available on-site. Nearly all of the respondents' laboratories performed thick and thin smears on-site; approximately 50% had access to molecular testing; and only 17% had access to rapid diagnostic tests on-site. Seventy-three percent reported fewer than five confirmed cases of malaria in their laboratory during the 12-month period preceding the survey. Twenty-eight percent stated that results of species identification took more than 24 hours to report. Only five of 149 respondents that performed testing 24 hours a day, 7 days a week complied with all of the Clinical and Laboratory Standards Institute (CLSI guidelines for analysis and reporting of results. Conclusion Although malaria diagnostic testing services were available to a majority of U.S. laboratories surveyed, very few were in complete compliance with all of the CLSI guidelines for analysis and reporting of results, and most respondents reported very few cases of malaria annually. Laboratories' difficulty in adhering to the rigorous CLSI guidelines and their personnel's lack of practice and proficiency may account for delays and errors in diagnosis. It is recommended that laboratories that infrequently process samples for malaria seek opportunities for practice and proficiency training annually and take advantage of available resources to assist in
Matthew B Laurens
Full Text Available The FMP2.1/AS02A candidate malaria vaccine was tested in a Phase 2 study in Mali. Based on results from the first eight months of follow-up, the vaccine appeared well-tolerated and immunogenic. It had no significant efficacy based on the primary endpoint, clinical malaria, but marginal efficacy against clinical malaria in secondary analyses, and high allele-specific efficacy. Extended follow-up was conducted to evaluate extended safety, immunogenicity and efficacy.A randomized, double-blinded trial of safety, immunogenicity and efficacy of the candidate Plasmodium falciparum apical membrane antigen 1 (AMA1 vaccine FMP2.1/AS02A was conducted in Bandiagara, Mali. Children aged 1-6 years were randomized in a 1∶1 ratio to receive FMP2.1/AS02A or control rabies vaccine on days 0, 30 and 60. Using active and passive surveillance, clinical malaria and adverse events as well as antibodies against P. falciparum AMA1 were monitored for 24 months after the first vaccination, spanning two malaria seasons.400 children were enrolled. Serious adverse events occurred in nine participants in the FMP2.1/AS02A group and three in the control group; none was considered related to study vaccination. After two years, anti-AMA1 immune responses remained significantly higher in the FMP2.1/AS02A group than in the control group. For the entire 24-month follow-up period, vaccine efficacy was 7.6% (p = 0.51 against first clinical malaria episodes and 9.9% (p = 0.19 against all malaria episodes. For the final 16-month follow-up period, vaccine efficacy was 0.9% (p = 0.98 against all malaria episodes. Allele-specific efficacy seen in the first malaria season did not extend into the second season of follow-up.Allele-specific vaccine efficacy was not sustained in the second malaria season, despite continued high levels of anti-AMA1 antibodies. This study presents an opportunity to evaluate correlates of partial protection against clinical malaria that waned during
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Staedke, Sarah G; Maiteki-Sebuguzi, Catherine; Rehman, Andrea M; Kigozi, Simon P; Gonahasa, Samuel; Okiring, Jaffer; Lindsay, Steve W; Kamya, Moses R; Chandler, Clare I R; Dorsey, Grant; Drakeley, Chris
Intermittent preventive treatment (IPT) is a well established malaria control intervention. Evidence that delivering IPT to schoolchildren could provide community-level benefits is limited. We did a cluster-randomised controlled trial to assess the effect of IPT of primary schoolchildren with dihydroartemisinin-piperaquine (DP) on indicators of malaria transmission in the community, in Jinja, Uganda. We included 84 clusters, each comprising one primary school and the 100 closest available households. The clusters were randomly assigned 1:1 to receive IPT with DP or standard care (control) by restricted randomisation to ensure balance by geography and school type. Children in intervention schools received IPT monthly for up to six rounds (June to December, 2014). We did cross-sectional community surveys in randomly selected households at baseline and in January to April, 2015, during which we measured participants' temperatures and obtained finger-prick blood smears for measurement of parasite prevalence by microscopy. We also did entomological surveys 1 night per month in households from 20 randomly selected IPT and 20 control clusters. The primary trial outcome was parasite prevalence in the final community survey. The primary entomological survey outcome was the annual entomological inoculation rate (aEIR) from July, 2014, to April, 2015. This trial is registered at ClinicalTrials.gov, number NCT02009215. Among 23 280 students registered in the 42 intervention schools, 10 079 (43%) aged 5-20 years were enrolled and received at least one dose of DP. 9286 (92%) of 10 079 received at least one full course of DP (three doses). Community-level parasite prevalence was lower in the intervention clusters than in the control clusters (19% vs 23%, adjusted risk ratio 0·85, 95% CI 0·73-1·00, p=0·05). The aEIR was lower in the intervention group than in the control group, but not significantly so (10·1 vs 15·2 infective bites per person, adjusted incidence rate
Samuels, Aaron M; Awino, Nobert; Odongo, Wycliffe; Abong'o, Benard; Gimnig, John; Otieno, Kephas; Shi, Ya Ping; Were, Vincent; Allen, Denise Roth; Were, Florence; Sang, Tony; Obor, David; Williamson, John; Hamel, Mary J; Patrick Kachur, S; Slutsker, Laurence; Lindblade, Kim A; Kariuki, Simon; Desai, Meghna
Most human Plasmodium infections in western Kenya are asymptomatic and are believed to contribute importantly to malaria transmission. Elimination of asymptomatic infections requires active treatment approaches, such as mass testing and treatment (MTaT) or mass drug administration (MDA), as infected persons do not seek care for their infection. Evaluations of community-based approaches that are designed to reduce malaria transmission require careful attention to study design to ensure that important effects can be measured accurately. This manuscript describes the study design and methodology of a cluster-randomized controlled trial to evaluate a MTaT approach for malaria transmission reduction in an area of high malaria transmission. Ten health facilities in western Kenya were purposively selected for inclusion. The communities within 3 km of each health facility were divided into three clusters of approximately equal population size. Two clusters around each health facility were randomly assigned to the control arm, and one to the intervention arm. Three times per year for 2 years, after the long and short rains, and again before the long rains, teams of community health volunteers visited every household within the intervention arm, tested all consenting individuals with malaria rapid diagnostic tests, and treated all positive individuals with an effective anti-malarial. The effect of mass testing and treatment on malaria transmission was measured through population-based longitudinal cohorts, outpatient visits for clinical malaria, periodic population-based cross-sectional surveys, and entomological indices.
Full Text Available Intermittent preventive treatment in pregnancy (IPTp with sulfadoxine-pyrimethamine (SP is recommended by WHO to prevent malaria in African pregnant women. The spread of SP parasite resistance has raised concerns regarding long-term use for IPT. Mefloquine (MQ is the most promising of available alternatives to SP based on safety profile, long half-life, and high efficacy in Africa. We evaluated the safety and efficacy of MQ for IPTp compared to those of SP in HIV-negative women.A total of 4,749 pregnant women were enrolled in an open-label randomized clinical trial conducted in Benin, Gabon, Mozambique, and Tanzania comparing two-dose MQ or SP for IPTp and MQ tolerability of two different regimens. The study arms were: (1 SP, (2 single dose MQ (15 mg/kg, and (3 split-dose MQ in the context of long lasting insecticide treated nets. There was no difference on low birth weight prevalence (primary study outcome between groups (360/2,778 [13.0%] for MQ group and 177/1,398 (12.7% for SP group; risk ratio [RR], 1.02 (95% CI 0.86-1.22; p=0.80 in the ITT analysis. Women receiving MQ had reduced risks of parasitemia (63/1,372 [4.6%] in the SP group and 88/2,737 [3.2%] in the MQ group; RR, 0.70 [95% CI 0.51-0.96]; p=0.03 and anemia at delivery (609/1,380 [44.1%] in the SP group and 1,110/2743 [40.5%] in the MQ group; RR, 0.92 [95% CI 0.85-0.99]; p=0.03, and reduced incidence of clinical malaria (96/551.8 malaria episodes person/year [PYAR] in the SP group and 130/1,103.2 episodes PYAR in the MQ group; RR, 0.67 [95% CI 0.52-0.88]; p=0.004 and all-cause outpatient attendances during pregnancy (850/557.8 outpatients visits PYAR in the SP group and 1,480/1,110.1 visits PYAR in the MQ group; RR, 0.86 [0.78-0.95]; p=0.003. There were no differences in the prevalence of placental infection and adverse pregnancy outcomes between groups. Tolerability was poorer in the two MQ groups compared to SP. The most frequently reported related adverse events were dizziness
In the early 17th century, the “Peruvian Bark” or Jesuits Powder” was discovered to be of value in the treatment of certain fevers. The tree was later to be named cinchona from which quinine was extracted in 1820. Such fever was known as the agues in England, in Italy as mal'aria and in France as Palludisme due to their ...
Full Text Available This was a retrospective study done on 110 patients hospitalized with P. vivax malaria in three medical college hospitals, one in the union territory of Chandigarh and the other two in Gujarat, that is, Ahmedabad and Surat. The clinical presentation, treatment, and outcome were recorded. As per WHO criteria for severity, 19 of 110 patients had severe disease—six patients had clinical jaundice with hepatic dysfunction, three patients had severe anemia, three had spontaneous bleeding, two had acute respiratory distress syndrome, and one had cerebral malaria, hyperparasitemia, renal failure, circulatory collapse, and metabolic acidosis. All patients with severe P. vivax malaria survived, but one child with cerebral malaria had neurological sequelae. There was wide variation in the antimalarial treatment received at the three centres. Plasmodium vivax malaria can no longer be considered a benign condition. WHO guidelines for treatment of P. vivax malaria need to be reinforced.
Ali, H.; Mahmood, T.; Ahmed, N.
To determine the impact of percentage parasitemia and clinical features on morbidity and mortality in patients with P. falciparum malaria. Seventy-six adult patients of smear positive P. falciparum malaria were selected for the study. Parasite density was estimated on thin blood film and expressed as percentage of red blood cells parasitized. Patients were divided into three groups on the basis of parasite density. The data was analyzed on SPSS version 12. Results were expressed as percentages, mean and standard deviations. P-value 10%. Comparative analysis of the groups showed that pallor, impaired consciousness, jaundice or malarial hepatitis, thrombocytopenia, acute renal failure, DIC, and mortality were all strongly associated with the density of Plasmodium falciparum malaria (p=0.001). Parasite density was not related to age, gender and hepatosplenomegaly. High parasite density was associated with severe clinical illness, complications and mortality. Parasite counts of > 5% may be considered as hyperparasitaemia in this population of the world. (author)
Ramírez-Olivencia, G; Herrero, M D; Subirats, M; de Juanes, J R; Peña, J M; Puente, S
Few data are available in Spain data on human immunodeficiency virus (HIV) patients coinfected with malaria. This study has aimed to determine the epidemiological and clinical characteristics of imported malaria in patients coinfected with HIV. A case-series retrospective study was performed using the patient's medical records. The study population consisted on patients diagnosed with malaria attended in our center from january 1, 2002 to december 31, 2007. A total of 484 episodes of malaria, 398 of which were included in this study, were identified. Co-infection with HIV was described in 32 cases. All of them occurred in individuals presumably with some degree of semi-immunity. In the coinfected group, there were 13 cases (40.6%) asymptomatic, whereas this event occurred in 99 cases of patients not coinfected (37.2%) (P=0.707). The greater presence of anemia in co-infected patients (62.5% vs 32.3% in non-coinfected [P=0.001]) stands out. In present study, the clinical presentation forms were similar, regardless of the presence or absence of HIV infection. Although the study population does not reflect all possible scenarios of malaria and HIV coinfection, our results indicate the reality of patients attended in the Autonomous Community of Madrid. Copyright © 2011 Elsevier España, S.L. All rights reserved.
Ndyomugyenyi, Richard; Magnussen, Pascal; Lal, Sham
OBJECTIVE: To compare the impact of malaria rapid diagnostic tests (mRDTs), used by community health workers (CHWs), on the proportion of children ...-randomized trials were conducted in two contrasting areas of moderate-to-high and low malaria transmission in rural Uganda. Each trial examined the effectiveness of mRDTs in the management of malaria and targeting of ACTs by CHWs comparing two diagnostic approaches: (i) presumptive clinical diagnosis of malaria...
Gowri, S; Kannan, Sridharan
Evidence-based practice requires clinical trials to be performed. In India, if any clinical trial has to be performed, it has to be registered with clinical trial registry of India. Studies have shown that the report of clinical trials is poor in dentistry. Hence, the present study has been conducted to assess the type and trends of clinical trials being undertaken in dentistry in India over a span of 6 years. All the clinical trials which were registered with the Central Trial Registry of India (CTRI) (www.ctri.nic.in) from January 1, 2007 to March 3, 2014 were evaluated using the keyword "dental." Following information were collected for each of the clinical trials obtained from the search; number of centres (single center/multicentric), type of the institution undertaking the research (government/private/combined), study (observational/interventional), study design (randomized/single blinded/double-blinded), type of health condition, type of participants (healthy/patients), sponsors (academia/commercial), phase of clinical trial (Phase 1/2/3/4), publication details (published/not published), whether it was a postgraduate thesis or not and prospective or retrospective registration of clinical trials, methodological quality (method of randomization, allocation concealment). Descriptive statistics was used for analysis of various categories. Trend analysis was done to assess the changes over a period of time. The search yielded a total of 84 trials of which majority of them were single centered. Considering the study design more than half of the registered clinical trials were double-blinded (47/84 [56%]). With regard to the place of conducting a trial, most of the trials were planned to be performed in private hospitals (56/84 [66.7%]). Most (79/84, 94.1%) of the clinical trials were interventional while only 5/84 (5.9%) were observational. Majority (65/84, 77.4%) of the registered clinical trials were recruiting patients while the rest were being done in healthy
Menya, Diana; Logedi, John; Manji, Imran; Armstrong, Janice; Neelon, Brian; O'Meara, Wendy Prudhomme
In high-resource settings, 'pay-for-performance' (P4P) programs have generated interest as a potential mechanism to improve health service delivery and accountability. However, there has been little or no experimental evidence to guide the development or assess the effectiveness of P4P incentive programs in developing countries. In the developing world, P4P programs are likely to rely, at least initially, on external funding from donors. Under these circumstances, the sustainability of such programs is in doubt and needs assessment. We describe a cluster-randomized controlled trial underway in 18 health centers in western Kenya that is testing an innovative incentive strategy to improve management of an epidemiologically and economically important problem--diagnosis and treatment of malaria. The incentive scheme in this trial promotes adherence to Ministry of Health guidelines for laboratory confirmation of malaria before treatment, a priority area for the Ministry of Health. There are three important innovations that are unique to this study among those from other resource-constrained settings: the behavior being incentivized is quality of care rather than volume of service delivery; the incentives are applied at the facility-level rather than the individual level, thus benefiting facility infrastructure and performance overall; and the incentives are designed to be budget-neutral if effective. Linking appropriate case management for malaria to financial incentives has the potential to improve patient care and reduce wastage of expensive antimalarials. In our study facilities, on average only 25% of reported malaria cases were confirmed by laboratory diagnosis prior to the intervention, and the total treatment courses of antimalarials dispensed did not correspond to the number of cases reported. This study will demonstrate whether facility rather than individual incentives are compelling enough to improve case management, and whether these incentives lead to
Jaki, Thomas; Parry, Alice; Winter, Katherine; Hastings, Ian
There are a variety of methods used to estimate the effectiveness of antimalarial drugs in clinical trials, invariably on a per-person basis. A person, however, may have more than one malaria infection present at the time of treatment. We evaluate currently used methods for analysing malaria trials on a per-individual basis and introduce a novel method to estimate the cure rate on a per-infection (clone) basis. We used simulated and real data to highlight the differences of the various methods. We give special attention to classifying outcomes as cured, recrudescent (infections that never fully cleared) or ambiguous on the basis of genetic markers at three loci. To estimate cure rates on a per-clone basis, we used the genetic information within an individual before treatment to determine the number of clones present. We used the genetic information obtained at the time of treatment failure to classify clones as recrudescence or new infections. On the per-individual level, we find that the most accurate methods of classification label an individual as newly infected if all alleles are different at the beginning and at the time of failure and as a recrudescence if all or some alleles were the same. The most appropriate analysis method is survival analysis or alternatively for complete data/per-protocol analysis a proportion estimate that treats new infections as successes. We show that the analysis of drug effectiveness on a per-clone basis estimates the cure rate accurately and allows more detailed evaluation of the performance of the treatment. Copyright © 2012 John Wiley & Sons, Ltd.
Dijkstra, Boukje A G; De Jong, Cor A J; Wensing, Michel; Krabbe, Paul F M; van der Staak, Cees P F
Controlled clinical trials have high internal validity but suffer from difficulties in external validity. This study evaluates the generalizability of the results of a controlled clinical trial on rapid detoxification in the everyday clinical practice of two addiction treatment centers. The results
Woodrow Charles J
Full Text Available Abstract Background Afghanistan's national guidelines recommend chloroquine for the treatment of Plasmodium vivax infection, the parasite responsible for the majority of its malaria burden. Chloroquine resistance in P. vivax is emerging in Asia. Therapeutic responses across Afghanistan have not been evaluated in detail. Methods Between July 2007 and February 2009, an open-label, randomized controlled trial of chloroquine and dihydroartemisinin-piperaquine in patients aged three months and over with slide-confirmed P. vivax mono-infections was conducted. Consistent with current national guidelines, primaquine was not administered. Subjects were followed up daily during the acute phase of illness (days 0-3 and weekly until day 56. The primary endpoint was the overall cumulative parasitological failure rate at day 56 after the start of treatment, with the hypothesis being that dihydroartemisinin-piperaquine was non-inferior compared to chloroquine (Δ = 5% difference in proportion of failures. Results Of 2,182 individuals with positive blood films for P. vivax, 536 were enrolled in the trial. The day 28 cure rate was 100% in both treatment groups. Parasite clearance was more rapid with dihydroartemisinin-piperaquine than chloroquine. At day 56, there were more recurrent infections in the chloroquine arm (8.9%, 95% CI 6.0-13.1% than the dihydroartemisinin-piperaquine arm (2.8%, 95% CI 1.4-5.8%, a difference in cumulative recurrence rate of 6.1% (2-sided 90%CI +2.6 to +9.7%. The log-rank test comparing the survival curves confirmed the superiority of dihydroartemisinin-piperaquine over chloroquine (p = 0.003. Multivariate analysis showed that a lower initial haemoglobin concentration was also independently associated with recurrence. Both regimens were well tolerated and no serious adverse events were reported. Conclusions Chloroquine remains an efficacious treatment for the treatment of vivax malaria in Afghanistan. In a setting where radical
Cher, Daniel J; Capobianco, Robyn A
Multicenter prospective randomized clinical trials represent the best evidence to support the safety and effectiveness of medical devices. Industry sponsorship of multicenter clinical trials is purported to lead to bias. To determine what proportion of spine device-related trials are industry-sponsored and the effect of industry sponsorship on trial design. Analysis of data from a publicly available clinical trials database. Clinical trials of spine devices registered on ClinicalTrials.gov, a publicly accessible trial database, were evaluated in terms of design, number and location of study centers, and sample size. The relationship between trial design characteristics and study sponsorship was evaluated using logistic regression and general linear models. One thousand six hundred thrity-eight studies were retrieved from ClinicalTrials.gov using the search term "spine." Of the 367 trials that focused on spine surgery, 200 (54.5%) specifically studied devices for spine surgery and 167 (45.5%) focused on other issues related to spine surgery. Compared with nondevice trials, device trials were far more likely to be sponsored by the industry (74% vs. 22.2%, odds ratio (OR) 9.9 [95% confidence interval 6.1-16.3]). Industry-sponsored device trials were more likely multicenter (80% vs. 29%, OR 9.8 [4.8-21.1]) and had approximately four times as many participating study centers (pdevices not sponsored by the industry. Most device-related spine research is industry-sponsored. Multicenter trials are more likely to be industry-sponsored. These findings suggest that previously published studies showing larger effect sizes in industry-sponsored vs. nonindustry-sponsored studies may be biased as a result of failure to take into account the marked differences in design and purpose. Copyright © 2015 Elsevier Inc. All rights reserved.
Gregory E D Mullen
Full Text Available Apical Membrane Antigen 1 (AMA1, a polymorphic merozoite surface protein, is a leading blood-stage malaria vaccine candidate. This is the first reported use in humans of an investigational vaccine, AMA1-C1/Alhydrogel, with the novel adjuvant CPG 7909.A phase 1 trial was conducted at the University of Rochester with 75 malaria-naive volunteers to assess the safety and immunogenicity of the AMA1-C1/Alhydrogel+CPG 7909 malaria vaccine. Participants were sequentially enrolled and randomized within dose escalating cohorts to receive three vaccinations on days 0, 28 and 56 of either 20 microg of AMA1-C1/Alhydrogel+564 microg CPG 7909 (n = 15, 80 microg of AMA1-C1/Alhydrogel (n = 30, or 80 microg of AMA1-C1/Alhydrogel+564 microg CPG 7909 (n = 30.Local and systemic adverse events were significantly more likely to be of higher severity with the addition of CPG 7909. Anti-AMA1 immunoglobulin G (IgG were detected by enzyme-linked immunosorbent assay (ELISA, and the immune sera of volunteers that received 20 microg or 80 microg of AMA1-C1/Alhydrogel+CPG 7909 had up to 14 fold significant increases in anti-AMA1 antibody concentration compared to 80 microg of AMA1-C1/Alhydrogel alone. The addition of CPG 7909 to the AMA1-C1/Alhydrogel vaccine in humans also elicited AMA1 specific immune IgG that significantly and dramatically increased the in vitro growth inhibition of homologous parasites to levels as high as 96% inhibition.The safety profile of the AMA1-C1/Alhydrogel+CPG 7909 malaria vaccine is acceptable, given the significant increase in immunogenicity observed. Further clinical development is ongoing.ClinicalTrials.gov NCT00344539.
