Clinical trial of artesunate and artemether on multidrug resistant falciparum malaria in Thailand. A preliminary report. A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria. An open randomized clinical trial of Artekin vs artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria. A randomized trial on effectiveness of artemether-lumefantrine versus artesunate plus amodiaquine for unsupervised treatment of uncomplicated Plasmodium falciparum malaria in Ghanaian children. Clinical trial of beta-arteether versus quinine for the treatment of cerebral malaria in children in Yaounde, Cameroon. High efficacy of two artemisinin-based combinations (artemether-lumefantrine and artesunate plus amodiaquine) for acute uncomplicated malaria in Ibadan, Nigeria. Comparative clinical trial of two-fixed combinations dihydroartemisinin-napthoquine-trimethoprim (DNP) and artemether-lumefantrine (Coartem/Riamet) in the treatment of acute uncomplicated falciparum malaria in Thailand. A comparative clinical trial of artemether and the sequential regimen of artemether-mefloquine in multidrug resistant falciparum malaria. Outcome reporting among drug trials registered in ClinicalTrials.gov.
A 5-day course of oral artesunate at total doses of 1200, 600, 650 mg and intramuscular artemether 480 mg proved effective (90-100% cured) in the treatment of multidrug resistant falciparum malaria in Thailand. Shorter courses yielded high recrudescence rates. The fever clearance and parasite clearance times were short. The side effects were mild and transient including occasional abnormal electrocardiograms and pain at the injection site. Slight reduction of neutrophil leucocytes and reticulocytes was observed. Further studies of artesunate and artemether should be carried out to find the optimum dosage regimen and to clarify the hematological effects. The efficacy and safety of intramuscular artemotil (ARTECEF) was compared to intravenous quinine in African children with cerebral malaria. This prospective block randomized open-label study was conducted at two centers in Zambia. Subjects were children aged 0 to 10 years of age with cerebral malaria and a Blantyre Coma Score of 2 or less. Ninety two children were studied; 48 received artemotil and 44 quinine. No significant differences in survival, coma resolution time, neurologic sequelae, parasite clearance time, and fever resolution time were seen between the two regimens. Rates for negative malaria smears one month after therapy were similar in both groups. Artemotil was a well-tolerated drug in the 48 patients in this study. It appears to be at least therapeutically equivalent to quinine for the treatment of pediatric cerebral malaria. It has the advantage of being able to be given intramuscularly once daily for only five days. Malaria remains a major cause of morbidity and mortality in tropical countries and subtropical regions in the world. Southeast Asia has the most resistant malaria parasites in the world, which has limited treatment options in this region. In response to this situation, short-course artemisinin-based combination therapies (ACTs) have been developed. The combination of dihydroartemisinin (DHA) and piperaquine (PQP) in the form of Artekin has been developed as an alternative to established combinations, such as artesunate-mefloquine, primarily to reduce treatment costs and toxicity. We conducted a study comparing a standard treatment for acute uncomplicated falciparum malaria (artesunate 4 mg/kg/day together with mefloquine 8 mg/kg/day oral route once a day for 3 days) (Group A) and a combination of dihydroartemisinin 40 mg and piperaquine 320