Okonta, Patrick I
The conduct of clinical trials for the development and licensing of drugs is a very important aspect of healthcare. Drug research, development and promotion have grown to a multi-billion dollar global business. Like all areas of human endeavour involving generation and control of huge financial resources, it could be subject to deviant behaviour, sharp business practices and unethical practices. The main objective of this review is to highlight potential ethical challenges in the conduct of clinical trials in Nigeria and outline ways in which these can be avoided. Current international and national regulatory and ethical guidelines are reviewed to illustrate the requirements for ethical conduct of clinical trials. Past experiences of unethical conduct of clinical trials especially in developing countries along with the increasing globalisation of research makes it imperative that all players should be aware of the ethical challenges in clinical trials and the benchmarks for ethical conduct of clinical research in Nigeria.
Kateera, Fredrick; Nsobya, Sam L; Tukwasibwe, Stephen; Mens, Petra F; Hakizimana, Emmanuel; Grobusch, Martin P; Mutesa, Leon; Kumar, Nirbhay; van Vugt, Michele
Malaria remains a public health challenge in sub-Saharan Africa with Plasmodium falciparum being the principal cause of malaria disease morbidity and mortality. Plasmodium falciparum virulence is attributed, in part, to its population-level genetic diversity-a characteristic that has yet to be studied in Rwanda. Characterizing P. falciparum molecular epidemiology in an area is needed for a better understand of malaria transmission and to inform choice of malaria control strategies. In this health-facility based survey, malaria case clinical profiles and parasite densities as well as parasite genetic diversity were compared among P. falciparum-infected patients identified at two sites of different malaria transmission intensities in Rwanda. Data on demographics and clinical features and finger-prick blood samples for microscopy and parasite genotyping were collected(.) Nested PCR was used to genotype msp-2 alleles of FC27 and 3D7. Patients' variables of age group, sex, fever (both by patient report and by measured tympanic temperatures), parasite density, and bed net use were found differentially distributed between the higher endemic (Ruhuha) and lower endemic (Mubuga) sites. Overall multiplicity of P. falciparum infection (MOI) was 1.73 but with mean MOI found to vary significantly between 2.13 at Ruhuha and 1.29 at Mubuga (p < 0.0001). At Ruhuha, expected heterozygosity (EH) for FC27 and 3D7 alleles were 0.62 and 0.49, respectively, whilst at Mubuga, EH for FC27 and 3D7 were 0.26 and 0.28, respectively. In this study, a higher geometrical mean parasite counts, more polyclonal infections, higher MOI, and higher allelic frequency were observed at the higher malaria-endemic (Ruhuha) compared to the lower malaria-endemic (Mubuga) area. These differences in malaria risk and MOI should be considered when choosing setting-specific malaria control strategies, assessing p. falciparum associated parameters such as drug resistance, immunity and impact of used
Chirebvu, Elijah; Chimbari, Moses John; Ngwenya, Barbara Ntombi; Sartorius, Benn
Good knowledge on the interactions between climatic variables and malaria can be very useful for predicting outbreaks and preparedness interventions. We investigated clinical malaria transmission patterns and its temporal relationship with climatic variables in Tubu village, Botswana. A 5-year retrospective time series data analysis was conducted to determine the transmission patterns of clinical malaria cases at Tubu Health Post and its relationship with rainfall, flood discharge, flood extent, mean minimum, maximum and average temperatures. Data was obtained from clinical records and respective institutions for the period July 2005 to June 2010, presented graphically and analysed using the Univariate ANOVA and Pearson cross-correlation coefficient tests. Peak malaria season occurred between October and May with the highest cumulative incidence of clinical malaria cases being recorded in February. Most of the cases were individuals aged >5 years. Associations between the incidence of clinical malaria cases and several factors were strong at lag periods of 1 month; rainfall (r = 0.417), mean minimum temperature (r = 0.537), mean average temperature (r = 0.493); and at lag period of 6 months for flood extent (r = 0.467) and zero month for flood discharge (r = 0.497). The effect of mean maximum temperature was strongest at 2-month lag period (r = 0.328). Although malaria transmission patterns varied from year to year the trends were similar to those observed in sub-Saharan Africa. Age group >5 years experienced the greatest burden of clinical malaria probably due to the effects of the national malaria elimination programme. Rainfall, flood discharge and extent, mean minimum and mean average temperatures showed some correlation with the incidence of clinical malaria cases.
Sauboin, Christophe J; Van Bellinghen, Laure-Anne; Van De Velde, Nicolas; Van Vlaenderen, Ilse
Adding malaria vaccination to existing interventions could help to reduce the health burden due to malaria. This study modelled the potential public health impact of the RTS,S candidate malaria vaccine in 42 malaria-endemic countries in sub-Saharan Africa. An individual-based Markov cohort model was constructed with three categories of malaria transmission intensity and six successive malaria immunity levels. The cycle time was 5 days. Vaccination was assumed to reduce the risk of infection, with no other effects. Vaccine efficacy was assumed to wane exponentially over time. Malaria incidence and vaccine efficacy data were taken from a Phase III trial of the RTS,S vaccine with 18 months of follow-up (NCT00866619). The model was calibrated to reproduce the malaria incidence in the control arm of the trial in each transmission category and published age distribution data. Individual-level heterogeneity in malaria exposure and vaccine protection was accounted for. Parameter uncertainty and variability were captured by using stochastic model transitions. The model followed a cohort from birth to 10 years of age without malaria vaccination, or with RTS,S malaria vaccination administered at age 6, 10 and 14 weeks or at age 6, 7-and-a-half and 9 months. Median and 95% confidence intervals were calculated for the number of clinical malaria cases, severe cases, malaria hospitalizations and malaria deaths expected to be averted by each vaccination strategy. Univariate sensitivity analysis was conducted by varying the values of key input parameters. Vaccination assuming the coverage of diphtheria-tetanus-pertussis (DTP3) at age 6, 10 and 14 weeks is estimated to avert over five million clinical malaria cases, 119,000 severe malaria cases, 98,600 malaria hospitalizations and 31,000 malaria deaths in the 42 countries over the 10-year period. Vaccination at age 6, 7-and-a-half and 9 months with 75% of DTP3 coverage is estimated to avert almost 12.5 million clinical malaria cases
clinical efforts that will impact the NEER network going forward and laid the ground work for the CTECs to participate in ongoing clinical trials for...Clinical Implications: • How will the proposed clinical trial have a significant impact on disease outcome? 34 • How will the clinical trial offer...was 0 041U>< for pat<t!nts NPtS and <H08, 0 4 1ux !01 Ct 110, 1nd 10.0 lux f01 < H13 OJ)Ilo •her on~tion are indiuttd AhtrNtor19 stimuli Wl’f1! pres
Asad Mustafa Karim
Full Text Available Military conflict has been a major challenge in the detection and control of emerging infectious diseases such as malaria. It poses issues associated with enhancing emergence and transmission of infectious diseases by destroying infrastructure and collapsing healthcare systems. The Orakzai agency in Pakistan has witnessed a series of intense violence and destruction. Military conflicts and instability in Afghanistan have resulted in the migration of refugees into the area and possible introduction of many infectious disease epidemics. Due to the ongoing violence and Talibanization, it has been a challenge to conduct an epidemiological study.All patients were sampled within the transmission season. After a detailed clinical investigation of patients, data were recorded. Baseline venous blood samples were taken for microscopy and nested polymerase chain reaction (nPCR analysis. Plasmodium species were detected using nested PCR (nPCR and amplification of the small subunit ribosomal ribonucleic acid (ssrRNA genes using the primer pairs. We report a clinical assessment of the epidemic situation of malaria caused by Plasmodium vivax (86.5% and Plasmodium falciparum (11.79% infections with analysis of complications in patients such as decompensated shock (41%, anemia (8.98%, hypoglycaemia (7.3%, multiple convulsions (6.7%, hyperpyrexia (6.17%, jaundice (5%, and hyperparasitaemia (4.49%.This overlooked distribution of P. vivax should be considered by malaria control strategy makers in the world and by the Government of Pakistan. In our study, children were the most susceptible population to malaria infection while they were the least expected to use satisfactory prevention strategies in such a war-torn deprived region. Local health authorities should initiate malaria awareness programs in schools and malaria-related education should be further promoted at the local level reaching out to both children and parents.
Full Text Available Abstract Background New antimalarial regimens, including artemisinin-based combination therapies (ACTs, have been adopted widely as first-line treatment for uncomplicated malaria. Although these drugs appear to be safe and well-tolerated, experience with their use in Africa is limited and continued assessment of safety is a priority. However, no standardized guidelines for evaluating drug safety and tolerability in malaria studies exist. A system for monitoring adverse events in antimalarial trials conducted in Uganda was developed. Here the reporting system is described, and difficulties faced in analysing and interpreting the safety results are illustrated, using data from the trials. Case description Between 2002 and 2007, eleven randomized, controlled clinical trials were conducted to compare the efficacy, safety, and tolerability of different antimalarial regimens for treatment of uncomplicated malaria in Uganda. The approach to adverse event monitoring was similar in all studies. A total of 5,614 treatments were evaluated in 4,876 patients. Differences in baseline characteristics and patterns of adverse event reporting were noted between the sites, which limited the ability to pool and analyse data. Clinical failure following antimalarial treatment confounded associations between treatment and adverse events that were also common symptoms of malaria, particularly in areas of lower transmission intensity. Discussion and evaluation Despite prospectively evaluating for adverse events, limitations in the monitoring system were identified. New standardized guidelines for monitoring safety and tolerability in antimalarial trials are needed, which should address how to detect events of greatest importance, including serious events, those with a causal relationship to the treatment, those which impact on adherence, and events not previously reported. Conclusion Although the World Health Organization has supported the development of
Vidyavathi B Chitharagi
Full Text Available Introduction: Malaria is an endemic vector borne parasitic infection. Plasmodium vivax has been associated with severe malaria while P. falciparum is traditionally associated with severe course. Of late, P. vivax is increasingly reported to cause severe and life threatening disease. However, majority of P. vivax are sensitive to antimalarials and therefore, it is important to speculate this pathogen. Aim: To study the clinical profile of confirmed malaria cases. Materials and Methods: This prospective study was undertaken at SDM College of Medical Sciences and Hospital, Dharwad, Karnataka, India, between the period of 2010 to 2012 for the duration of two years. A total of 124 clinically suspected malaria cases aged from 8 years to 65 years were included in the study. Laboratory identification was done by Quantitative Buffy Coat (QBC. A comparative analysis of clinical presentations in 62 QBC positive samples and an equal number of age and sex matched QBC negative was done. Results: Out of 62 QBC positive samples, Plasmodium vivax was seen in 40/62 (64.52% patients while P. falciparum in 10/40 (16.13% cases. Mixed infection by P. vivax and P. falciparum was seen in 12/40 (19.35% cases. Fever, chills and headache were common symptoms. Pallor was seen in 23/40 (37.1% cases and icterus, splenomegaly and vomiting were seen in 14/62 (22.6% cases followed by hepatosplenomegaly in 11 (17.7% cases. Among QBC negative controls, fever (100%, chills 51/62 (82.3%, rigors 21/62 (33.9% and pain abdomen (24.2 % were the common symptoms. Pallor and hepatomegaly was seen in 19.4 % and 11.3% respectively among the QBC negatives. Ten out of 11 (90.9% of females and 37/51 (72.5% of males suffering from malaria had anaemia. Thrombocytopenia was seen in 59/62 (95.2% cases of which 33 cases had moderate thrombocytopenia (53.2% while 17 cases had severe thrombocytopenia. In QBC negative controls, severe thrombocytopenia was noted in 4 (6.5% samples, mild and moderate
C. A. Caramori
Full Text Available Scientific development that has been achieved through decades finds in clinical research a great possibility of translating findings to human health application. Evidence given by clinical trials allows everyone to have access to the best health services. However, the millionaire world of pharmaceutical industries has stained clinical research with doubt and improbability. Study results (fruits of controlled clinical trials and scientific publications (selective, manipulated and with wrong conclusions led to an inappropriate clinical practice, favoring the involved economic aspect. In 2005, the International Committee of Medical Journal Editors (ICMJE, supported by the World Association of Medical Editors, started demanding as a requisite for publication that all clinical trials be registered at the database ClinicalTrials.gov. In 2006, the World Health Organization (WHO created the International Clinical Trial Registry Platform (ICTRP, which gathers several registry centers from all over the world, and required that all researchers and pharmaceutical industries register clinical trials. Such obligatory registration has progressed and will extend to all scientific journals indexed in all worldwide databases. Registration of clinical trials means another step of clinical research towards transparency, ethics and impartiality, resulting in real evidence to the forthcoming changes in clinical practice as well as in the health situation.
Information for researchers about developing, reporting, and managing NCI-funded cancer prevention clinical trials. Protocol Information Office The central clearinghouse for clinical trials management within the Division of Cancer Prevention.Read more about the Protocol Information Office. | Information for researchers about developing, reporting, and managing NCI-funded
inherited orphan retinal degenerative diseases and dry age-related macular degeneration (AMD) through the conduct of clinical trials and other...design and conduct of effective and efficient clinical trials for inherited orphan retinal degenerative diseases and dry AMD; • Limited number and...linica l trial in the NEER network for autosomal dominant retinitis pigmentosa, and the ProgSTAR studies for Stargardt disease ) . As new interventions b
C. A. Caramori
Scientific development that has been achieved through decades finds in clinical research a great possibility of translating findings to human health application. Evidence given by clinical trials allows everyone to have access to the best health services. However, the millionaire world of pharmaceutical industries has stained clinical research with doubt and improbability. Study results (fruits of controlled clinical trials) and scientific publications (selective, manipulated and with wrong c...
Maninder Singh Setia
Full Text Available In a clinical trial, study participants are (usually divided into two groups. One group is then given the intervention and the other group is not given the intervention (or may be given some existing standard of care. We compare the outcomes in these groups and assess the role of intervention. Some of the trial designs are (1 parallel study design, (2 cross-over design, (3 factorial design, and (4 withdrawal group design. The trials can also be classified according to the stage of the trial (Phase I, II, III, and IV or the nature of the trial (efficacy vs. effectiveness trials, superiority vs. equivalence trials. Randomization is one of the procedures by which we allocate different interventions to the groups. It ensures that all the included participants have a specified probability of being allocated to either of the groups in the intervention study. If participants and the investigator know about the allocation of the intervention, then it is called an "open trial." However, many of the trials are not open - they are blinded. Blinding is useful to minimize bias in clinical trials. The researcher should familiarize themselves with the CONSORT statement and the appropriate Clinical Trials Registry of India.
Setia, Maninder Singh
In a clinical trial, study participants are (usually) divided into two groups. One group is then given the intervention and the other group is not given the intervention (or may be given some existing standard of care). We compare the outcomes in these groups and assess the role of intervention. Some of the trial designs are (1) parallel study design, (2) cross-over design, (3) factorial design, and (4) withdrawal group design. The trials can also be classified according to the stage of the trial (Phase I, II, III, and IV) or the nature of the trial (efficacy vs. effectiveness trials, superiority vs. equivalence trials). Randomization is one of the procedures by which we allocate different interventions to the groups. It ensures that all the included participants have a specified probability of being allocated to either of the groups in the intervention study. If participants and the investigator know about the allocation of the intervention, then it is called an "open trial." However, many of the trials are not open - they are blinded. Blinding is useful to minimize bias in clinical trials. The researcher should familiarize themselves with the CONSORT statement and the appropriate Clinical Trials Registry of India.
Mahamadou A Thera
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.
Årdal, Christine; Røttingen, John-Arne
Greater investment is required in developing new drugs and vaccines against malaria in order to eradicate malaria. These precious funds must be carefully managed to achieve the greatest impact. We evaluate existing efforts to discover and develop new drugs and vaccines for malaria to determine how best malaria R&D can benefit from an enhanced open source approach and how such a business model may operate. We assess research articles, patents, clinical trials and conducted a smaller survey among malaria researchers. Our results demonstrate that the public and philanthropic sectors are financing and performing the majority of malaria drug/vaccine discovery and development, but are then restricting access through patents, 'closed' publications and hidden away physical specimens. This makes little sense since it is also the public and philanthropic sector that purchases the drugs and vaccines. We recommend that a more "open source" approach is taken by making the entire value chain more efficient through greater transparency which may lead to more extensive collaborations. This can, for example, be achieved by empowering an existing organization like the Medicines for Malaria Venture (MMV) to act as a clearing house for malaria-related data. The malaria researchers that we surveyed indicated that they would utilize such registry data to increase collaboration. Finally, we question the utility of publicly or philanthropically funded patents for malaria medicines, where little to no profits are available. Malaria R&D benefits from a publicly and philanthropically funded architecture, which starts with academic research institutions, product development partnerships, commercialization assistance through UNITAID and finally procurement through mechanisms like The Global Fund to Fight AIDS, Tuberculosis and Malaria and the U.S.' President's Malaria Initiative. We believe that a fresh look should be taken at the cost/benefit of patents particularly related to new malaria
Full Text Available Greater investment is required in developing new drugs and vaccines against malaria in order to eradicate malaria. These precious funds must be carefully managed to achieve the greatest impact. We evaluate existing efforts to discover and develop new drugs and vaccines for malaria to determine how best malaria R&D can benefit from an enhanced open source approach and how such a business model may operate. We assess research articles, patents, clinical trials and conducted a smaller survey among malaria researchers. Our results demonstrate that the public and philanthropic sectors are financing and performing the majority of malaria drug/vaccine discovery and development, but are then restricting access through patents, 'closed' publications and hidden away physical specimens. This makes little sense since it is also the public and philanthropic sector that purchases the drugs and vaccines. We recommend that a more "open source" approach is taken by making the entire value chain more efficient through greater transparency which may lead to more extensive collaborations. This can, for example, be achieved by empowering an existing organization like the Medicines for Malaria Venture (MMV to act as a clearing house for malaria-related data. The malaria researchers that we surveyed indicated that they would utilize such registry data to increase collaboration. Finally, we question the utility of publicly or philanthropically funded patents for malaria medicines, where little to no profits are available. Malaria R&D benefits from a publicly and philanthropically funded architecture, which starts with academic research institutions, product development partnerships, commercialization assistance through UNITAID and finally procurement through mechanisms like The Global Fund to Fight AIDS, Tuberculosis and Malaria and the U.S.' President's Malaria Initiative. We believe that a fresh look should be taken at the cost/benefit of patents particularly related
Garner, John B; Grayburn, Paul A; Yancy, Clyde W
Each year, a number of clinical trials emerge with data sufficient to change clinical practice. Determining which findings will result in practice change and which will provide only incremental benefit can be a dilemma for clinicians. The authors review selected clinical trials reported in 2010 in journals, at society meetings, and at conferences, focusing on those studies that have the potential to change clinical practice. This review offers 3 separate means of analysis: an abbreviated text summary, organized by subject area; a comprehensive table of relevant clinical trials that provides a schematic review of the hypotheses, interventions, methods, primary end points, results, and implications; and a complete bibliography for further reading as warranted. It is hoped that this compilation of relevant clinical trials and their important findings released in 2010 will be of benefit in the everyday practice of cardiovascular medicine. Copyright © 2011 Elsevier Inc. All rights reserved.
reduces the burden of malaria in under-five children. The Ministry of Health of Ethiopia in collaboration with other partners should design similar strategies in high-risk areas to control malaria in Ethiopia. Trial registration Australia and New Zealand Clinical Trials Register (ANZCTR: ACTRN12610000035022
Nyunt, Myat Htut; Han, Jin-Hee; Wang, Bo; Aye, Khin Myo; Aye, Kyin Hla; Lee, Seong-Kyun; Htut, Ye; Kyaw, Myat Phone; Han, Kay Thwe; Han, Eun-Taek
One of the major challenges for control and elimination of malaria is ongoing spread and emergence of drug resistance. While epidemiology and surveillance of the drug resistance in falciparum malaria is being explored globally, there are few studies on drug resistance vivax malaria. To assess the spread of drug-resistant vivax malaria in Myanmar, a multisite, prospective, longitudinal study with retrospective analysis of previous therapeutic efficacy studies, was conducted. A total of 906 from nine study sites were included in retrospective analysis and 208 from three study sites in prospective study. Uncomplicated vivax mono-infected patients were recruited and monitored with longitudinal follow-up until day 28 after treatment with chloroquine. Amplification and sequence analysis of molecular markers, such as mutations in pvcrt-O, pvmdr1, pvdhps and pvdhfr, were done in day-0 samples in prospective study. Clinical failure cases were found only in Kawthaung, southern Myanmar and western Myanmar sites within 2009-2016. Chloroquine resistance markers, pvcrt-O 'AAG' insertion and pvmdr1 mutation (Y976F) showed higher mutant rate in southern and central Myanmar than western site: 66.7, 72.7 vs 48.3% and 26.7, 17.0 vs 1.7%, respectively. A similar pattern of significantly higher mutant rate of antifolate resistance markers, pvdhps (S382A, K512M, A553G) and pvdhfr (F57L/I, S58R, T61M, S117T/N) were noted. Although clinical failure rate was low, widespread distribution of chloroquine and antifolate resistance molecular makers alert to the emergence and spread of drug resistance vivax malaria in Myanmar. Proper strategy and action plan to eliminate and contain the resistant strain strengthened together with clinical and molecular surveillance on drug resistance vivax is recommended.
Woodsong, Cynthia; MacQueen, Kathleen; Amico, K Rivet; Friedland, Barbara; Gafos, Mitzy; Mansoor, Leila; Tolley, Elizabether; McCormack, Sheena
After two decades of microbicide clinical trials it remains uncertain if vaginally- delivered products will be clearly shown to reduce the risk of HIV infection in women and girls. Furthermore, a microbicide product with demonstrated clinical efficacy must be used correctly and consistently if it is to prevent infection. Information on adherence that can be gleaned from microbicide trials is relevant for future microbicide safety and efficacy trials, pre-licensure implementation trials, Phase IV post-marketing research, and microbicide introduction and delivery. Drawing primarily from data and experience that has emerged from the large-scale microbicide efficacy trials completed to-date, the paper identifies six broad areas of adherence lessons learned: (1) Adherence measurement in clinical trials, (2) Comprehension of use instructions/Instructions for use, (3) Unknown efficacy and its effect on adherence/Messages regarding effectiveness, (4) Partner influence on use, (5) Retention and continuation and (6) Generalizability of trial participants' adherence behavior. Each is discussed, with examples provided from microbicide trials. For each of these adherence topics, recommendations are provided for using trial findings to prepare for future microbicide safety and efficacy trials, Phase IV post-marketing research, and microbicide introduction and delivery programs.
Miiro, George M; Oukem-Boyer, Odile Ouwe Missi; Sarr, Ousmane; Rahmani, Maerangis; Ntoumi, Francine; Dheda, Keertan; Pym, Alexander; Mboup, Souleymane; Kaleebu, Pontiano
Achieving the Millennium Development Goals (MDGs) and combating hotspots with escalating but preventable communicable diseases remain major challenges in Africa. The European and Developing Countries Clinical Trials Partnership (EDCTP) intervened to combat poverty-related diseases including malaria, tuberculosis and HIV/AIDS, and to conduct multi-centre clinical trials and multi-disciplinary health research through an innovative model of regional Networks of Excellence (NoEs). We participated in a quasi-formative evaluation between October and December 2011 on the 4 regional-led research networks. These included the: Central Africa Network on Tuberculosis, HIV/AIDS and Malaria (CANTAM); East African Consortium for Clinical Research (EACCR); West African Network of Excellence for TB, AIDS and Malaria (WANETAM), and the Trials of Excellence for Southern Africa (TESA) launched between 2009 and 2010. We shared a participatory appraisal of field reports, progress reports and presentations from each network to jointly outline the initial experiences of the merits, outputs and lessons learnt. The self-regulating democratic networks, with 64 institutions in 21 African countries, have trained over 1, 000 African scientists, upgraded 36 sites for clinical trials, leveraged additional € 24 million and generated 38 peer-reviewed publications through networking and partnerships. The shared initial merits and lessons learnt portray in part the strengthened capacity of these networks for improved research coordination and conduct of planned multi-center clinical trials in Africa. Increased funding by African agencies, governments and international health partners will ensure sustainability of these networks for research capacity development and demonstrate their commitment to achieving the MDGs in Africa.
Arvay, C A
Over the years, clinical trials with their structured treatment plans and multicenter involvement have been instrumental in developing new treatments and establishing standard of care therapy. While clinical trials strive to advance medical knowledge, they provide scientifically sound, state of the art care and their use should be increased. The Brain Tumor Cooperative Group, one such NCI-sponsored cooperative group, has been the primary group for the treatment of malignant gliomas. As the field of neuro-oncology expands, the neuroscience nurse needs to develop an understanding of clinical trials and their operation. The nurse is in an optimal position to support medical research and the research participant.
economic and political imperatives surrounding randomised controlled trials and the ambiguous, or even ..... the medicinal properties of the plant, as reported both in the book, and also in the .... London, UK: Harvard University Press. Latour, B.
Entwistle Vikki A
Full Text Available Abstract Background Publicly funded clinical trials require a substantial commitment of time and money. To ensure that sufficient numbers of patients are recruited it is essential that they address important questions in a rigorous manner and are managed well, adopting effective marketing strategies. Methods Using methods of analysis drawn from management studies, this paper presents a structured assessment framework or reference model, derived from a case analysis of the MRC's CRASH trial, of 12 factors that may affect the success of the marketing and sales activities associated with clinical trials. Results The case study demonstrates that trials need various categories of people to buy in – hence, to be successful, trialists must embrace marketing strategies to some extent. Conclusion The performance of future clinical trials could be enhanced if trialists routinely considered these factors.
Francis, David; Roberts, Ian; Elbourne, Diana R; Shakur, Haleema; Knight, Rosemary C; Garcia, Jo; Snowdon, Claire; Entwistle, Vikki A; McDonald, Alison M; Grant, Adrian M; Campbell, Marion K
Publicly funded clinical trials require a substantial commitment of time and money. To ensure that sufficient numbers of patients are recruited it is essential that they address important questions in a rigorous manner and are managed well, adopting effective marketing strategies. Using methods of analysis drawn from management studies, this paper presents a structured assessment framework or reference model, derived from a case analysis of the MRC's CRASH trial, of 12 factors that may affect the success of the marketing and sales activities associated with clinical trials. The case study demonstrates that trials need various categories of people to buy in - hence, to be successful, trialists must embrace marketing strategies to some extent. The performance of future clinical trials could be enhanced if trialists routinely considered these factors.
Full Text Available Most adults dying from falciparum malaria will die within 48 hours of their hospitalisation. An essential component of early supportive care is the rapid identification of patients at greatest risk. In resource-poor settings, where most patients with falciparum malaria are managed, decisions regarding patient care must frequently be made using clinical evaluation alone.We retrospectively analysed 4 studies of 1801 adults with severe falciparum malaria to determine whether the presence of simple clinical findings might assist patient triage.If present on admission, shock, oligo-anuria, hypo- or hyperglycaemia, an increased respiratory rate, a decreased Glasgow Coma Score and an absence of fever were independently predictive of death. The variables were used to construct a simple clinical algorithm. When applied to the 1801 patients, this algorithm's positive predictive value for survival to 48 hours was 99.4 (95% confidence interval (CI 97.8-99.9 and for survival to discharge 96.9% (95% CI 94.3-98.5. In the 712 patients receiving artesunate, the algorithm's positive predictive value for survival to 48 hours was 100% (95% CI 97.3-100 and to discharge was 98.5% (95% CI 94.8-99.8.Simple clinical findings are closely linked to the pathophysiology of severe falciparum malaria in adults. A basic algorithm employing these indices can facilitate the triage of patients in settings where intensive care services are limited. Patients classified as low-risk by this algorithm can be safely managed initially on a general ward whilst awaiting senior clinical review and laboratory data.
Fitzgerald, G K; Hinman, R S; Zeni, J; Risberg, M A; Snyder-Mackler, L; Bennell, K L
A Task Force of the Osteoarthritis Research Society International (OARSI) has previously published a set of guidelines for the conduct of clinical trials in osteoarthritis (OA) of the hip and knee. Limited material available on clinical trials of rehabilitation in people with OA has prompted OARSI to establish a separate Task Force to elaborate guidelines encompassing special issues relating to rehabilitation of OA. The Task Force identified three main categories of rehabilitation clinical trials. The categories included non-operative rehabilitation trials, post-operative rehabilitation trials, and trials examining the effectiveness of devices (e.g., assistive devices, bracing, physical agents, electrical stimulation, etc.) that are used in rehabilitation of people with OA. In addition, the Task Force identified two main categories of outcomes in rehabilitation clinical trials, which include outcomes related to symptoms and function, and outcomes related to disease modification. The guidelines for rehabilitation clinical trials provided in this report encompass these main categories. The report provides guidelines for conducting and reporting on randomized clinical trials. The topics include considerations for entering patients into trials, issues related to conducting trials, considerations for selecting outcome measures, and recommendations for statistical analyses and reporting of results. The focus of the report is on rehabilitation trials for hip, knee and hand OA, however, we believe the content is broad enough that it could be applied to rehabilitation trials for other regions as well. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Danika L Hill
Full Text Available Naturally acquired humoral immunity to the malarial parasite Plasmodium falciparum can protect against disease, although the precise mechanisms remain unclear. Although antibody levels can be measured by ELISA, few studies have investigated functional antibody assays in relation to clinical outcomes. In this study we applied a recently developed functional assay of antibody-mediated opsonisation of merozoites, to plasma samples from a longitudinal cohort study conducted in a malaria endemic region of Papua New Guinea (PNG. Phagocytic activity was quantified by flow cytometry using a standardized and high-throughput protocol, and was subsequently evaluated for association with protection from clinical malaria and high-density parasitemia. Opsonising antibody responses were found to: i increase with age, ii be enhanced by concurrent infection, and iii correlate with protection from clinical episodes and high-density parasitemia. Stronger protective associations were observed in individuals with no detectable parasitemia at baseline. This study presents the first evidence for merozoite phagocytosis as a correlate of acquired immunity and clinical protection against P. falciparum malaria.
Sirima, Sodiomon B; Mordmüller, Benjamin; Milligan, Paul
randomized to receive three injections of either 100μg GMZ2 adjuvanted with aluminum hydroxide or a control vaccine (rabies) four weeks apart and were followed up for six months to measure the incidence of malaria defined as fever or history of fever and a parasite density ⩾5000/μL. RESULTS: A cohort of 1849...... in the rabies vaccine group and 14 in the GMZ2 group), VE 27% (95% CI -44%, 63%). CONCLUSIONS: GMZ2 is the first blood-stage malaria vaccine to be evaluated in a large multicenter trial. GMZ2 was well tolerated and immunogenic, and reduced the incidence of malaria, but efficacy would need to be substantially...
Hartgerink, C.H.J.; George, Stephen
Clinical trials are crucial in determining the effectiveness of treatments and directly affect clinical and policy decisions. These decisions are undermined if the data are problematic due to data fabrication or other errors. Researchers have worked on developing statistical methods to detect
Getawen, Solomon Kinde; Ashine, Temesgen; Massebo, Fekadu; Woldeyes, Daniel; Lindtjørn, Bernt
House is the major site for malaria infection where most human-vector contact takes place. Hence, improving housing might reduce the risk of malaria infection by limiting house entry of vectors. This study aimed to explore the impact of screening doors and windows with wire meshes on density and entomological inoculation rate (EIR) of malaria vector, and malaria incidence, and assess the acceptability, durability, and cost of the intervention. The susceptibility status of malaria vector was also assessed. A two-arm randomized trial was done in Arba Minch Town, southwest Ethiopia. 92 houses were randomly included in the trial. The baseline entomological and malaria prevalence data were collected. The mosquito sampling was done twice per household per month by Centers for Diseases Control and Prevention (CDC) light traps for six months. The baseline prevalence of malaria was assessed by testing 396 (83% of the 447 study participants) household members in all the eligible houses. The 92 houses were then randomized into control and intervention groups using mosquito and malaria prevalence baseline data to make the two groups comparable except the intervention. Then, we put wire-mesh on doors and windows of 46 houses. Post-screening mosquito collection was done in each household twice per month for three months. Each household member was visited twice per month for six months to assess malaria episodes. The frequency of damage to different structure of screening was measured twice. In-depth interview was conducted with 24 purposely selected household heads from intervention group. Speciation of Anopheles mosquito was done by morphological key, and the circum-sporozoite proteins (CSPs) analysis was done using enzyme-linked immunosorbent assay. A generalized estimating equation with a negative binomial distribution was used to assess the impact of the intervention on the indoor density of vectors. Clinical malaria case data were analyzed using Poisson regression with
Castellanos María Eugenia
Full Text Available Abstract This is a report of the first Plasmodium vivax congenital malaria case in Guatemala and the first case in Latin America with genotypical, histological and clinical characterization. The findings show that maternal P. vivax infection still occurs in areas that are in the pathway towards malaria elimination, and can be associated with detrimental health effects for the neonate. It also highlights the need in very low transmission areas of not only maintaining, but increasing awareness of the problem and developing surveillance strategies, based on population risk, to detect the infection especially in this vulnerable group of the population.
Gustafsson, Finn; Atar, Dan; Pitt, Bertram
, in particular with respect to collaboration with the trial sponsor and to analytic pitfalls. The advantages of creating screening databases in conjunction with a given clinical trial are described; and finally, the potential for posttrial database studies to become a platform for training young scientists...
Full Text Available Jay JH Park,1 Kristian Thorlund,2,3 Edward J Mills2,3 1Department of Medicine, University of British Columbia, Vancouver, BC, Canada; 2Department of Health Research Methods, Evidence, and Impact (HEI, McMaster University, Hamilton, ON, Canada; 3The Bill and Melinda Gates Foundation, Seattle, WA, USA Abstract: Adaptive clinical trials are an innovative trial design aimed at reducing resources, decreasing time to completion and number of patients exposed to inferior interventions, and improving the likelihood of detecting treatment effects. The last decade has seen an increasing use of adaptive designs, particularly in drug development. They frequently differ importantly from conventional clinical trials as they allow modifications to key trial design components during the trial, as data is being collected, using preplanned decision rules. Adaptive designs have increased likelihood of complexity and also potential bias, so it is important to understand the common types of adaptive designs. Many clinicians and investigators may be unfamiliar with the design considerations for adaptive designs. Given their complexities, adaptive trials require an understanding of design features and sources of bias. Herein, we introduce some common adaptive design elements and biases and specifically address response adaptive randomization, sample size reassessment, Bayesian methods for adaptive trials, seamless trials, and adaptive enrichment using real examples. Keywords: adaptive designs, response adaptive randomization, sample size reassessment, Bayesian adaptive trials, seamless trials, adaptive enrichment
Aug 3, 2012 ... Medical Department of Juba Teaching Hospital (JTH). The World ... Assess vital signs: • temperature .... March 2012. NICE 2002 Principles for best practice in Clinical Audit. 4. ... A clinical audit cycle has a number of phases: 1.
Chen, Ding-Geng; Peace, Karl E
.... Case studies demonstrate how to select the appropriate clinical trial data. The authors introduce the corresponding biostatistical analysis methods, followed by the step-by-step data analysis using R...
Adolescents, young adults, and the elderly lag far behind other age groups when it comes to enrolling in clinical trials. Their participation is critical to advancing effective therapies for these age groups.
Hróbjartsson, A; Boutron, I
Blinding, or "masking," is a crucial method for reducing bias in randomized clinical trials. In this paper, we review important methodological aspects of blinding, emphasizing terminology, reporting, bias mechanisms, empirical evidence, and the risk of unblinding. Theoretical considerations...
Jan 22, 2008 ... The US database, on the other hand, clearly identifies 172 ... operating within extended clinical trials R&D value chains. Companies often ... Source: CeSTII Survey Management and Results System internal database. Table III.
Plasmodium falciparum malaria in pregnancy: prevalence of peripheral parasitaemia, anaemia and malaria care-seeking behaviour among pregnant women attending two antenatal clinics in Edo State, Nigeria.
Enato, E F O; Mens, P F; Okhamafe, A O; Okpere, E E; Pogoson, E; Schallig, H D F H
This study evaluated malaria care-seeking behaviour, as well as the prevalence of parasitaemia and anaemia among pregnant women attending antenatal clinics of two tertiary healthcare facilities in Edo State, Nigeria. Malaria was highly prevalent in the study group (20% by microscopy and estimated 25% by PCR), but parasitaemia and incidence decreased with increasing number of pregnancies. Although the level of education of the study participants was relatively high, antimalarial control measures during pregnancy were found to be poorly utilised by the women and malaria care-seeking was often delayed. A minority of the interviewed pregnant women said they had received sulphadoxine/pyrimethamine-based intermittent preventive therapy (IPT) during current pregnancy. Moreover, the use of inferior antimalaria treatment (e.g. chloroquine) was frequent. The majority of the pregnant women, mainly primigravidae, were anaemic. Efforts to improve antimalaria healthcare must be intensified, targeting pregnant women, particularly the primigravidae and secundigravidae and the healthcare providers.
Reekie, J; Mocroft, A; J, Neaton
Since the introduction of combination antiretroviral therapy, there has been a decrease in both AIDS-defining illnesses and deaths. This decrease meant that performing clinical trials with clinical outcomes in HIV infection became more time consuming and hence costly. Improved understanding...... the infection, so when treatment is started it is currently a lifelong commitment. Is it reasonable then that guidelines are based almost completely on short-term randomized trials and observational studies of surrogate markers, or is there still a need for trials with clinical outcomes?...
Reekie, J; Mocroft, A; J, Neaton
Since the introduction of combination antiretroviral therapy, there has been a decrease in both AIDS-defining illnesses and deaths. This decrease meant that performing clinical trials with clinical outcomes in HIV infection became more time consuming and hence costly. Improved understanding...... and knowledge of HIV led to short-term trials using surrogate outcomes such as viral load and CD4 count. This established a faster drug approval process that complimented the rapid need to evaluate and provide access to drugs based on short-term trials. However, no treatment has yet been found that eradicates...... the infection, so when treatment is started it is currently a lifelong commitment. Is it reasonable then that guidelines are based almost completely on short-term randomized trials and observational studies of surrogate markers, or is there still a need for trials with clinical outcomes?...
Esen, Meral; Kremsner, Peter G; Schleucher, Regina
Malaria is a major public health problem in Sub-Saharan Africa. In highly endemic regions infants, children and pregnant women are mostly affected. An effective malaria vaccine would complement existing malaria control strategies because it can be integrated in existing immunization programs easily....... Here we present the results of the first phase Ia clinical trial of GMZ2 adjuvanted in aluminium hydroxide. GMZ2 is a malaria vaccine candidate, designed upon the rationale to induce immune responses against asexual blood stages of Plasmodium falciparum similar to those encountered in semi...... is a safe and immunogenic malaria vaccine candidate suitable for further clinical development....
Full Text Available Wuchereria bancrofti (Wb and Mansonella perstans (Mp are blood-borne filarial parasites that are endemic in many countries of Africa, including Mali. The geographic distribution of Wb and Mp overlaps considerably with that of malaria, and coinfection is common. Although chronic filarial infection has been shown to alter immune responses to malaria parasites, its effect on clinical and immunologic responses in acute malaria is unknown.To address this question, 31 filaria-positive (FIL+ and 31 filaria-negative (FIL- children and young adults, matched for age, gender and hemoglobin type, were followed prospectively through a malaria transmission season. Filarial infection was defined by the presence of Wb or Mp microfilariae on calibrated thick smears performed between 10 pm and 2 am and/or by the presence of circulating filarial antigen in serum. Clinical malaria was defined as axillary temperature ≥37.5°C or another symptom or sign compatible with malaria infection plus the presence of asexual malaria parasites on a thick blood smear. Although the incidence of clinical malaria, time to first episode, clinical signs and symptoms, and malaria parasitemia were comparable between the two groups, geometric mean hemoglobin levels were significantly decreased in FIL- subjects at the height of the transmission season compared to FIL+ subjects (11.4 g/dL vs. 12.5 g/dL, p<0.01. Plasma levels of IL-1ra, IP-10 and IL-8 were significantly decreased in FIL+ subjects at the time of presentation with clinical malaria (99, 2145 and 49 pg/ml, respectively as compared to 474, 5522 and 247 pg/ml in FIL- subjects.These data suggest that pre-existent filarial infection attenuates immune responses associated with severe malaria and protects against anemia, but has little effect on susceptibility to or severity of acute malaria infection. The apparent protective effect of filarial infection against anemia is intriguing and warrants further study in a larger cohort.
Oud, Johan; Ghidey, Wendimagegn
This book describes various ways of approaching and interpreting the data produced by clinical trial studies, with a special emphasis on the essential role that biostatistics plays in clinical trials. Over the past few decades the role of statistics in the evaluation and interpretation of clinical data has become of paramount importance. As a result the standards of clinical study design, conduct and interpretation have undergone substantial improvement. The book includes 18 carefully reviewed chapters on recent developments in clinical trials and their statistical evaluation, with each chapter providing one or more examples involving typical data sets, enabling readers to apply the proposed procedures. The chapters employ a uniform style to enhance comparability between the approaches.
Kaplan, Celia P
.... While inroads to increasing minority inclusion in breast cancer clinical trials have been made, recent reports continue to demonstrate lower enrollment among African Americans, Asian Americans...
Greenberg, Rachel G; Gamel, Breck; Bloom, Diane; Bradley, John; Jafri, Hasan S; Hinton, Denise; Nambiar, Sumathi; Wheeler, Chris; Tiernan, Rosemary; Smith, P Brian; Roberts, Jamie; Benjamin, Daniel K
Enrollment of children into pediatric clinical trials remains challenging. More effective strategies to improve recruitment of children into trials are needed. This study used in-depth qualitative interviews with parents who were approached to enroll their children in a clinical trial in order to gain an understanding of the barriers to pediatric clinical trial participation. Twenty-four parents whose children had been offered the opportunity to participate in a clinical trial were interviewed: 19 whose children had participated in at least 1 clinical trial and 5 who had declined participation in any trial. Each study aspect, from the initial explanation of the study to the end of the study, can affect the willingness of parents to consent to the proposed study and future studies. Establishing trust, appropriate timing, a transparent discussion of risks and benefits oriented to the layperson, and providing motivation for children to participate were key factors that impacted parents' decisions. In order for clinical trial accrual to be successful, parents' priorities and considerations must be a central focus, beginning with initial trial design. The recommendations from the parents who participated in this study can be used to support budget allocations that ensure adequate training of study staff and improved staffing on nights and weekends. Studies of parent responses in outpatient settings and additional inpatient settings will provide valuable information on the consent process from the child's and parent's perspectives. Further studies are needed to explore whether implementation of such strategies will result in improved recruitment for pediatric clinical trials.
Patient engagement is an increasingly important aspect of successful clinical trials. Over the past decade, as patient group involvement in clinical trials has continued to increase and diversify, the Clinical Trials Transformation Initiative has not only recognized the crucial role patients play in improving the clinical trial enterprise but also made a deep commitment to help grow and shape the emerging field of patient engagement. This article describes the evolution of patient engagement including the origins of the patient engagement movement; barriers to successful engagement and remaining challenges to full and valuable collaboration between patient groups and trial sponsors; and Clinical Trials Transformation Initiative's role in influencing the field through organizational practices, formal project work and resulting recommendations, and external advocacy efforts.
better tolerability to reduce malaria in this particularly vulnerable group. MQ was associated with an increased risk of mother to child transmission of HIV, which warrants a better understanding of the pharmacological interactions between antimalarials and antiretroviral drugs. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00811421; Pan African Clinical Trials Registry PACTR 2010020001813440 Please see later in the article for the Editors' Summary.
Witsell, David L; Schulz, Kristine A; Lee, Walter T; Chiswell, Karen
To describe the conditions studied, interventions used, study characteristics, and funding sources of otolaryngology clinical trials from the ClinicalTrials.gov database; compare this otolaryngology cohort of interventional studies to clinical visits in a health care system; and assess agreement between clinical trials and clinical activity. Database analysis. Trial registration data downloaded from ClinicalTrials.gov and administrative data from the Duke University Medical Center from October 1, 2007 to September 27, 2010. Data extraction from ClinicalTrials.gov was done using MeSH and non-MeSH disease condition terms. Studies were subcategorized to create the following groupings for descriptive analysis: ear, nose, allergy, voice, sleep, head and neck cancer, thyroid, and throat. Duke Health System visits were queried by using selected ICD-9 codes for otolaryngology and non-otolaryngology providers. Visits were grouped similarly to ClinicalTrials.gov for further analysis. Chi-square tests were used to explore differences between groups. A total of 1115 of 40,970 registered interventional trials were assigned to otolaryngology. Head and neck cancer trials predominated. Study models most frequently incorporated parallel design (54.6%), 2 study groups (46.6%), and randomization (69.1%). Phase 2 or 3 studies constituted 46.4% of the cohort. Comparison of the ClinicalTrials.gov database with administrative health system visit data by disease condition showed discordance between national research activity and clinical visit volume for patients with otolaryngology complaints. Analysis of otolaryngology-related clinical research as listed in ClinicalTrials.gov can inform patients, physicians, and policy makers about research focus areas. The relative burden of otolaryngology-associated conditions in our tertiary health system exceeds research activity within the field.
Plétan, Yannick; Zannad, Faïez; Jaillon, Patrice
Be it to restore the confused image of clinical research in relation to the lay public, or to develop new ways of accruing healthy volunteers or patients for clinical trials, there is a need to draft some guidance on how best to provide information on research. Although the French legal and regulatory armamentarium in this area is essentially liberal, there is currently little-justified reluctance among study sponsors to advertise publicly. A group of academic and pharmaceutical industry researchers, assembled for a workshop, together with regulators, journalists, representatives from ethics committees, social security, patient and health consumer groups and other French institutional bodies, has suggested the following series of recommendations: there is no need for additional legal or regulatory constraints; sponsors should be aware of and make use of direct public information on trials; a 'good practice charter' on public communication about clinical trials should be developed; all professionals should be involved in this communication platform; communication in the patient's immediate vicinity should be preferred (primary-care physician, local press); clinical databases and websites accessible to professionals, but also to patients and non-professionals, should be developed; genuine instruction on clinical trials for physicians and health professionals unfamiliar with such trials should be developed and disseminated; media groups should receive at least some training in the fundamentals of clinical research.
Full Text Available AbstrakMalaria masih merupakan masalah kesehatan masyarakat dunia. Berdasarkan klasifikasi klinis, malaria dibedakan atas malaria berat dan malaria tanpa komplikasi. Malaria serebral merupakan komplikasi terberat dari malaria falsiparum.Telah dilakukan penelitian seksi silang terhadap penderita malaria falciparum yang dirawat inap di Bangsal Penyakit Dalam RS. Perjan. Dr. M. Djamil Padang dari bulan Juni 2002 sampai Juni 2006. Pada penelitian ini didapatkan jumlah sampel sebanyak 60 orang, terdiri dari 16 orang penderita malaria serebral dan 44 orang penderita malaria tanpa komplikasi.Data penelitian menunjukan terdapat perbedaan bermakna nilai hematokrit (p<0,05 dan jumlah leukosit (p<0,05 antara penderita malaria serebral dengan penderita malaria tanpa komplikasi. Dan terdapat korelasi positif antara nilai hemoglobin dengan hematokrit (r=0,864; p<0,05 pada penderita malaria falsiparum.Kata kunci: malaria serebral, malaria tanpa komplikasi, malaria falsiparumAbstract Malaria is still a problem of health of world society. Based on the clinical classification, are distinguished on severe malaria and uncomplicated malaria. Cerebral malaria is the worst complication of falciparum malaria. Cross section of the research done at the Hospital Dr. M. Djamil Padang againts medical record of malaria patients who are hospitalized in the Internal Medicine from June 2002 until June 2004. In this study, a total sample of 60 people, consisting of 16 cerebral malaria and 44 uncomplicated malaria. Data showed there were significant differences for hematocrit values (p <0.05 and total leukocytes values (p <0.05 between cerebral malaria and uncomplicated malaria patients. There is a positive correlation between hemoglobin with hematocrit values (r = 0.864; p <0.05 of falciparum malaria patients. Keywords: cerebral malaria, uncomplicated malaria, falciparum malaria
Neuberger, Ami; Okebe, Joseph; Yahav, Dafna; Paul, Mical
Background Iron-deficiency anaemia is common during childhood. Iron administration has been claimed to increase the risk of malaria. Objectives To evaluate the effects and safety of iron supplementation, with or without folic acid, in children living in areas with hyperendemic or holoendemic malaria transmission. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library, MEDLINE (up to August 2015) and LILACS (up to February 2015). We also checked the metaRegister of Controlled Trials (mRCT) and World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) up to February 2015. We contacted the primary investigators of all included trials, ongoing trials, and those awaiting assessment to ask for unpublished data and further trials. We scanned references of included trials, pertinent reviews, and previous meta-analyses for additional references. Selection criteria We included individually randomized controlled trials (RCTs) and cluster RCTs conducted in hyperendemic and holoendemic malaria regions or that reported on any malaria-related outcomes that included children younger than 18 years of age. We included trials that compared orally administered iron, iron with folic acid, and iron with antimalarial treatment versus placebo or no treatment. We included trials of iron supplementation or fortification interventions if they provided at least 80% of the Recommended Dietary Allowance (RDA) for prevention of anaemia by age. Antihelminthics could be administered to either group, and micronutrients had to be administered equally to both groups. Data collection and analysis The primary outcomes were clinical malaria, severe malaria, and death from any cause. We assessed the risk of bias in included trials with domain-based evaluation and assessed the quality of the evidence using the Grading of Recommendations Assessment
Hussain-Gambles, M; Leese, B; Atkin, K; Brown, J; Mason, S; Tovey, P
To investigate how South Asian patients conceptualise the notion of clinical trials and to identify key processes that impact on trial participation and the extent to which communication difficulties, perceptions of risk and attitudes to authority influence these decisions. Also to identify whether 'South Asian' patients are homogeneous in these issues, and which factors differ between different South Asian subgroups and finally how professionals regard the involvement of South Asian patients and their views on strategies to increase participation. A review of the literature on minority ethnic participation in clinical trials was followed by three qualitative interview studies. Interviews were taped and transcribed (and translated if required) and subjected to framework analysis. Face-to-face interviews were conducted with 25 health professionals; 60 South Asian lay people who had not taken part in a trial and 15 South Asian trial participants. Motivations for trial participation were identified as follows: to help society, to improve own health or that of family and friends, out of obligation to the doctor and to increase scientific knowledge. Deterrents were concerns about drug side-effects, busy lifestyles, language, previous bad experiences, mistrust and feelings of not belonging to British society. There was no evidence of antipathy amongst South Asians to the concept of clinical trials and, overall, the younger respondents were more knowledgeable than the older ones. Problems are more likely to be associated with service delivery. Lack of being approached was a common response. Lay-reported factors that might affect South Asian participation in clinical trials include age, language, social class, feeling of not belonging/mistrust, culture and religion. Awareness of clinical trials varied between each group. There are more similarities than differences in attitudes towards clinical trial participation between the South Asian and the general population
Baird, J. Kevin
Malaria caused by Plasmodium vivax threatens over 2 billion people globally and sickens tens of millions annually. Recent clinical evidence discredits the long-held notion of this infection as intrinsically benign revealing an often threatening course associated with mortality. Most acute attacks by this species derive from latent forms in the human liver called hypnozoites. Radical cure for P. vivax malaria includes therapy aimed both at the acute attack (blood schizontocidal) and against fu...
Hollingdale, Michael R; Sedegah, Martha; Limbach, Keith
Malaria remains a major threat to endemic populations and travelers, including military personnel to these areas. A malaria vaccine is feasible, as radiation attenuated sporozoites induce nearly 100% efficacy. Areas covered: This review covers current malaria clinical trials using adenoviruses and pre-clinical research. Heterologous prime-boost regimens, including replication-deficient human adenovirus 5 (HuAd5) carrying malaria antigens, are efficacious. However, efficacy appears to be adversely affected by pre-existing anti-HuAd5 antibodies. Current strategies focus on replacing HuAd5 with rarer human adenoviruses or adenoviruses isolated from non-human primates (NHPs). The chimpanzee adenovirus ChAd63 is undergoing evaluation in clinical trials including infants in malaria-endemic areas. Key antigens have been identified and are being used alone, in combination, or with protein subunit vaccines. Gorilla adenoviruses carrying malaria antigens are also currently being evaluated in preclinical models. These replacement adenovirus vectors will be successfully used to develop vaccines against malaria, as well as other infectious diseases. Expert commentary: Simplified prime-boost single shot regimens, dry-coated live vector vaccines or silicon microneedle arrays could be developed for malaria or other vaccines. Replacement vectors with similar or superior immunogenicity have rapidly advanced, and several are now in extensive Phase 2 and beyond in malaria as well as other diseases, notably Ebola.
Quality of clinical trials depends on data integrity and subject protection. Globalization, outsourcing and increasing complexicity of clinical trials have made the target of achieving global quality challenging. The quality, as judged by regulatory inspections of the investigator sites, sponsors/contract research organizations and Institutional Review Board, has been of concern to the US Food and Drug Administration, as there has been hardly any change in frequency and nature of common deficiencies. To meet the regulatory expectations, the sponsors need to improve quality by developing systems with specific standards for each clinical trial process. The quality systems include: personnel roles and responsibilities, training, policies and procedures, quality assurance and auditing, document management, record retention, and reporting and corrective and preventive action. With an objective to improve quality, the FDA has planned new inspection approaches such as risk-based inspections, surveillance inspections, real-time oversight, and audit of sponsor quality systems. The FDA has partnered with Duke University for Clinical Trials Transformation Initiative, which will conduct research projects on design principles, data quality and quantity including monitoring, study start-up, and adverse event reporting. These recent initiatives will go a long way in improving quality of clinical trials. PMID:22145122
Full Text Available Quality of clinical trials depends on data integrity and subject protection. Globalization, outsourcing and increasing complexicity of clinical trials have made the target of achieving global quality challenging. The quality, as judged by regulatory inspections of the investigator sites, sponsors/contract research organizations and Institutional Review Board, has been of concern to the US Food and Drug Administration, as there has been hardly any change in frequency and nature of common deficiencies. To meet the regulatory expectations, the sponsors need to improve quality by developing systems with specific standards for each clinical trial process. The quality systems include: personnel roles and responsibilities, training, policies and procedures, quality assurance and auditing, document management, record retention, and reporting and corrective and preventive action. With an objective to improve quality, the FDA has planned new inspection approaches such as risk-based inspections, surveillance inspections, real-time oversight, and audit of sponsor quality systems. The FDA has partnered with Duke University for Clinical Trials Transformation Initiative, which will conduct research projects on design principles, data quality and quantity including monitoring, study start-up, and adverse event reporting. These recent initiatives will go a long way in improving quality of clinical trials.
Full Text Available Abstract Background Antipyretic drugs are widely used in children with fever, though there is a controversy about the benefit of reducing fever in children with malaria. In order to assess the effect of ibuprofen on fever compared to placebo in children with uncomplicated Plasmodium falciparum malaria in Gabon, a randomized double blind placebo controlled trial, was designed. Methods Fifty children between two and seven years of age with uncomplicated malaria were included in the study. For the treatment of fever, all patients "received" mechanical treatment when the temperature rose above 37.5°C. In addition to the mechanical treatment, continuous fanning and cooling blanket, patients were assigned randomly to receive ibuprofen (7 mg/kg body weight, every eight hours or placebo. Results The fever clearance time using a fever threshold of 37.5°C was similar in children receiving ibuprofen compared to those receiving placebo. The difference was also not statistically significant using a fever threshold of 37.8°C or 38.0°C. However, the fever time and the area under the fever curve were significantly smaller in the ibuprofen group compared to the placebo group. Conclusion Ibuprofen is effective in reducing the time with fever. The effect on fever clearance is less obvious and depends on definition of the fever threshold. Trial registration The trial registration number is: NCT00167713
Peter, Emanuel L; Rumisha, Susan F; Mashoto, Kijakazi O; Minzi, Omary Ms; Mfinanga, Sayoki
Indigenous community of Mkuranga district have been using aqueous extract of H. sabdariffa L. for treating anemia. However, there have been neither safety nor efficacy studies to validate this medicinal product in anemia. The purpose of this study was to establish efficacy and safety of standardized aqueous extract of H. sabdariffa L. in anemic adults. This was a randomized controlled clinical trial in which 130 adults' men and women aged 18-50 years were involved after meeting the inclusion criteria. Initially, standardized aqueous extract of H. sabdariffa L. was prepared using optimized extraction parameters. Stratified randomization was used to randomize participants into four fixed dose groups. The first group received oral dose of 1000ml while the 2nd group was randomized to receive 1500ml orally. The last two groups were given a dose of 2000ml of extract and 200mg ferrous sulphate tablet respectively. Primary endpoint was the actual change of iron status indicators at the end of 30 days follow up period as compared to those recorded at baseline. Adverse effects were assessed at every 10th day scheduled visit. In all arms, HB and hematopoietic parameters were measured using HemoCue hemoglobinometer® (HemoCue, Ängelholm, Sweden) and hematology analyzer® respectively at the trial site. Follow up was done for 30 days. A total of 82 participants were included for analysis. A standardized aqueous extract of H. sabdariffa L. did not improve iron status in anemic adults in malaria endemic region (P>0.005). However, there was evidence to support the safety of the extract for human consumptions as herbal supplement. Iron and organic acids contents of H. sabdariffa L. extract showed the potential of improving hematopoietic parameters. Studies with bigger sample size are therefore needed to establish the efficacy of the extract when concurrently used with malaria chemoprophylaxis in malaria endemic areas. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.
Entwistle Vikki A; Snowdon Claire; Garcia Jo; Knight Rosemary C; Shakur Haleema; Elbourne Diana R; Roberts Ian; Francis David; McDonald Alison M; Grant Adrian M; Campbell Marion K
Abstract Background Publicly funded clinical trials require a substantial commitment of time and money. To ensure that sufficient numbers of patients are recruited it is essential that they address important questions in a rigorous manner and are managed well, adopting effective marketing strategies. Methods Using methods of analysis drawn from management studies, this paper presents a structured assessment framework or reference model, derived from a case analysis of the MRC's CRASH trial, o...
Logemann, Jeri A
Randomized clinical trials (RCTs) are often known as the gold standard in treatment efficacy studies. This article defines the characteristics of RCTs and the factors that investigators must consider in designing clinical trials in dysphagia. Design issues unique to behavioral treatments often used in dysphagia are discussed. Ongoing RCTs in dysphagia are described including studies of (1) the effectiveness of the Shaker exercise versus standardized treatment in patients with severe dysphagia resulting from stroke or treatment for head and neck cancer who have been nonoral for at least three months; (2) the comparative effects of nectar- and honey-thickened liquids versus chin tuck posture and in patients with dementia or Parkinson's disease with or without dementia who aspirate on thin liquids; and (3) the comparative effects of muscle exercise versus sensory postural therapy for dysphagia resulting from treatment for head and neck cancer. Issues in generalizing from the results of clinical trials are also described.
Sun, Fengmei; Zhang, Juan; Pu, Yuepu
This study is designed to perform a meta-analysis and trial sequential analysis (TSA) to investigate whether people with G6PD deficiency suffered less malarial infection. We searched from PubMed, Science Direct, Springer Link, CNKI, and Wan Fang databases for case-control study, cohort study or cross section study until April 2017. TSA was used to determine the state of evidence and calculate the required sample size. Eight case-control studies and five cross-sectional studies (30,683participants) were included in this meta-analysis. Compared with normal control group, we found significant protection from severe malaria (OR 0.644, 95% CI [0.493-0.842]; P=0.001) among people with decreasing G6PD activity. People with variations of G6PD gene at nucleotide 202(G6PD A-) were also found to be associated with resistance on severe malaria pooled (OR 0.851, 95% CI [0.779-0.930]; P =0.0001). Sex-stratified test suggested that protection of severe malaria is conferred to both G6PD A-males and heterozygous females (with a single copy of the variant). In conclusion, our study found a significant protection from severe malaria among G6PD deficient people compared to the
Del Parigi, Angelo
The quality of the clinical data supporting the development and ultimately the approval for medical use of new drugs is often challenged. Many share the perception that the business goals of the pharmaceutical industry overrule the best scientific efforts to accrue critical knowledge on a new molecule, in order to inform investment of resources, regulatory approvals and appropriate use by patients. Despite this common belief, few scientists have attempted to assess objectively the quality of industry funded (IF) clinical trials by measuring it and comparing it with non-industry funded (NIF) clinical trials in a data-driven fashion. Overall, the average quality of IF clinical research has been reported to be higher than the quality of NIF clinical research.
Mestan, Karen K; Ilkhanoff, Leonard; Mouli, Samdeep; Lin, Simon
Abstract Human genome sequencing is the process by which the exact order of nucleic acid base pairs in the 24 human chromosomes is determined. Since the completion of the Human Genome Project in 2003, genomic sequencing is rapidly becoming a major part of our translational research efforts to understand and improve human health and disease. This article reviews the current and future directions of clinical research with respect to genomic sequencing, a technology that is just beginning to fin...
Research has established the principle of hormonal male contraception based on suppression of gonadotropins and spermatogenesis. All hormonal male contraceptives use testosterone, but only in East Asian men can testosterone alone suppress spermatogenesis to a level compatible with contraceptive protection. In Caucasians, additional agents are required of which progestins are favored. Clinical trials concentrate on testosterone combined with norethisterone, desogestrel, etonogestrel or depot-medroxyprogesterone acetate. The first randomized, placebo-controlled clinical trial performed by the pharmaceutical industry demonstrated the effectiveness of a combination of testosterone undecanoate and etonogestrel in suppressing spermatogenesis in volunteers. Copyright © 2010 Elsevier Inc. All rights reserved.
Colombian professor Manuel Patarroyo developed a new malaria vaccine (SPF66). In February 1995, WHO and the Colombian government agreed to establish a manufacturing plant in Colombia for mass production of SPF66. This vaccine is likely to be available to persons in Africa, where 90% of all annual global cases live. In fact, Africa witnesses one million of 1.5 million annual malaria cases. Many children die from malaria. An extensive clinical trial of the SPF66 vaccine in Colombia achieved a 22-77% protection rate. The young and the very old had the high protection rates. A series of human clinical trials in the Gambia and Tanzania indicate that SPF66 produces a strong immune response against malaria without any harmful side effects. The results of field tests in the Gambia and Thailand and of trials in Colombia are expected in 1995. If the vaccine could reduce the incidence of malaria by just 50%, the lives of as many as 500,000 African children could be saved. SPF66 contains a combination of synthetic peptides (=or 2 amino acids). Mass production would make it affordable (estimated $5/injection). At least five other malaria vaccines hold promise and are ready for human testing in endemic countries. SPF66 is approximately three years ahead of all other promising malaria vaccines. 20 more vaccines are in the development stage. The large scale production of SPF66 in Colombia could begin within three years. Professor Patarroyo has financed his 12-year-old research himself because he wants to protect the lives of persons in developing countries. In 1992, the Congo's president petitioned the international community at the WHO summit in Amsterdam to join the fight against malaria since it is now in a position to defeat malaria since it finished the cold war.
Abbas, Ismail; Rovira, Joan; Casanovas, Josep
The patient recruitment process of clinical trials is an essential element which needs to be designed properly. In this paper we describe different simulation models under continuous and discrete time assumptions for the design of recruitment in clinical trials. The results of hypothetical examples of clinical trial recruitments are presented. The recruitment time is calculated and the number of recruited patients is quantified for a given time and probability of recruitment. The expected delay and the effective recruitment durations are estimated using both continuous and discrete time modeling. The proposed type of Monte Carlo simulation Markov models will enable optimization of the recruitment process and the estimation and the calibration of its parameters to aid the proposed clinical trials. A continuous time simulation may minimize the duration of the recruitment and, consequently, the total duration of the trial.
Graz, Bertrand; Dicko, Moussa; Willcox, Merlin L; Lambert, Bernard; Falquet, Jacques; Forster, Mathieu; Giani, Sergio; Diakite, Chiaka; Dembele, Eugène M; Diallo, Drissa; Barennes, Hubert
Background Hypoglycaemia is a poor prognostic indicator in severe malaria. Intravenous infusions are rarely feasible in rural areas. The efficacy of sublingual sugar (SLS) was assessed in a pilot randomized controlled trial among hypoglycaemic children with severe malaria in Mali. Methods Of 151 patients with presumed severe malaria, 23 children with blood glucose concentrations = 3.3 mmol/l (60 mg/dl) within 40 minutes after admission. Secondary outcome measures were early treatment response at 20 minutes, relapse (early and late), maximal BGC gain (CGmax), and treatment delay. Results There was no significant difference between the groups in the primary outcome measure. Treatment response occurred in 71% and 67% for SLS and IVG, respectively. Among the responders, relapses occurred in 30% on SLS at 40 minutes and in 17% on IVG at 20 minutes. There was one fatality in each group. Treatment failures in the SLS group were related to children with clenched teeth or swallowing the sugar, whereas in the IVG group, they were due to unavoidable delays in beginning an infusion (median time 17.5 min (range 3–40). Among SLS, the BGC increase was rapid among the nine patients who really kept the sugar sublingually. All but one increased their BGC by 10 minutes with a mean gain of 44 mg/dl (95%CI: 20.5–63.4). Conclusion Sublingual sugar appears to be a child-friendly, well-tolerated and effective promising method of raising blood glucose in severely ill children. More frequent repeated doses are needed to prevent relapse. Children should be monitored for early swallowing which leads to delayed absorption, and in this case another dose of sugar should be given. Sublingual sugar could be proposed as an immediate "first aid" measure while awaiting intravenous glucose. In many cases it may avert the need for intravenous glucose. PMID:19025610
Full Text Available Abstract Background Hypoglycaemia is a poor prognostic indicator in severe malaria. Intravenous infusions are rarely feasible in rural areas. The efficacy of sublingual sugar (SLS was assessed in a pilot randomized controlled trial among hypoglycaemic children with severe malaria in Mali. Methods Of 151 patients with presumed severe malaria, 23 children with blood glucose concentrations = 3.3 mmol/l (60 mg/dl within 40 minutes after admission. Secondary outcome measures were early treatment response at 20 minutes, relapse (early and late, maximal BGC gain (CGmax, and treatment delay. Results There was no significant difference between the groups in the primary outcome measure. Treatment response occurred in 71% and 67% for SLS and IVG, respectively. Among the responders, relapses occurred in 30% on SLS at 40 minutes and in 17% on IVG at 20 minutes. There was one fatality in each group. Treatment failures in the SLS group were related to children with clenched teeth or swallowing the sugar, whereas in the IVG group, they were due to unavoidable delays in beginning an infusion (median time 17.5 min (range 3–40. Among SLS, the BGC increase was rapid among the nine patients who really kept the sugar sublingually. All but one increased their BGC by 10 minutes with a mean gain of 44 mg/dl (95%CI: 20.5–63.4. Conclusion Sublingual sugar appears to be a child-friendly, well-tolerated and effective promising method of raising blood glucose in severely ill children. More frequent repeated doses are needed to prevent relapse. Children should be monitored for early swallowing which leads to delayed absorption, and in this case another dose of sugar should be given. Sublingual sugar could be proposed as an immediate "first aid" measure while awaiting intravenous glucose. In many cases it may avert the need for intravenous glucose.
Full Text Available Abstract T cell therapy represents an emerging and promising modality for the treatment of both infectious disease and cancer. Data from recent clinical trials have highlighted the potential for this therapeutic modality to effect potent anti-tumor activity. Biomarkers, operationally defined as biological parameters measured from patients that provide information about treatment impact, play a central role in the development of novel therapeutic agents. In the absence of information about primary clinical endpoints, biomarkers can provide critical insights that allow investigators to guide the clinical development of the candidate product. In the context of cell therapy trials, the definition of biomarkers can be extended to include a description of parameters of the cell product that are important for product bioactivity. This review will focus on biomarker studies as they relate to T cell therapy trials, and more specifically: i. An overview and description of categories and classes of biomarkers that are specifically relevant to T cell therapy trials, and ii. Insights into future directions and challenges for the appropriate development of biomarkers to evaluate both product bioactivity and treatment efficacy of T cell therapy trials.
Menya, Diana; Platt, Alyssa; Manji, Imran; Sang, Edna; Wafula, Rebeccah; Ren, Jing; Cheruiyot, Olympia; Armstrong, Janice; Neelon, Brian; O'Meara, Wendy Prudhomme
from baseline to quarter 4 in the intervention arm was nearly three times that of the comparison arm (ratio of adjusted odds ratios for baseline to quarter 4 = 0.36, 95% CI: 0.24-0.57). The rate of prescription of AL to patients without a test was five times lower in the intervention arm (adjusted incidence rate ratio = 0.18, 95% CI: 0.07-0.48). Prescription of AL to patients with confirmed infection was not significantly different between the groups over the study period. Facility-based incentives coupled with training may be more effective than training alone and could complement other quality improvement approaches. This study was registered with ClinicalTrials.gov (NCT01809873) on 11 March 2013.
A Zimmerman, T Duong, J Florence and the CINRG Investigators. Pulmonary Function Characteristics of Boys with Duchenne and Becker Muscular Dystrophy ...designated CINRG site staff 1. Has the participant been clinically diagnosed with Limb-Girdle or Becker muscular dystrophy ? LGMD BMD 2. Was...Number: W81XWH-09-1-0592 TITLE: CINRG: Infrastructure for Clinical Trials in Duchenne Dystrophy PRINCIPAL INVESTIGATOR: Avital Cnaan, PhD
John Chandy C
Full Text Available Abstract Background Infection with severe malaria in African children is associated with not only a high mortality but also a high risk of cognitive deficits. There is evidence that interventions done a few years after the illness are effective but nothing is known about those done immediately after the illness. We designed a study in which children who had suffered from severe malaria three months earlier were enrolled into a cognitive intervention program and assessed for the immediate benefit in cognitive, academic and behavioral outcomes. Methods This parallel group randomised study was carried out in Kampala City, Uganda between February 2008 and October 2010. Sixty-one Ugandan children aged 5 to 12 years with severe malaria were assessed for cognition (using the Kaufman Assessment Battery for Children, second edition and the Test of Variables of Attention, academic skills (Wide Range Achievement Test, third edition and psychopathologic behaviour (Child Behaviour Checklist three months after an episode of severe malaria. Twenty-eight were randomised to sixteen sessions of computerised cognitive rehabilitation training lasting eight weeks and 33 to a non-treatment group. Post-intervention assessments were done a month after conclusion of the intervention. Analysis of covariance was used to detect any differences between the two groups after post-intervention assessment, adjusting for age, sex, weight for age z score, quality of the home environment, time between admission and post-intervention testing and pre-intervention score. The primary outcome was improvement in attention scores for the intervention group. This trial is registered with Current Controlled Trials, number ISRCTN53183087. Results Significant intervention effects were observed in the intervention group for learning mean score (SE, [93.89 (4.00 vs 106.38 (4.32, P = 0.04] but for working memory the intervention group performed poorly [27.42 (0.66 vs 25.34 (0.73, P = 0.04]. No
Kremsner, P G; Looareesuwan, S; Chulay, J D
Safe and effective new drugs are needed for treatment of malaria. Atovaquone and proguanil hydrochloride is a new antimalarial combination that has recently become available in many countries. Data from clinical trials evaluating atovaquone/proguanil for treatment of malaria were reviewed. In 10 open-label clinical trials, treatment of uncomplicated falciparum malaria with 1000 mg atovaquone and 400 mg proguanil hydrochloride (or the equivalent based on body weight in patients proguanil has been used to provide radical cure of asymptomatic Plasmodium falciparum infections prior to initiation of placebo-controlled trials of malaria prophylaxis. Recurrent parasitemia occurred within 28 days in 0 of 99 subjects who subsequently received prophylaxis with atovaquone/proguanil and 1 of 81 subjects who subsequently received placebo. Atovaquone/proguanil is also effective for treatment of malaria caused by the other three Plasmodium species that cause malaria in humans. For treatment of vivax malaria, therapy with primaquine in addition to atovaquone/proguanil is needed to prevent relapse from latent hepatic hypnozoites. Atovaquone and proguanil hydrochloride is a safe and effective combination for treatment of malaria.
Geller, Nancy L; Kim, Dong-Yun; Tian, Xin
This article describes the use of smart technology by investigators and patients to facilitate lung disease clinical trials and make them less costly and more efficient. By "smart technology" we include various electronic media, such as computer databases, the Internet, and mobile devices. We first describe the use of electronic health records for identifying potential subjects and then discuss electronic informed consent. We give several examples of using the Internet and mobile technology in clinical trials. Interventions have been delivered via the World Wide Web or via mobile devices, and both have been used to collect outcome data. We discuss examples of new electronic devices that recently have been introduced to collect health data. While use of smart technology in clinical trials is an exciting development, comparison with similar interventions applied in a conventional manner is still in its infancy. We discuss advantages and disadvantages of using this omnipresent, powerful tool in clinical trials, as well as directions for future research. Published by Elsevier Inc.
New treatments for lung cancer and aspects of joining a clinical trial are discussed in this 30-minute Facebook Live event, hosted by NCI’s Dr. Shakun Malik, head of thoracic oncology therapeutics, and Janet Freeman-Daily, lung cancer patient activist and founding member of #LCSM.
Malmstrom, Kerstin; Peszek, Iza; Al Botto; Lu, Susan; Enright, Paul L; Reiss, Theodore F
Accuracy and repeatability of spirometry measurements are essential to obtain reliable efficacy data in randomized asthma clinical trials. We report our experience with a centralized spirometry quality assurance program that we implemented in our phase III asthma trials. Six asthma trials of 4 to 21 weeks in duration were conducted at 232 clinical centers in 31 countries. Approximately 23,100 prebronchodilator and 13,700 postbronchodilator spirometry tests were collected from 2523 adult and 336 pediatric asthmatic patients. The program used a standard spirometer (the Renaissance spirometry system) with maneuver quality messages and automated quality grading of the spirometry tests. Each clinical center transmitted spirometry data weekly to a central database, where uniform monitoring of data quality was performed and feedback was provided in weekly quality reports. Seventy-nine percent of all patients performed spirometry sessions with quality that either met or exceeded American Thoracic Society standards and improved over time. Good-quality spirometry was associated with (1) less severe asthma; (2) active treatment; (3) infrequent nocturnal awakenings; (4) age above 15 years; and (5) low body weight. Maneuver-induced bronchospasm was rare. Good-quality spirometry was observed in multicenter asthma clinical trials that employed a standard spirometer and continuous monitoring. Both within- and between-patient variability decreased. Spirometry quality improved with time as study participants and technicians gained experience.
Jan 22, 2008 ... companies to manufacture pharmaceuticals, 24 to carry out quality control and ... represents a 3% real growth from 2004/2005, it represents a slight decline from ... manufacturer for the pharmas, or can it leverage strengths in medical ... increased clinical trials activity, R&D investment is too low to make it a ...
Multinational pharmaceutical companies ('pharmas') import and produce pharmaceuticals and also conduct clinical trials which are an important aspect of research and development (R&D). This may raise the question: Is South Africa a guinea pig for the pharmas? The Department of Trade and Industry National Industrial ...
Jason W Bennett
Full Text Available A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001, a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP and a truncated repeat region that contains repeat sequences from both the VK210 (type 1 and the VK247 (type 2 parasites, was developed as a vaccine candidate for global use.We conducted a first-in-human Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI of VMP001 formulated in the GSK Adjuvant System AS01B. A total of 30 volunteers divided into 3 groups (10 per group were given 3 intramuscular injections of 15 μg, 30 μg, or 60 μg respectively of VMP001, all formulated in 500 μL of AS01B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls.The vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not induce sterile protection; however, a small but significant delay in time to parasitemia was seen in 59% of vaccinated subjects compared to the control group. An association was identified between levels of anti-type 1 repeat antibodies and prepatent period.This trial was the first to assess the efficacy of a P. vivax CSP vaccine candidate by CHMI. The association of type 1 repeat-specific antibody responses with delay in the prepatency period suggests that augmenting the immune responses to this domain may improve strain-specific vaccine efficacy. The availability of a P. vivax CHMI model will accelerate the process of P. vivax vaccine development, allowing better selection of candidate vaccines for advancement to field trials.
Lal, Sham; Ndyomugenyi, Richard; Magnussen, Pascal
Malaria-endemic countries have implemented community health worker (CHW) programs to provide malaria diagnosis and treatment to populations living beyond the reach of health systems. However, there is limited evidence describing the referral practices of CHWs. We examined the impact of malaria...... rapid diagnostic tests (mRDTs) on CHW referral in two cluster-randomized trials, one conducted in a moderate-to-high malaria transmission setting and one in a low-transmission setting in Uganda, between January 2010 and July 2012. All CHWs were trained to prescribe artemisinin-based combination therapy...... (ACT) for malaria and recognize signs and symptoms for referral to health centers. CHWs in the control arm used a presumptive diagnosis for malaria based on clinical symptoms, whereas intervention arm CHWs used mRDTs. CHWs recorded ACT prescriptions, mRDT results, and referral inpatient registers...
Viergever Roderik F
Full Text Available Abstract Information on blinding is part of the data that should be provided upon registration of a trial at a clinical trials registry. Reporting of blinding is often absent or of low quality in published articles of clinical trials. This study researched the presence and quality of information on blinding in registered records of clinical trials and highlights the important role of data-recording formats at clinical trial registries in ensuring high-quality registration.
Meeker-O'Connell, Ann; Glessner, Coleen
Over the past decade, clinical trial quality has evolved from an after-the-fact, reactive activity to one focused on the important work of evidence generation from well-designed trials. This article explores the role the Clinical Trials Transformation Initiative has played in advancing quality as a core element of clinical trial design, through project work that initially focused on monitoring but evolved into a holistic, prospective, and comprehensive quality by design approach to clinical trial design and conduct.
Houzé, Sandrine; Boutron, Isabelle; Marmorat, Anne; Dalichampt, Marie; Choquet, Christophe; Poilane, Isabelle; Godineau, Nadine; Le Guern, Anne-Sophie; Thellier, Marc; Broutier, Hélène; Fenneteau, Odile; Millet, Pascal; Dulucq, Stéphanie; Hubert, Véronique; Houzé, Pascal; Tubach, Florence; Le Bras, Jacques; Matheron, Sophie
We compared the performance of four rapid diagnostic tests (RDTs) for imported malaria, and particularly Plasmodium falciparum infection, using thick and thin blood smears as the gold standard. All the tests are designed to detect at least one protein specific to P. falciparum ( Plasmodium histidine-rich protein 2 (PfHRP2) or Plasmodium LDH (PfLDH)) and one pan-Plasmodium protein (aldolase or Plasmodium LDH (pLDH)). 1,311 consecutive patients presenting to 9 French hospitals with suspected malaria were included in this prospective study between April 2006 and September 2008. Blood smears revealed malaria parasites in 374 cases (29%). For the diagnosis of P. falciparum infection, the three tests detecting PfHRP2 showed high and similar sensitivity (96%), positive predictive value (PPV) (90%) and negative predictive value (NPV) (98%). The PfLDH test showed lower sensitivity (83%) and NPV (80%), despite good PPV (98%). For the diagnosis of non-falciparum species, the PPV and NPV of tests targeting pLDH or aldolase were 94–99% and 52–64%, respectively. PfHRP2-based RDTs are thus an acceptable alternative to routine microscopy for diagnosing P. falciparum malaria. However, as malaria may be misdiagnosed with RDTs, all negative results must be confirmed by the reference diagnostic method when clinical, biological or other factors are highly suggestive of malaria. PMID:24098699
Cihoric, Nikola; Tsikkinis, Alexandros; Miguelez, Cristina Gutierrez; Strnad, Vratislav; Soldatovic, Ivan; Ghadjar, Pirus; Jeremic, Branislav; Dal Pra, Alan; Aebersold, Daniel M; Lössl, Kristina
To evaluate the current status of prospective interventional clinical trials that includes brachytherapy (BT) procedures. The records of 175,538 (100 %) clinical trials registered at ClinicalTrials.gov were downloaded on September 2014 and a database was established. Trials using BT as an intervention were identified for further analyses. The selected trials were manually categorized according to indication(s), BT source, applied dose rate, primary sponsor type, location, protocol initiator and funding source. We analyzed trials across 8 available trial protocol elements registered within the database. In total 245 clinical trials were identified, 147 with BT as primary investigated treatment modality and 98 that included BT as an optional treatment component or as part of the standard treatment. Academic centers were the most frequent protocol initiators in trials where BT was the primary investigational treatment modality (p < 0.01). High dose rate (HDR) BT was the most frequently investigated type of BT dose rate (46.3 %) followed by low dose rate (LDR) (42.0 %). Prostate was the most frequently investigated tumor entity in trials with BT as the primary treatment modality (40.1 %) followed by breast cancer (17.0 %). BT was rarely the primary investigated treatment modality for cervical cancer (6.8 %). Most clinical trials using BT are predominantly in early phases, investigator-initiated and with low accrual numbers. Current investigational activities that include BT mainly focus on prostate and breast cancers. Important questions concerning the optimal usage of BT will not be answered in the near future.
Cihoric, Nikola; Tsikkinis, Alexandros; Miguelez, Cristina Gutierrez; Strnad, Vratislav; Soldatovic, Ivan; Ghadjar, Pirus; Jeremic, Branislav; Dal Pra, Alan; Aebersold, Daniel M.; Lössl, Kristina
To evaluate the current status of prospective interventional clinical trials that includes brachytherapy (BT) procedures. The records of 175,538 (100 %) clinical trials registered at ClinicalTrials.gov were downloaded on September 2014 and a database was established. Trials using BT as an intervention were identified for further analyses. The selected trials were manually categorized according to indication(s), BT source, applied dose rate, primary sponsor type, location, protocol initiator and funding source. We analyzed trials across 8 available trial protocol elements registered within the database. In total 245 clinical trials were identified, 147 with BT as primary investigated treatment modality and 98 that included BT as an optional treatment component or as part of the standard treatment. Academic centers were the most frequent protocol initiators in trials where BT was the primary investigational treatment modality (p < 0.01). High dose rate (HDR) BT was the most frequently investigated type of BT dose rate (46.3 %) followed by low dose rate (LDR) (42.0 %). Prostate was the most frequently investigated tumor entity in trials with BT as the primary treatment modality (40.1 %) followed by breast cancer (17.0 %). BT was rarely the primary investigated treatment modality for cervical cancer (6.8 %). Most clinical trials using BT are predominantly in early phases, investigator-initiated and with low accrual numbers. Current investigational activities that include BT mainly focus on prostate and breast cancers. Important questions concerning the optimal usage of BT will not be answered in the near future. The online version of this article (doi:10.1186/s13014-016-0624-8) contains supplementary material, which is available to authorized users
Koch, H J; Raschka, C
Clinical trials in volunteers and patients are essential to ensure rational treatment of patients. As a rule, drugs are routinely developed for adults, but children are excluded. A major reason for this restriction are ethical justifications, in particular the lack of autonomy on the part of children. The principle of fairness, however, requires that everyone should benefit from progress. Industry, science and society are therefore called upon to find ways of making available safe and adequate treatment for children as quickly as possible, by defining the required conditions for pediatric clinical trials. Important principles are minimal risk, minimal invasivity, rapid decision-making, and careful documentation of trial results. Dynamic ethical principles, such as autonomy and competence in adolescents must be considered on equal footing with existing international GCP guidelines. Aspects of child psychology indicate that the autonomy of adolescents should be respected. Where economic incentives for such trials are absent, for example, in the case of non-pharmacological problems, pediatric trials must be considered a task for society as a whole.
malaria transmission.ClinicalTrials.gov NCT00712374.
Dynamics of malaria transmission and susceptibility to clinical malaria episodes following treatment of Plasmodium falciparum asymptomatic carriers: results of a cluster-randomized study of community-wide screening and treatment, and a parallel entomology study.
Tiono, Alfred B; Guelbeogo, Moussa W; Sagnon, N Falé; Nébié, Issa; Sirima, Sodiomon B; Mukhopadhyay, Amitava; Hamed, Kamal
In malaria-endemic countries, large proportions of individuals infected with Plasmodium falciparum are asymptomatic and constitute a reservoir of parasites for infection of newly hatched mosquitoes. Two studies were run in parallel in Burkina Faso to evaluate the impact of systematic identification and treatment of asymptomatic carriers of P. falciparum, detected by rapid diagnostic test, on disease transmission and susceptibility to clinical malaria episodes. A clinical study assessed the incidence of symptomatic malaria episodes with a parasite density >5,000/μL after three screening and treatment campaigns ~1 month apart before the rainy season; and an entomological study determined the effect of these campaigns on malaria transmission as measured by entomological inoculation rate. The intervention arm had lower prevalence of asymptomatic carriers of asexual parasites and lower prevalence of gametocyte carriers during campaigns 2 and 3 as compared to the control arm. During the entire follow-up period, out of 13,767 at-risk subjects, 2,516 subjects (intervention arm 1,332; control arm 1,184) had symptomatic malaria. Kaplan-Meier analysis of the incidence of first symptomatic malaria episode with a parasite density >5,000/μL showed that, in the total population, the two treatment arms were similar until Week 11-12 after campaign 3, corresponding with the beginning of the malaria transmission season, after which the probability of being free of symptomatic malaria was lower in the intervention arm (logrank p entomological inoculation rate was comparable in both arms, with September peaks in both indices. Community screening and targeted treatment of asymptomatic carriers of P. falciparum had no effect on the dynamics of malaria transmission, but seemed to be associated with an increase in the treated community's susceptibility to symptomatic malaria episodes after the screening campaigns had finished. These results highlight the importance of further
Taylor, Walter R J; Cañon, Viviam; White, Nicholas J
Lung involvement in malaria has been recognized for more than 200 hundred years, yet our knowledge of its pathogenesis and management is limited. Pulmonary edema is the most severe form of lung involvement. Increased alveolar capillary permeability leading to intravascular fluid loss into the lungs is the main pathophysiologic mechanism. This defines malaria as another cause of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).Pulmonary edema has been described most often in non-immune individuals with Plasmodium falciparum infections as part of a severe systemic illness or as the main feature of acute malaria. P.vivax and P.ovale have also rarely caused pulmonary edema.Clinically, patients usually present with acute breathlessness that can rapidly progress to respiratory failure either at disease presentation or, interestingly, after treatment when clinical improvement is taking place and the parasitemia is falling. Pregnant women are particularly prone to developing pulmonary edema. Optimal management of malaria-induced ALI/ARDS includes early recognition and diagnosis. Malaria must always be suspected in a returning traveler or a visitor from a malaria-endemic country with an acute febrile illness. Slide microscopy and/or the use of rapid antigen tests are standard diagnostic tools. Malaria must be treated with effective drugs, but current choices are few: e.g. parenteral artemisinins, intravenous quinine or quinidine (in the US only). A recent trial in adults has shown that intravenous artesunate reduces severe malaria mortality by a third compared with adults treated with intravenous quinine. Respiratory compromise should be managed on its merits and may require mechanical ventilation.Patients should be managed in an intensive care unit and particular attention should be paid to the energetic management of other severe malaria complications, notably coma and acute renal failure. ALI/ARDS may also be related to a coincidental bacterial
. Conclusion This research was conducted to inform LLIN procurement as part of the national malaria control and elimination programme in SI. The success of malaria elimination in the Pacific and elsewhere relies on provision of acceptable interventions, consideration of local-level realities and engagement of communities in strategy development. Trial Registrations Clinical trials ACTRN12608000322336
Hideghety, K.; Moss, R.; Vries, M. de
Due to ethical reasons, a separated optimization of the two components of BNCT in the frame of clinical investigations can only be performed applying the whole binary system. The ongoing trial at HFR (High Flux Reactor Petten) has proven the feasibility of BNCT under defined conditions. On that basis the European Commission supported a comprehensive research project on boron imaging including three further clinical studies. In the first trial the boron uptake related to the blood boron concentration and surrounding normal tissue in various solid tumours will be examined using BSH (Sodiumborocaptate), BPA (Boronophenylalanine) or both in order to explore tumour entities, which may gain benefit from BNCT. The major objectives of the second trial are to define the maximum tolerated single and cumulative dose, and the dose limiting toxicity of BSH. The third clinical trial, a phase II study is designed to evaluate the anti-tumour effect of fractionated BNCT at the Petten treatment facility against cerebral metastasis of malignant melanoma using BPA. (author)
Rosa, Carmen; Campbell, Aimee N C; Miele, Gloria M; Brunner, Meg; Winstanley, Erin L
Clinical trials have been slow to incorporate e-technology (digital and electronic technology that utilizes mobile devices or the Internet) into the design and execution of studies. In the meantime, individuals and corporations are relying more on electronic platforms and most have incorporated such technology into their daily lives. This paper provides a general overview of the use of e-technologies in clinical trials research, specifically within the last decade, marked by rapid growth of mobile and Internet-based tools. Benefits of and challenges to the use of e-technologies in data collection, recruitment and retention, delivery of interventions, and dissemination are provided, as well as a description of the current status of regulatory oversight of e-technologies in clinical trials research. As an example of ways in which e-technologies can be used for intervention delivery, a summary of e-technologies for treatment of substance use disorders is presented. Using e-technologies to design and implement clinical trials has the potential to reach a wide audience, making trials more efficient while also reducing costs; however, researchers should be cautious when adopting these tools given the many challenges in using new technologies, as well as threats to participant privacy/confidentiality. Challenges of using e-technologies can be overcome with careful planning, useful partnerships, and forethought. The role of web- and smartphone-based applications is expanding, and the increasing use of those platforms by scientists and the public alike make them tools that cannot be ignored. Published by Elsevier Inc.
Ling, Judith; Baird, J Kevin; Fryauff, David J; Sismadi, Priyanto; Bangs, Michael J; Lacy, Mark; Barcus, Mazie J; Gramzinski, Robert; Maguire, Jason D; Kumusumangsih, Marti; Miller, Gerri B; Jones, Trevor R; Chulay, Jeffrey D; Hoffman, Stephen L
The increasing prevalence of resistance to antimalarial drugs reduces options for malaria prophylaxis. Atovaquone/proguanil (Malarone; GlaxoSmithKline) has been >95% effective in preventing Plasmodium falciparum malaria in lifelong residents of areas of holoendemicity, but data from persons without clinical immunity or who are at risk for Plasmodium vivax malaria have not been described. We conducted a randomized, double-blinded study involving 297 people from areas of nonendemicity in Indonesia who migrated to Papua (where malaria is endemic) proguanil hydrochloride; n=148) or placebo (n=149) per day for 20 weeks. Hematologic and clinical chemistry values did not change significantly. The protective efficacy of atovaquone/proguanil was 84% (95% confidence interval [CI], 44%-95%) for P. vivax malaria, 96% (95% CI, 72%-99%) for P. falciparum malaria, and 93% (95% CI, 77%-98%) overall. Atovaquone/proguanil was well tolerated, safe, and effective for the prevention of drug-resistant P. vivax and P. falciparum malaria in individuals without prior malaria exposure who migrated to Papua, Indonesia.
challenges of studying the severe malaria syndromes using proteomics were the high complexity and variability among the samples. We hypothesized that hepatic injury and nitric oxide play roles in the pathophysiology of cerebral malaria and respiratory
McGraw, Deven; Greene, Sarah M; Miner, Caroline S; Staman, Karen L; Welch, Mary Jane; Rubel, Alan
With pragmatic clinical trials, an opportunity exists to answer important questions about the relative risks, burdens, and benefits of therapeutic interventions. However, concerns about protecting the privacy of this information are significant and must be balanced with the imperative to learn from the data gathered in routine clinical practice. Traditional privacy protections for research uses of identifiable information rely disproportionately on informed consent or authorizations, based on a presumption that this is necessary to fulfill ethical principles of respect for persons. But frequently, the ideal of informed consent is not realized in its implementation. Moreover, the principle of respect for persons—which encompasses their interests in health information privacy—can be honored through other mechanisms. Data anonymization also plays a role in protecting privacy but is not suitable for all research, particularly pragmatic clinical trials. In this article, we explore both the ethical foundation and regulatory framework intended to protect privacy in pragmatic clinical trials. We then review examples of novel approaches to respecting persons in research that may have the added benefit of honoring patient privacy considerations. © The Author(s) 2015.
Martinez, Diego A; Tsalatsanis, Athanasios; Yalcin, Ali; Zayas-Castro, José L; Djulbegovic, Benjamin
The administrative process associated with clinical trial activation has been criticized as costly, complex, and time-consuming. Prior research has concentrated on identifying administrative barriers and proposing various solutions to reduce activation time, and consequently associated costs. Here, we expand on previous research by incorporating social network analysis and discrete-event simulation to support process improvement decision-making. We searched for all operational data associated with the administrative process of activating industry-sponsored clinical trials at the Office of Clinical Research of the University of South Florida in Tampa, Florida. We limited the search to those trials initiated and activated between July 2011 and June 2012. We described the process using value stream mapping, studied the interactions of the various process participants using social network analysis, and modeled potential process modifications using discrete-event simulation. The administrative process comprised 5 sub-processes, 30 activities, 11 decision points, 5 loops, and 8 participants. The mean activation time was 76.6 days. Rate-limiting sub-processes were those of contract and budget development. Key participants during contract and budget development were the Office of Clinical Research, sponsors, and the principal investigator. Simulation results indicate that slight increments on the number of trials, arriving to the Office of Clinical Research, would increase activation time by 11 %. Also, incrementing the efficiency of contract and budget development would reduce the activation time by 28 %. Finally, better synchronization between contract and budget development would reduce time spent on batching documentation; however, no improvements would be attained in total activation time. The presented process improvement analytic framework not only identifies administrative barriers, but also helps to devise and evaluate potential improvement scenarios. The strength
Beach, J E
When contract research organizations (CROs) were first formed, pharmaceutical companies outsourced to them only certain aspects of the conduct of their clinical trials. At first CROs were highly specialized entities, providing, for example, either biostatistical advice, clinical research associates who monitored investigational sites for regulatory compliance, or regulatory support. Gradually, full service CROs emerged, offering a full range of services for clinical trials, including the selection of investigators and investigational sites, assistance with patient recruitment, safety surveillance and reporting, site audits, and data management and biostatistics. This evolving relationship between CROs and the pharmaceutical and medical device industries has resulted in CROs assuming more and more of the regulatory and ethical risks and responsibilities inherent in the conduct of clinical trials. In this full service role, CROs, unlike sponsors, are not interested in the outcome of study, but like sponsors, are subject to heavy regulation by the federal government, must follow applicable state laws, must respect international guidelines, and are obliged to follow their own operating procedures. Moreover, they are judged by the industry on the basis of the scope and quality of services provided, including the degree of adherence to the research protocol, regulatory requirements, and timelines; the quality of the professional working relationships with investigators and institutions, both academic and community-based; and the validity of the data. Further, CROs are subject to comprehensive audits by sponsoring companies, FDA, and other regulatory authorities. For all these reasons, CROs are being tasked with strict vigilance of all stages of the clinical trial process to ensure that the laws, regulations, and industry standards designed for the protection of human subjects and data integrity are maintained.
Dal-Ré, Rafael; Moher, David; Gluud, Christian
Rafael Dal-Ré and colleagues argue that the recruitment targets and performance of all site investigators in multi-centre clinical trials should be disclosed in trial registration sites before a trial starts, and when it ends.......Rafael Dal-Ré and colleagues argue that the recruitment targets and performance of all site investigators in multi-centre clinical trials should be disclosed in trial registration sites before a trial starts, and when it ends....
Huang, Grant D; Bull, Jonca; Johnston McKee, Kelly; Mahon, Elizabeth; Harper, Beth; Roberts, Jamie N
Patient recruitment is widely recognized as a key determinant of success for clinical trials. Yet a substantial number of trials fail to reach recruitment goals-a situation that has important scientific, financial, ethical, and policy implications. Further, there are important effects on stakeholders who directly contribute to the trial including investigators, sponsors, and study participants. Despite efforts over multiple decades to identify and address barriers, recruitment challenges persist. To advance a more comprehensive approach to trial recruitment, the Clinical Trials Transformation Initiative (CTTI) convened a project team to examine the challenges and to issue actionable, evidence-based recommendations for improving recruitment planning that extend beyond common study-specific strategies. We describe our multi-stakeholder effort to develop a framework that delineates three areas essential to strategic recruitment planning efforts: (1) trial design and protocol development, (2) trial feasibility and site selection, and (3) communication. Our recommendations propose an upstream approach to recruitment planning that has the potential to produce greater impact and reduce downstream barriers. Additionally, we offer tools to help facilitate adoption of the recommendations. We hope that our framework and recommendations will serve as a guide for initial efforts in clinical trial recruitment planning irrespective of disease or intervention focus, provide a common basis for discussions in this area and generate targets for further analysis and continual improvement. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Rachel G. Greenberg
In order for clinical trial accrual to be successful, parents' priorities and considerations must be a central focus, beginning with initial trial design. The recommendations from the parents who participated in this study can be used to support budget allocations that ensure adequate training of study staff and improved staffing on nights and weekends. Studies of parent responses in outpatient settings and additional inpatient settings will provide valuable information on the consent process from the child's and parent's perspectives. Further studies are needed to explore whether implementation of such strategies will result in improved recruitment for pediatric clinical trials.
Giha, H A; Elghazali, G; A-Elgadir, T M E
A hospital-based study was carried out in Gedarif town, eastern Sudan, an area of markedly unstable malaria transmission. Among the 2488 diagnosed malaria patients, 4.4% fulfilled the WHO criteria for severe malaria, and seven died of cerebral malaria. The predominant complication was severe mala...
Kiss, Daniel; Anwaruddin, Saif
With widespread adoption of transcatheter aortic valve replacement, there has been a change in the approach to management of valvular heart disease. New interest has taken hold in transcatheter therapies for valvular heart disease, as well as research into pathophysiology and progression of disease. Additionally, several key trials have further refined our understanding of surgical management of valvular heart disease. This review will elucidate recent clinical trial data leading to changes in practice. There have been several landmark trials expanding the indications for transcatheter aortic valve replacement. Additionally, although still early, trials are beginning to demonstrate the feasibility and safety of transcatheter mitral valves. Options for transcatheter management of right-sided valvular disease continue to evolve, and these are areas of active investigation. The emergence of novel therapies for valvular heart disease has expanded the management options available, allowing physicians to better individualize treatment of patients with valvular heart disease. This review will focus on the recent (within 2 years) trials in this field of interest.
Kuria Isabel W
Full Text Available Abstract Background The study sought to determine the effect of using insecticide-treated clothes (ITCs on personal protection against malaria infection. The specific objectives were to determine the effect of using ITCs on the rate of infection with malaria parasites and the effect on indoor mosquito density. Methods This study was done in Dadaab refugee camps, North Eastern Province Kenya between April and August 2002, and involved a total of 198 participants, all refugees of Somali origin. The participants were selected through multi-stage cluster sampling. Half of the participants (treatment group had their personal clothes worn on a daily basis (Diras, Saris, Jalbaabs, Ma'awis and shirts and their bedding (sheets and blankets treated with insecticide (permethrin. The other half (comparison group had their clothes treated with placebo (plain water. Indoor mosquito density was determined from twelve households belonging to the participants; six in the treatment block and six in the comparison block. During pre-test and post-test, laboratory analysis of blood samples was done, indoor mosquito density determined and questionnaires administered. Using STATA statistical package, tests for significant difference between the two groups were conducted. Results Use of ITCs reduced both malaria infection rates and indoor mosquito density significantly. The odds of malaria infection in the intervention group were reduced by about 70 percent. The idea of using ITCs for malaria infection control was easily accepted among the refugees and they considered it beneficial. No side effects related to use of the ITCs were observed from the participants. Conclusion The use of ITCs reduces malaria infection rate and has potential as an appropriate method of malaria control. It is recommended, therefore, that this strategy be considered for use among poor communities like slum dwellers and other underprivileged communities, such as street children and refugees
Tagbor, Harry; Cairns, Matthew; Bojang, Kalifa
BACKGROUND: The efficacy of intermittent preventive treatment for malaria with sulfadoxine-pyrimethamine (IPTp-SP) in pregnancy is threatened in parts of Africa by the emergence and spread of resistance to SP. Intermittent screening with a rapid diagnostic test (RDT) and treatment of positive women...... with malaria parasitemia between routine antenatal clinics (310 vs 182 episodes, rate difference: 49.4 per 1,000 pregnancies [95% CI 30.5, 68.3], but the number of hospital admissions for malaria was similar in the two groups. CONCLUSIONS: Despite low levels of resistance to SP in the study areas, ISTp......-AL performed as well as IPTp-SP. In the absence of an effective alternative medication to SP for IPTp, ISTp-AL is a potential alternative to IPTp in areas where SP resistance is high. It may also have a role in areas where malaria transmission is low and for the prevention of malaria in HIV positive women...
Prognostic value of clinical and parasitological signs for severe malaria in patients from Colombia Utilidad pronóstica para malaria grave de signos clínicos y parasitológicos en pacientes de Colombia
Full Text Available Introduction. Early recognition of danger signs in patients with malaria can reduce complications and deaths, but little is known about its prognostic value for severe malaria, especially in areas of low transmission and unstable malaria.
Objective. Assess the prognostic value for gravity that has different clinical and parasitological signs in patients with malaria.
Materials and methods. A prospective cohort of patients from five municipalities in Colombia with diagnosis of malaria by Plasmodium falciparum or P. vivax, in whom was studied the association between clinical and parasitological signs with complicated malaria. Results. Was obtained a predictive model with a 47,4% sensitivity, 92,8% specificity, 63,2% positive predictive value and 87,1% negative predictive value, that includes jaundice, dark urine, hyperpyrexia and signs of dehydration.
Conclusions. To impact the complicated cases caused by malaria it is proposed a strategy for the early recognition of danger signs by non-medical personnel, which could be accompanied by other elements of the healthcare, such as providing an adequate and appropriate antimalarial treatment. Also are proposed diagnostic criteria for moderate complications.
Introducción. El reconocimiento temprano de signos de peligro en los pacientes con malaria puede reducir las complicaciones y muertes, sin embargo se conoce poco acerca de su valor pronóstico para malaria complicada, especialmente en zonas de transmisión baja e inestable de malaria.
Objetivo. Estimar el valor pronóstico de gravedad que tienen diversos signos clínicos y parasitológicos en pacientes con malaria.
Materiales y métodos. Cohorte prospectiva con pacientes de cinco municipios de Colombia con diagnóstico de malaria por Plasmodium falciparum y P. vivax, en quienes se estudió la asociación entre signos clínicos y parasitológicos con malaria complicada.
Resultados. Se obtuvo un modelo predictivo con
Phyo, Aung Pyae; Jittamala, Podjanee; Nosten, François H; Pukrittayakamee, Sasithon; Imwong, Mallika; White, Nicholas J; Duparc, Stephan; Macintyre, Fiona; Baker, Mark; Möhrle, Jörg J
Artefenomel (OZ439) is a novel synthetic trioxolane with improved pharmacokinetic properties compared with other antimalarial drugs with the artemisinin pharmacophore. Artefenomel has been generally well tolerated in volunteers at doses up to 1600 mg and is being developed as a partner drug in an antimalarial combination treatment. We investigated the efficacy, tolerability, and pharmacokinetics of artefenomel at different doses in patients with Plasmodium falciparum or Plasmodium vivax malaria. This phase 2a exploratory, open-label trial was done at the Hospital for Tropical Diseases, Bangkok, and the Shoklo Malaria Research Unit in Thailand. Adult patients with acute, uncomplicated P falciparum or P vivax malaria received artefenomel in a single oral dose (200 mg, 400 mg, 800 mg, or 1200 mg). The first cohort received 800 mg. Testing of a new dose of artefenomel in a patient cohort was decided on after safety and efficacy assessment of the preceding cohort. The primary endpoint was the natural log parasite reduction per 24 h. Definitive oral treatment was given at 36 h. This trial is registered with ClinicalTrials.gov, number NCT01213966. Between Oct 24, 2010, and May 25, 2012, 82 patients were enrolled (20 in each of the 200 mg, 400 mg, and 800 mg cohorts, and 21 in the 1200 mg cohort). One patient withdrew consent (before the administration of artefenomel) but there were no further dropouts. The parasite reduction rates per 24 h ranged from 0·90 to 1·88 for P falciparum, and 2·09 to 2·53 for P vivax. All doses were equally effective in both P falciparum and P vivax malaria, with median parasite clearance half-lives of 4·1 h (range 1·3-6·7) to 5·6 h (2·0-8·5) for P falciparum and 2·3 h (1·2-3·9) to 3·2 h (0·9-15·0) for P vivax. Maximum plasma concentrations, dose-proportional to 800 mg, occurred at 4 h (median). The estimated elimination half-life was 46-62 h. No serious drug-related adverse effects were reported; other adverse effects were
Kumar, Sanjai; Epstein, Judith E; Richie, Thomas L; Nkrumah, Francis K; Soisson, Lorraine; Carucci, Daniel J; Hoffman, Stephen L
Scientists from several organizations worldwide are working together to develop a multistage, multigene DNA-based vaccine against Plasmodium falciparum malaria. This collaborative vaccine development effort is named Multi-Stage DNA-based Malaria Vaccine Operation. An advisory board of international experts in vaccinology, malariology and field trials provides the scientific oversight to support the operation. This article discusses the rationale for the approach, underlying concepts and the pre-clinical development process, and provides a brief outline of the plans for the clinical testing of a multistage, multiantigen malaria vaccine based on DNA plasmid immunization technology.
Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5–17 months in Kenya and Tanzania: a randomised controlled trial
Olotu, Ally; Lusingu, John; Leach, Amanda; Lievens, Marc; Vekemans, Johan; Msham, Salum; Lang, Trudie; Gould, Jayne; Dubois, Marie-Claude; Jongert, Erik; Vansadia, Preeti; Carter, Terrell; Njuguna, Patricia; Awuondo, Ken O; Malabeja, Anangisye; Abdul, Omar; Gesase, Samwel; Mturi, Neema; Drakeley, Chris J; Savarese, Barbara; Villafana, Tonya; Lapierre, Didier; Ballou, W Ripley; Cohen, Joe; Lemnge, Martha M; Peshu, Norbert; Marsh, Kevin; Riley, Eleanor M; von Seidlein, Lorenz; Bejon, Philip
Summary Background RTS,S/AS01E is the lead candidate malaria vaccine. We recently showed efficacy against clinical falciparum malaria in 5–17 month old children, during an average of 8 months follow-up. We aimed to assess the efficacy of RTS,S/AS01E during 15 months of follow-up. Methods Between March, 2007, and October, 2008, we enrolled healthy children aged 5–17 months in Kilifi, Kenya, and Korogwe, Tanzania. Computer-generated block randomisation was used to randomly assign participants (1:1) to receive three doses (at month 0, 1, and 2) of either RTS,S/AS01E or human diploid-cell rabies vaccine. The primary endpoint was time to first clinical malaria episode, defined as the presence of fever (temperature ≥37·5°C) and a Plasmodium falciparum density of 2500/μL or more. Follow-up was 12 months for children from Korogwe and 15 months for children from Kilifi. Primary analysis was per protocol. In a post-hoc modelling analysis we characterised the associations between anti-circumsporozoite antibodies and protection against clinical malaria episodes. This study is registered with ClinicalTrials.gov, number NCT00380393. Findings 894 children were assigned, 447 in each treatment group. In the per-protocol analysis, 82 of 415 children in the RTS,S/AS01E group and 125 of 420 in the rabies vaccine group had first or only clinical malaria episode by 12 months, vaccine efficacy 39·2% (95% CI 19·5–54·1, p=0·0005). At 15 months follow-up, 58 of 209 children in the RTS,S/AS01E group and 85 of 206 in the rabies vaccine group had first or only clinical malaria episode, vaccine efficacy 45·8% (24·1–61·3, p=0·0004). At 12 months after the third dose, anti-circumsporozoite antibody titre data were available for 390 children in the RTS,S/AS01E group and 391 in the rabies group. A mean of 15 months (range 12–18 months) data were available for 172 children in the RTS,S/AS01E group and 155 in the rabies group. These titres at 1 month after the third dose were
A cost-effectiveness analysis of provider interventions to improve health worker practice in providing treatment for uncomplicated malaria in Cameroon: a study protocol for a randomized controlled trial
Full Text Available Abstract Background Governments and donors all over Africa are searching for sustainable, affordable and cost-effective ways to improve the quality of malaria case management. Widespread deficiencies have been reported in the prescribing and counselling practices of health care providers treating febrile patients in both public and private health facilities. Cameroon is no exception with low levels of adherence to national guidelines, the frequent selection of non-recommended antimalarials and the use of incorrect dosages. This study evaluates the effectiveness and cost-effectiveness of introducing two different provider training packages, alongside rapid diagnostic tests (RDTs, designed to equip providers with the knowledge and practical skills needed to effectively diagnose and treat febrile patients. The overall aim is to target antimalarial treatment better and to facilitate optimal use of malaria treatment guidelines. Methods/Design A 3-arm stratified, cluster randomized trial will be conducted to assess whether introducing RDTs with provider training (basic or enhanced is more cost-effective than current practice without RDTs, and whether there is a difference in the cost effectiveness of the provider training interventions. The primary outcome is the proportion of patients attending facilities that report a fever or suspected malaria and receive treatment according to malaria guidelines. This will be measured by surveying patients (or caregivers as they exit public and mission health facilities. Cost-effectiveness will be presented in terms of the primary outcome and a range of secondary outcomes, including changes in provider knowledge. Costs will be estimated from a societal and provider perspective using standard economic evaluation methodologies. Trial Registration ClinicalTrials.gov: NCT00981877
Magris, M; Rubio-Palis, Y; Alexander, N; Ruiz, B; Galván, N; Frias, D; Blanco, M; Lines, J
We conducted a community-randomized controlled trial in an area of moderate malaria transmission in the Amazon region, southern Venezuela, home of the Yanomami indigenous ethnic group. The aim was to compare the malaria incidence rate in villages with lambdacyhalothrin-treated hammock nets (ITHN) or with placebo-treated hammock nets (PTHN). In both arms of the study, intensive surveillance for early case detection was maintained and prompt malaria treatment was administered. Baseline data were collected before the intervention and a population of around 924 Yanomami was followed for 2 years. Despite the recent introduction of nets in the Yanomami villages and the adverse natural conditions in the area, the nets were accepted enthusiastically by the study population, used conscientiously and looked after carefully. The malaria incidence rate per thousand person-years at risk was 114.6 in the IHTN group and 186.8 in the PTHN group. The adjusted rate ratios indicated that ITHN prevent 56% [IRR: 0.44, 95% confidence interval (CI): 52-59%] of new malaria cases. ITHN reduced the prevalence of parasitaemia by 83% [relative risks (RR): 0.17, 95% CI: 47-100%], according to a cross-sectional survey carried out during the high transmission season. The prevalence of splenomegaly and anaemia was too low to detect any possible reduction as a result of ITHN. The main conclusion of the present study is that ITHN can reduce malaria incidence in the area and it is the most feasible method for malaria control in a forested area where indigenous villages are scattered over a large territory. This is the first community-level epidemiological trial to show that ITHN are highly effective against malaria transmitted by Anopheles darlingi.
Kloppenburg, M; Maheu, E; Kraus, V B; Cicuttini, F; Doherty, M; Dreiser, R-L; Henrotin, Y; Jiang, G-L; Mandl, L; Martel-Pelletier, J; Nelson, A E; Neogi, T; Pelletier, J-P; Punzi, L; Ramonda, R; Simon, L S; Wang, S
Hand osteoarthritis (OA) is a very frequent disease, but yet understudied. However, a lot of works have been published in the past 10 years, and much has been done to better understand its clinical course and structural progression. Despite this new knowledge, few therapeutic trials have been conducted in hand OA. The last OARSI recommendations for the conduct of clinical trials in hand OA dates back to 2006. The present recommendations aimed at updating previous recommendations, by incorporating new data. The purpose of this expert opinion, consensus driven exercise is to provide evidence-based guidance on the design, execution and analysis of clinical trials in hand OA, where published evidence is available, supplemented by expert opinion, where evidence is lacking, to perform clinical trials in hand OA, both for symptom and for structure-modification. They indicate core outcome measurement sets for studies in hand OA, and list the methods and instruments that should be used to measure symptoms or structure. For both symptom- and structure-modification, at least pain, physical function, patient global assessment, HR-QoL, joint activity and hand strength should be assessed. In addition, for structure-modification trials, structural progression should be measured by radiographic changes. We also provide a research agenda listing many unsolved issues that seem to most urgently need to be addressed from the perspective of performing "good" clinical trials in hand OA. These updated OARSI recommendations should allow for better standardizing the conduct of clinical trials in hand OA in the next future. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Kraus, V B; Blanco, F J; Englund, M; Henrotin, Y; Lohmander, L S; Losina, E; Önnerfjord, P; Persiani, S
The objective of this work was to describe requirements for inclusion of soluble biomarkers in osteoarthritis (OA) clinical trials and progress toward OA-related biomarker qualification. The Guidelines for Biomarkers Working Group, representing experts in the field of OA biomarker research from both academia and industry, convened to discuss issues related to soluble biomarkers and to make recommendations for their use in OA clinical trials based on current knowledge and anticipated benefits. This document summarizes current guidance on use of biomarkers in OA clinical trials and their utility at five stages, including preclinical development and phase I to phase IV trials. As demonstrated by this summary, biomarkers can provide value at all stages of therapeutics development. When resources permit, we recommend collection of biospecimens in all OA clinical trials for a wide variety of reasons but in particular, to determine whether biomarkers are useful in identifying those individuals most likely to receive clinically important benefits from an intervention; and to determine whether biomarkers are useful for identifying individuals at earlier stages of OA in order to institute treatment at a time more amenable to disease modification. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Kurbel, Sven; Mihaljević, Slobodan
Clinical trial results are often interpreted by inductive reasoning, in a trial design-limited manner, directed toward modifications of the current clinical practice. Deductive reasoning is an alternative in which results of relevant trials are combined in indisputable premises that lead to a conclusion easily testable in future trials. © 2017 WILEY Periodicals, Inc.
Natama, Hamtandi Magloire; Ouedraogo, Delwendé Florence; Sorgho, Hermann; Rovira-Vallbona, Eduard; Serra-Casas, Elisa; Somé, M. Athanase; Coulibaly-Traoré, Maminata; Mens, Petra F.; Kestens, Luc; Tinto, Halidou; Rosanas-Urgell, Anna
Congenital malaria diagnosis is challenging due to frequently observed low parasite density infections, while their clinical relevance during early infancy is not well characterized. In Nanoro health district (Burkina Faso), we determined the prevalence of congenital malaria by real-time
Kokwaro, Gilbert O; Ogutu, Bernhards R; Muchohi, Simon N; Otieno, Godfrey O; Newton, Charles R J C
Aims Phenobarbital is commonly used to treat status epilepticus in resource-poor countries. Although a dose of 20 mg kg−1 is recommended, this dose, administered intramuscularly (i.m.) for prophylaxis, is associated with an increase in mortality in children with cerebral malaria. We evaluated a 15-mg kg−1 intravenous (i.v.) dose of phenobarbital to determine its pharmacokinetics and clinical effects in children with severe falciparum malaria and status epilepticus. Methods Twelve children (M/F: 11/1), aged 7–62 months, received a loading dose of phenobarbital (15 mg kg−1) as an i.v. infusion over 20 min and maintenance dose of 5 mg kg−1 at 24 and 48 h later. The duration of convulsions and their recurrence were recorded. Vital signs were monitored. Plasma and cerebrospinal fluid (CSF) phenobarbital concentrations were measured with an Abbott TDx FLx® fluorescence polarisation immunoassay analyser (Abbott Laboratories, Diagnostic Division, Abbott Park, IL, USA). Simulations were performed to predict the optimum dosage regimen that would maintain plasma phenobarbital concentrations between 15 and 20 mg l−1 for 72 h. Results All the children achieved plasma concentrations above 15 mg l−1 by the end of the infusion. Mean (95% confidence interval or median and range for Cmax) pharmacokinetic parameters were: area under curve [AUC (0, ∞) ]: 4259 (3169, 5448) mg l−1.h, t½: 82.9 (62, 103) h, CL: 5.8 (4.4, 7.3) ml kg−1 h−1, Vss: 0.8 (0.7, 0.9) l kg −1, CSF: plasma phenobarbital concentration ratio: 0.7 (0.5, 0.8; n = 6) and Cmax: 19.9 (17.9–27.9) mg l−1. Eight of the children had their convulsions controlled and none of them had recurrence of convulsions. Simulations suggested that a loading dose of 15 mg kg−1 followed by two maintenance doses of 2.5 mg kg−1 at 24 h and 48 h would maintain plasma phenobarbital concentrations between 16.4 and 20 mg l−1 for 72 h. Conclusions Phenobarbital, given as an i.v. loading dose, 15 mg kg−1
Joshi, Vinayak; Agurto, Carla; Barriga, Simon; Nemeth, Sheila; Soliz, Peter; MacCormick, Ian J.; Lewallen, Susan; Taylor, Terrie E.; Harding, Simon P.
Cerebral malaria (CM), a complication of malaria infection, is the cause of the majority of malaria-associated deaths in African children. The standard clinical case definition for CM misclassifies ~25% of patients, but when malarial retinopathy (MR) is added to the clinical case definition, the specificity improves from 61% to 95%. Ocular fundoscopy requires expensive equipment and technical expertise not often available in malaria endemic settings, so we developed an automated software system to analyze retinal color images for MR lesions: retinal whitening, vessel discoloration, and white-centered hemorrhages. The individual lesion detection algorithms were combined using a partial least square classifier to determine the presence or absence of MR. We used a retrospective retinal image dataset of 86 pediatric patients with clinically defined CM (70 with MR and 16 without) to evaluate the algorithm performance. Our goal was to reduce the false positive rate of CM diagnosis, and so the algorithms were tuned at high specificity. This yielded sensitivity/specificity of 95%/100% for the detection of MR overall, and 65%/94% for retinal whitening, 62%/100% for vessel discoloration, and 73%/96% for hemorrhages. This automated system for detecting MR using retinal color images has the potential to improve the accuracy of CM diagnosis.
Ramirez, Amelie G; Wildes, Kimberly; Talavera, Greg; Nápoles-Springer, Anna; Gallion, Kipling; Pérez-Stable, Eliseo J
Ethnic differences in physicians' attitudes and behaviors related to clinical trials might partially account for disparities in clinical trial participation among Latino patients. Literature regarding Latino physicians' clinical trials attitudes and practices, in comparison to White physicians, was lacking. Cross-sectional data from randomly selected physicians (N=695), stratified by ethnicity, were analyzed to test associations of ethnicity with physicians' participation in and attitudes toward referral of patients to clinical trials. Chi-square analyses showed significant (pLatino physicians were significantly less involved in clinical trials than White physicians and found less scientific value in them, highlighting areas for future education and intervention.
DerSimonian, Rebecca; Laird, Nan
In this paper, we revisit a 1986 article we published in this Journal, Meta-Analysis in Clinical Trials, where we introduced a random-effects model to summarize the evidence about treatment efficacy from a number of related clinical trials. Because of its simplicity and ease of implementation, our approach has been widely used (with more than 12,000 citations to date) and the "DerSimonian and Laird method" is now often referred to as the 'standard approach' or a 'popular' method for meta-analysis in medical and clinical research. The method is especially useful for providing an overall effect estimate and for characterizing the heterogeneity of effects across a series of studies. Here, we review the background that led to the original 1986 article, briefly describe the random-effects approach for meta-analysis, explore its use in various settings and trends over time and recommend a refinement to the method using a robust variance estimator for testing overall effect. We conclude with a discussion of repurposing the method for Big Data meta-analysis and Genome Wide Association Studies for studying the importance of genetic variants in complex diseases. Published by Elsevier Inc.
Cummings, J; Aisen, P; Barton, R; Bork, J; Doody, R; Dwyer, J; Egan, J C; Feldman, H; Lappin, D; Truyen, L; Salloway, S; Sperling, R; Vradenburg, G
Alzheimer's disease (AD) drug development is costly, time-consuming, and inefficient. Trial site functions, trial design, and patient recruitment for trials all require improvement. The Global Alzheimer Platform (GAP) was initiated in response to these challenges. Four GAP work streams evolved in the US to address different trial challenges: 1) registry-to-cohort web-based recruitment; 2) clinical trial site activation and site network construction (GAP-NET); 3) adaptive proof-of-concept clinical trial design; and 4) finance and fund raising. GAP-NET proposes to establish a standardized network of continuously funded trial sites that are highly qualified to perform trials (with established clinical, biomarker, imaging capability; certified raters; sophisticated management system. GAP-NET will conduct trials for academic and biopharma industry partners using standardized instrument versions and administration. Collaboration with the Innovative Medicines Initiative (IMI) European Prevention of Alzheimer's Disease (EPAD) program, the Canadian Consortium on Neurodegeneration in Aging (CCNA) and other similar international initiatives will allow conduct of global trials. GAP-NET aims to increase trial efficiency and quality, decrease trial redundancy, accelerate cohort development and trial recruitment, and decrease trial costs. The value proposition for sites includes stable funding and uniform training and trial execution; the value to trial sponsors is decreased trial costs, reduced time to execute trials, and enhanced data quality. The value for patients and society is the more rapid availability of new treatments for AD.
Background. The WHO recommends mefloquine, atovaquone/proguanil, and doxycycline for malaria chemoprophylaxis. Adherence to a drug is determined by many factors. Objective. To detect the determinants of travelers' adherence to malaria chemoprophylaxis. Methods. A prospective comparative study was conducted from January 2012 to July 2013 that included travelers (928 travelers) to malaria endemic countries who visited the THC. They were classified into 3 groups: the 1st is the mefloquine group ...
Andres E. Morales La Madrid
Full Text Available In spite of major recent advances in DIPG molecular characterization, this body of knowledge has not yet translated into better treatments.To date,more than 250 clinical trials evaluating radiotherapy along with conventional cytotoxic chemotherapy as well as newer biologic agents,have failed to improve the dismal outcome when compared to palliative radiation alone.The biology of DIPG remained unknown until recently when the neurosurgical expertise along with the recognition by the scientific and clinical community of the importance of tissue sampling at diagnosis;ideally in the context of a clinical trial and by trained neurosurgical teams to maximize patient safety.These pre-treatment tumor samples,and others coming from tissue obtained post-mortem,have yielded new insights into DIPG molecular biology.We now know that DIPG comprises a heterogeneous disease with variable molecular phenotypes, different from adult high grade glioma,other non-pontine pediatric high grade gliomas and even between pontine gliomas.The discovery of histone H3.3 or H3.1 mutations has been an important step forward in understanding tumor formation,maintenance and progression.Pharmacologic reversal of DIPG histone demethylation therefore offers an important potential intervention strategy for the treatment of DIPG.To date,clinical trials of newly diagnosed or progressive DIPG with epigenetic modifiers have been unsuccessful.Whether this failure represents limited activity of the agents used,their CNS penetration,redundant pathways within the tumor,or the possibility that histone mutations are necessary only to initiate DIPGs but not maintain their growth,suggest that a great deal still needs to be elucidated in both the underlying biology of these pathways,and the drugs designed to target them.In this review, we discuss the role of both epigenetic and genetic mutations within DIPG and the development of treatment strategies directed against the unique abnormalities
Full Text Available OBJECTIVE: In an effort to understand how results of human clinical trials are made public, we analyze a large set of clinical trials registered at ClinicalTrials.gov, the world's largest clinical trial registry. MATERIALS AND METHODS: We considered two trial result artifacts: (1 existence of a trial result journal article that is formally linked to a registered trial or (2 the deposition of a trial's basic summary results within the registry. RESULTS: The study sample consisted of 8907 completed, interventional, phase 2-or-higher clinical trials that were completed in 2006-2009. The majority of trials (72.2% had no structured trial-article link present. A total of 2367 trials (26.6% deposited basic summary results within the registry. Of those, 969 trials (10.9% were classified as trials with extended results and 1398 trials (15.7% were classified as trials with only required basic results. The majority of the trials (54.8% had no evidence of results, based on either linked result articles or basic summary results (silent trials, while a minimal number (9.2% report results through both registry deposition and publication. DISCUSSION: Our study analyzes the body of linked knowledge around clinical trials (which we refer to as the "trialome". Our results show that most trials do not report results and, for those that do, there is minimal overlap in the types of reporting. We identify several mechanisms by which the linkages between trials and their published results can be increased. CONCLUSION: Our study shows that even when combining publications and registry results, and despite availability of several information channels, trial sponsors do not sufficiently meet the mandate to inform the public either via a linked result publication or basic results submission.
Full Text Available Abstract In recent years, clinical trials with stem cells have taken the emerging field in many new directions. While numerous teams continue to refine and expand the role of bone marrow and cord blood stem cells for their vanguard uses in blood and immune disorders, many others are looking to expand the uses of the various types of stem cells found in bone marrow and cord blood, in particular mesenchymal stem cells, to uses beyond those that could be corrected by replacing cells in their own lineage. Early results from these trials have produced mixed results often showing minor or transitory improvements that may be attributed to extracellular factors. More research teams are accelerating the use of other types of adult stem cells, in particular neural stem cells for diseases where beneficial outcome could result from either in-lineage cell replacement or extracellular factors. At the same time, the first three trials using cells derived from pluripotent cells have begun.
Gelinas, Luke; Lynch, Holly Fernandez; Bierer, Barbara E; Cohen, I Glenn
It is not uncommon for multiple clinical trials at the same institution to recruit concurrently from the same patient population. When the relevant pool of patients is limited, as it often is, trials essentially compete for participants. There is evidence that such a competition is a predictor of low study accrual, with increased competition tied to increased recruitment shortfalls. But there is no consensus on what steps, if any, institutions should take to approach this issue. In this article, we argue that an institutional policy that prioritises some trials for recruitment ahead of others is ethically permissible and indeed prima facie preferable to alternative means of addressing recruitment competition. We motivate this view by appeal to the ethical importance of minimising the number of studies that begin but do not complete, thereby exposing their participants to unnecessary risks and burdens in the process. We then argue that a policy of prioritisation can be fair to relevant stakeholders, including participants, investigators and funders. Finally, by way of encouraging and helping to frame future debate, we propose some questions that would need to be addressed when identifying substantive ethical criteria for prioritising between studies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Participation in clinical trials by adult patients is dismally low. No one knows how many patients are offered the opportunity to enroll in trials. NCI researchers are studying how patients hear about trials, whether they discuss enrollment with their providers, and the roles they play in deciding to participate in a trial.
Jiao, X; Liu, G Y; Shan, C O; Zhao, X; Li, X W; Gathmann, I; Royce, C
One hundred and two Chinese out-patients with naturally acquired, previously untreated, falciparum malaria were selected to evaluate the efficacy of a new combination anti-malaria therapy, CGP 56697 (artemether plus benflumetol). In this open non-comparative trial each patient received a combination of 80 mg artemether and 480 mg benflumetol given orally at 0, 8, 24 and 48 hours (total: 320 mg artemether, 1,920 mg benflumetol). Patients were kept for 28 days in a transmission-free hospital in an area with chloroquine resistant falciparum malaria to prevent reinfection and to aid diagnosis of recrudescence. Progress and possible adverse effects were monitored by blood film parasitology, blood biochemistry assays, urinalysis, ECG and X-ray. Ninety-eight of the 102 patients were shown to be free of infection at 28 days, a 96.1% cure rate. Parasite reduction at 24 hours was 99.4%. Time to effect complete parasite clearance ranged from 24 to 54 hours (median 30 hours). Time for fever clearance ranged from 6 to 78 hours (median 18 hours). Recrudescence was low (3.9%). No significant adverse side-effects were encountered. It is concluded that CGP 56697, a combination anti-malaria therapy of artemether with benflumetol, offered a rapid and highly effective treatment for acute uncomplicated falciparum malaria in an area of chloroquine-resistant malaria in China.
Van Pham, Phuc
In recent years, both stem cell research and the clinical application of these promising cells have increased rapidly. About 1000 clinical trials using stem cells have to date been performed globally. More importantly, more than 10 stem cell-based products have been approved in some countries. With the rapid growth of stem cell applications, some countries have used clinical trials as a tool to diminish the rate of clinical stem cell applications. However, the point at which stem cell clinical trials are essential remains unclear. This commentary discusses when stem cell clinical trials are essential for stem cell transplantation therapies.
Gluud, C; Sørensen, T I
to cover investments, core staff, and running costs, but excluding housing costs and costs of randomised clinical trials that do not originate from trial coordination. In return, such a unit should be able to mount and launch 6-7 multicenter randomised clinical trials during a 5 year period, corresponding...
William A. Mattingly
Conclusion: We have designed and implemented a visualization dashboard for managing multi-site clinical trial enrollment in two community acquired pneumonia studies. Information dashboards are useful for clinical trial management. They can be used in a standalone trial or can be included into a larger management system.
Xu, Jun; Zhang, Yaoyun; Wu, Yonghui; Wang, Jingqi; Dong, Xiao; Xu, Hua
In scientific writing, positive credits and negative criticisms can often be seen in the text mentioning the cited papers, providing useful information about whether a study can be reproduced or not. In this study, we focus on citation sentiment analysis, which aims to determine the sentiment polarity that the citation context carries towards the cited paper. A citation sentiment corpus was annotated first on clinical trial papers. The effectiveness of n-gram and sentiment lexicon features, and problem-specified structure features for citation sentiment analysis were then examined using the annotated corpus. The combined features from the word n-grams, the sentiment lexicons and the structure information achieved the highest Micro F-score of 0.860 and Macro-F score of 0.719, indicating that it is feasible to use machine learning methods for citation sentiment analysis in biomedical publications. A comprehensive comparison between citation sentiment analysis of clinical trial papers and other general domains were conducted, which additionally highlights the unique challenges within this domain.
Research in human beings is an important chapter of medical ethics. In recent years, investigation has been taken over by profit driven corporations that must guarantee the medical and commercial application of results. This new model of investigation has generated conflicts of interest in doctor-patient, researcher-subject relationship. The inevitable debate and media reaction has led. These trials of controversial design to regions of the globe where the vulnerability of the populations continues to allow their undertaking. This article includes a historical perspective on experimentation in human beings and the conditions that led to its regulation: the Nuremberg CODE, followed by the Helsinky Declaration in its different versions, and the Belmont Report, that defend the subject according to the ethic of principles used in western medicine. There is then a review of the attempts to change international regulation to reintroduce clinical trials with placebo--which since 1996 is only permitted where there are no therapeutic or diagnostic methods--on populations that would otherwise have no access to treatment. This then leads on to the issue of double standards in medical investigation defended by many investigators and some official entities. The article concludes that it may be prudent to allow local ethical commissions to approve deviation from the established norm if such is necessary to resolve urgent questions of health in the country, but it is unacceptable that any such emergency is used as a reason to reduce the ethical prerequisites, in clinical trials. It also concludes that true urgency is in making available to all who need it the effective products already in existence. Furthermore, that the acceptance of ethical relativism can result in the exploitation of vulnerable third world populations for research programmes that cannot be undertaken in their sponsoring countries due to the ethical restrictions in place.
Kasemsuth, R.; Asavanich, A.; Sucharit, S.; Vutikes, S.; Vutikes, M.; Patamatum, S.
The sporozoite rate, species of parasite and vector are important in the epidemiology of malaria. The investigation of sporozoite by dissection and examination under a microscope is time-consuming and it could be done only on freshly killed mosquitoes. Immunoradiometric assay (IRMA) that can detect, identify and quantify malaria sporozoite (Zavala et al., 1982) was therefore applied to detect sporozoite in laboratory-maintained Anopheles dirus and wild-caught mosquitoes. Study on P. falciparum-infected An. dirus showed that the circumsporozoite (CS) antigen was first found in the abdomen on the 10th day post-infection, whilst the sporozoites were examined in salivary glands from day 15 onwards. The malaria infection in wild-caught mosquitoes were investigated in Anopheles spp collected by human baites from three endemic areas in Thailand. Since the sporozoite rate refers to the presence of sporozoite in the salivary gland, then only head-thorax part of the specimens were detected by IRMA to prevent an exaggeration over the true results. It was found that none of mosquitoes collected from Phrae was positive for malaria. Four out of 1243 An. dirus among eight species collected from Chantaburi were positive for P. falciparum with sporozoites ranged from 270 to 3875. Of all ten species collected from Kanchanaburi, two and one out of 3123 An. minimus were positive for P. falciparum and P. vivax with sporozoites found in head-thorax portions were 1880, 2380 and 1026 respectively. It is evident that the IRMA is suitable for the investigation of malaria sporozoites in this region. The application of this technique in the further epidemiological study is in progress
Full Text Available The RTS,S/AS02(D vaccine has been shown to have a promising safety profile, to be immunogenic and to confer protection against malaria in children and infants.We did a randomized, controlled, phase I/IIb trial of RTS,S/AS02(D given at 10, 14 and 18 weeks of age staggered with routine immunization vaccines in 214 Mozambican infants. The study was double-blind until the young child completed 6 months of follow-up over which period vaccine efficacy against new Plasmodium falciparum infections was estimated at 65.9% (95% CI 42.6-79.8, p<0.0001. We now report safety, immunogenicity and estimated efficacy against clinical malaria up to 14 months after study start. Vaccine efficacy was assessed using Cox regression models. The frequency of serious adverse events was 32.7% in the RTS,S/AS02(D and 31.8% in the control group. The geometric mean titers of anti-circumsporozoite antibodies declined from 199.9 to 7.3 EU/mL from one to 12 months post dose three of RTS,S/AS02(D, remaining 15-fold higher than in the control group. Vaccine efficacy against clinical malaria was 33% (95% CI: -4.3-56.9, p = 0.076 over 14 months of follow-up. The hazard rate of disease per 2-fold increase in anti-CS titters was reduced by 84% (95% CI 35.1-88.2, p = 0.003.The RTS,S/AS02(D malaria vaccine administered to young infants has a good safety profile and remains efficacious over 14 months. A strong association between anti-CS antibodies and risk of clinical malaria has been described for the first time. The results also suggest a decrease of both anti-CS antibodies and vaccine efficacy over time.ClinicalTrials.gov NCT00197028.
... Industry perspective on public clinical trial registries and results databases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...
Luís, H S; Morgado, I; Assunção, V; Bernardo, M F; Leroux, B; Martin, M D; DeRouen, T A; Leitão, J
Dental hygiene activities were developed as part of a randomized clinical trial designed to assess the safety of low-level mercury exposure from dental amalgam restorations. Along with dental-hygiene clinical work, a community programme was implemented after investigators noticed the poor oral hygiene habits of participants, and the need for urgent action to minimize oral health problems in the study population. Clinical and community activity goal was to promote oral health and prevent new disease. Community activities involved participants and their fellow students and were aimed at providing education on oral health in a school environment. Dental hygienists developed clinical work with prophylaxis, sealants application and topical fluoride and implemented the community programme with in-class sessions on oral health themes. Twice a month fluoride mouthrinses and bi-annual tooth brushing instructional activity took place. Participation at dental-hygiene activities, sealed teeth with no need of restoration and dental-plaque-index were measures used to evaluate success of the programme for the participants. Improvement in dental hygiene is shown by the decrease in dental plaque index scores (P dental hygiene activities. Teachers became aware of the problem and included oral-health in school curricula. Dental hygiene activities have shown to be helpful to promote dental hygiene, promote oral health and to provide school-age children with education on habits that will be important for their future good health.
Chan, An-Wen; Tetzlaff, Jennifer M; Altman, Douglas G; Laupacis, Andreas; Gøtzsche, Peter C; Krle A-Jerić, Karmela; Hrobjartsson, Asbjørn; Mann, Howard; Dickersin, Kay; Berlin, Jesse A; Dore, Caroline J; Parulekar, Wendy R; Summerskill, William S M; Groves, Trish; Schulz, Kenneth F; Sox, Harold C; Rockhold, Frank W; Rennie, Drummond; Moher, David
The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol guidelines vary greatly in content and quality. This article describes the systematic development and scope of SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013, a guideline for the minimum content of a clinical trial protocol. The 33-item SPIRIT checklist applies to protocols for all clinical trials and focuses on content rather than format. The checklist recommends a full description of what is planned; it does not prescribe how to design or conduct a trial. By providing guidance for key content, the SPIRIT recommendations aim to facilitate the drafting of high-quality protocols. Adherence to SPIRIT would also enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, sponsors, funders, research ethics committees or institutional review boards, peer reviewers, journals, trial registries, policymakers, regulators, and other key stakeholders.
Šolić, Ivana; Stipčić, Ana; Pavličević, Ivančica; Marušić, Ana
Despite increased visibility of clinical trials through international trial registries, patients often remain uninformed of their existence, especially if they do not have access to adequate information about clinical research, including the language of the information. The aim of this study was to describe the context for transparency of clinical trials in Croatia in relation to countries in Central and Eastern Europe, and to assess how informed Croatian patients are about clinical trials and their accessibility. We assessed the transparency of clinical trials from the data available in the public domain. We also conducted an anonymous survey on a convenience sample of 257 patients visiting two family medicine offices or an oncology department in south Croatia, and members of national patients' associations. Despite legal provisions for transparency of clinical trials in Croatia, they are still not sufficiently visible in the public domain. Among countries from Central and Eastern Europe, Croatia has the fewest number of registered trials in the EU Clinical Trials Registry. 66% of the patients in the survey were aware of the existence of clinical trials but only 15% were informed about possibilities of participating in a trial. Although 58% of the respondents were willing to try new treatments, only 6% actually participated in a clinical trial. Only 2% of the respondents were aware of publicly available trial registries. Our study demonstrates that there is low transparency of clinical trials in Croatia, and that Croatian patients are not fully aware of clinical trials and the possibilities of participating in them, despite reported availability of Internet resources and good communication with their physicians. There is a need for active policy measures to increase the awareness of and access to clinical trials to patients in Croatia, particularly in their own language.
Sivaramakrishnan, Gowri; Sridharan, Kannan
Clinical trials are the back bone for evidence-based practice (EBP) and recently EBP has been considered the best source of treatment strategies available. Clinical trial registries serve as databases of clinical trials. As regards to dentistry in specific data on the number of clinical trials and their quality is lacking. Hence, the present study was envisaged. Clinical trials registered in WHO-ICTRP (http://apps.who.int/trialsearch/AdvSearch.aspx) in dental specialties were considered. The details assessed from the collected trials include: Type of sponsors; Health condition; Recruitment status; Study design; randomization, method of randomization and allocation concealment; Single or multi-centric; Retrospective or prospective registration; and Publication status in case of completed studies. A total of 197 trials were identified. Maximum trials were from United States (n = 30) and United Kingdom (n = 38). Seventy six trials were registered in Clinical Trials.gov, 54 from International Standards of Reporting Clinical Trials, 13 each from Australia and New Zealand Trial Register and Iranian Registry of Clinical Trials, 10 from German Clinical Trial Registry, eight each from Brazilian Clinical Trial Registry and Nederland's Trial Register, seven from Japan Clinical Trial Registry, six from Clinical Trial Registry of India and two from Hong Kong Clinical Trial Registry. A total of 78.7% studies were investigator-initiated and 64% were completed while 3% were terminated. Nearly four-fifths of the registered trials (81.7%) were interventional studies of which randomized were the large majority (94.4%) with 63.2% being open label, 20.4% using single blinding technique and 16.4% were doubled blinded. The number, methodology and the characteristics of clinical trials in dentistry have been noted to be poor especially in terms of being conducted multi-centrically, employing blinding and the method for randomization and allocation concealment. More emphasis has to be
Pehrson, Caroline; Heno, Kristine Klysner; Adams, Yvonne
BACKGROUND: Malaria in pregnancy is associated with significant morbidity in pregnant women and their offspring. Plasmodium falciparum infected erythrocytes (IE) express VAR2CSA that mediates binding to chondroitin sulphate A (CSA) in the placenta. Two VAR2CSA-based vaccines for placental malaria...
Theisen, M.; Jore, M.M.; Sauerwein, R.
INTRODUCTION: Malaria is a devastating vector-borne disease caused by the Plasmodium parasite, resulting in almost 0.5 million casualties per year. The parasite has a complex life-cycle that includes asexual replication in human red blood cells, causing symptomatic malaria, and sexual stages which
Kun, Larry E.
Medulloblastoma is the seminal pediatric brain tumor providing opportunities for clinical investigation to define improved treatment strategies for both disease control and ultimate functional integrity. Recent studies addressing neuraxis radiation dose provide a 'standard' for conventional therapy while establishing 5-year disease control rates for 'favorable' or 'low risk' presentations approximating 60% following surgery and irradiation. A highly visible recent report of combined post-operative irradiation and chemotherapy incorporating a platinum- and alkylator-based regimen indicates 5-year disease control approaching 90% in localized medulloblastoma. Despite unfavorable outcome with reduced-dose neuraxis irradiation in earlier trials, further data from recent studies suggest the addition of post-operative chemotherapy to similarly reduced-dose neuraxis irradiation (23.4 Gy) in 'favorable' presentations may result in progression-free survival rates at least equivalent to those achieved with full-dose neuraxis irradiation (36 Gy) absent chemotherapy. The panel will (1) provide updated information regarding the major clinical trials that form the basis for current and planned protocols and (2) debate the therapeutic modifications appropriate for contemporary clinical investigations. Critical in planning future studies in the analysis of risk factors that may identify 'favorable' patients versus 'high risk' patients. Risk-related studies appropriately address maintaining or improving current disease control rates in the context of diminishing late treatment sequelae for 'favorable' presentations. For those identified as 'high risk' (e.g., patients with disease beyond the primary site), studies are in development that increase the intensity of chemotherapy and explore modifications of radiation delivery. Study designs that permit assessment of innovations in surgical, radiotherapeutic, and chemotherapeutic approaches will be presented and debated by the panelists
This paper traces the development of the Clinical Trial Registry-India (CTRI) against the backdrop of the inequities in healthcare and the limitations in the design, conduct, regulation, oversight and reporting of clinical trials in India. It describes the scope and goals of the CTRI, the data elements it seeks and the process of registering clinical trials. It reports progress in trial registration in India and discusses the challenges in ensuring that healthcare decisions are informed by all the evidence. A descriptive survey of developments in clinical trial registration in India from publications in the Indian medical literature supplemented by first hand knowledge of these developments and an evaluation of how well clinical trials registered in the CTRI up to 10 January, 2009 comply with the requirements of the CTRI and the World Health Organization's International Clinical Trial Registry (WHO ICTRP). Considerable inequities exist within the Indian health system. Deficiencies in healthcare provision and uneven regulation of, and access to, affordable healthcare co-exists with a large private health system of uneven quality. India is now a preferred destination for outsourced clinical trials but is plagued by poor ethical oversight of the many trial sites and scant information of their existence. The CTRI's vision of conforming to international requirements for transparency and accountability but also using trial registration as a means of improving trial design, conduct and reporting led to the selection of registry-specific dataset items in addition to those endorsed by the WHO ICTRP. Compliance with these requirements is good for the trials currently registered but these trials represent only a fraction of the trials in progress in India. Prospective trial registration is a reality in India. The challenges facing the CTRI include better engagement with key stakeholders to ensure increased prospective registration of clinical trials and utilization of
Rosas-Aguirre, Angel; Gamboa, Dionicia; Manrique, Paulo; Conn, Jan E; Moreno, Marta; Lescano, Andres G; Sanchez, Juan F; Rodriguez, Hugo; Silva, Hermann; Llanos-Cuentas, Alejandro; Vinetz, Joseph M
Malaria in Peru, dominated by Plasmodium vivax, remains a public health problem. The 1990s saw newly epidemic malaria emerge, primarily in the Loreto Department in the Amazon region, including areas near to Iquitos, the capital city, but sporadic malaria transmission also occurred in the 1990s-2000s in both north-coastal Peru and the gold mining regions of southeastern Peru. Although a Global Fund-supported intervention (PAMAFRO, 2005-2010) was temporally associated with a decrease of malaria transmission, from 2012 to the present, both P. vivax and Plasmodium falciparum malaria cases have rapidly increased. The Peruvian Ministry of Health continues to provide artemesinin-based combination therapy for microscopy-confirmed cases of P. falciparum and chloroquine-primaquine for P. vivax Malaria transmission continues in remote areas nonetheless, where the mobility of humans and parasites facilitates continued reintroduction outside of ongoing surveillance activities, which is critical to address for future malaria control and elimination efforts. Ongoing P. vivax research gaps in Peru include the following: identification of asymptomatic parasitemics, quantification of the contribution of patent and subpatent parasitemics to mosquito transmission, diagnosis of nonparasitemic hypnozoite carriers, and implementation of surveillance for potential emergence of chloroquine- and 8-aminoquinoline-resistant P. vivax Clinical trials of tafenoquine in Peru have been promising, and glucose-6-phosphate dehydrogenase deficiency in the region has not been observed to be a limitation to its use. Larger-scale challenges for P. vivax (and malaria in general) in Peru include logistical difficulties in accessing remote riverine populations, consequences of government policy and poverty trends, and obtaining international funding for malaria control and elimination. © The American Society of Tropical Medicine and Hygiene.
Rosas-Aguirre, Angel; Gamboa, Dionicia; Manrique, Paulo; Conn, Jan E.; Moreno, Marta; Lescano, Andres G.; Sanchez, Juan F.; Rodriguez, Hugo; Silva, Hermann; Llanos-Cuentas, Alejandro; Vinetz, Joseph M.
Malaria in Peru, dominated by Plasmodium vivax, remains a public health problem. The 1990s saw newly epidemic malaria emerge, primarily in the Loreto Department in the Amazon region, including areas near to Iquitos, the capital city, but sporadic malaria transmission also occurred in the 1990s–2000s in both north-coastal Peru and the gold mining regions of southeastern Peru. Although a Global Fund-supported intervention (PAMAFRO, 2005–2010) was temporally associated with a decrease of malaria transmission, from 2012 to the present, both P. vivax and Plasmodium falciparum malaria cases have rapidly increased. The Peruvian Ministry of Health continues to provide artemesinin-based combination therapy for microscopy-confirmed cases of P. falciparum and chloroquine–primaquine for P. vivax. Malaria transmission continues in remote areas nonetheless, where the mobility of humans and parasites facilitates continued reintroduction outside of ongoing surveillance activities, which is critical to address for future malaria control and elimination efforts. Ongoing P. vivax research gaps in Peru include the following: identification of asymptomatic parasitemics, quantification of the contribution of patent and subpatent parasitemics to mosquito transmission, diagnosis of nonparasitemic hypnozoite carriers, and implementation of surveillance for potential emergence of chloroquine- and 8-aminoquinoline-resistant P. vivax. Clinical trials of tafenoquine in Peru have been promising, and glucose-6-phosphate dehydrogenase deficiency in the region has not been observed to be a limitation to its use. Larger-scale challenges for P. vivax (and malaria in general) in Peru include logistical difficulties in accessing remote riverine populations, consequences of government policy and poverty trends, and obtaining international funding for malaria control and elimination. PMID:27799639
Alberto L. García-Basteiro
Full Text Available Eliciting an effective malaria vaccine has been the goal of the scientific community for many years. A malaria vaccine, added to existing tools and strategies, would further prevent and decrease the unacceptable malaria morbidity and mortality burden. Great progress has been made over the last decade, with some vaccine candidates in the clinical phases of development. The RTS,S malaria vaccine candidate, based on a recombinant P. falciparum protein, is the most advanced of such candidates, currently undergoing a large phase III trial. RTS,S has consistently shown an efficacy of around 50% against the first clinical episode of malaria, with protection in some cases extending up to 4 years of duration. Thus, it is hoped that this candidate vaccine will eventually become the first licensed malaria vaccine. This first vaccine against a human parasite is a groundbreaking achievement, but improved malaria vaccines conferring higher protection will be needed if the aspiration of malaria eradication is to be achieved
Full Text Available Abstract Background Recent studies have highlighted the over-diagnosis of malaria in clinical settings in Africa. This study assessed the impact of a training programme implemented as part of an intervention trial on diagnostic behaviour of clinicians in a rural district hospital in a low-moderate malaria transmission setting. Methods From the beginning of 2005, a randomized controlled trial (RCT of intermittent preventive treatment for malaria in infants (IPTi has been conducted at the study hospital. As part of the RCT, the study team offered laboratory quality assurance, and supervision and training of paediatric ward staff using information on malaria epidemiology in the community. Data on clinical and blood slide confirmed cases of malaria from 2001 to 2005 were extracted from the hospital records. Results The proportion of blood slides positive for malaria parasites had decreased from 21% in 2001 to 7% in 2005 (p Conclusion It may be possible to change the diagnostic behaviour of clinicians by rigorous training using local malaria epidemiology data and supportive supervision.
Baird, J Kevin
Malaria caused by Plasmodium vivax threatens over 2 billion people globally and sickens tens of millions annually. Recent clinical evidence discredits the long-held notion of this infection as intrinsically benign revealing an often threatening course associated with mortality. Most acute attacks by this species derive from latent forms in the human liver called hypnozoites. Radical cure for P. vivax malaria includes therapy aimed both at the acute attack (blood schizontocidal) and against future attacks (hypnozoitocidal). The only hypnozoitocide available is primaquine, a drug causing life-threatening acute hemolytic anemia in patients with the inherited blood disorder glucose-6-phosphate dehydrogenase (G6PD) deficiency. This disorder affects 400 million people worldwide, at an average prevalence of 8 % in malaria-endemic nations. In the absence of certain knowledge regarding the G6PD status of patients infected by P. vivax, providers must choose between the risk of harm caused by primaquine and that caused by the parasite by withholding therapy. Resolving this dilemma requires the availability of point-of-care G6PD diagnostics practical for use in the impoverished rural tropics where the vast majority of malaria patients seek care.
Kurth, Florian; Develoux, Michel; Mechain, Matthieu
Intravenous artesunate improves survival in severe malaria, but clinical trial data from nonendemic countries are scarce. The TropNet severe malaria database was analyzed to compare outcomes of artesunate vs quinine treatment. Artesunate reduced parasite clearance time and duration of intensive...
Thøgersen, Regitze L; Holder, Anthony A; Hill, Adrian Vs
scientists in academia and small and medium enterprises, together with partners in Africa. Research has added basic understanding of what is required of a malaria vaccine, allowing selected candidates to be prioritized and some to be moved forward into clinical trials. To end the health burden of malaria...
Garcia-Verdugo, Rosa; Erbach, Michael; Schnell, Oliver
Since the FDA requirement for cardiovascular safety of all new antihyperglycemic drugs to enter the market, the number and extent of phase 3 clinical trials has markedly increased. Unexpected trial results imply an enormous economic, personal and time cost and has deleterious effects over R&D. To prevent unforeseen developments in clinical trials, we recommend performing a comprehensive prospective outcome scenario analysis before launching the trial. In this commentary, we discuss the most important factors to take in consideration for prediction of clinical trial outcome scenarios and propose a theoretical model for decision making.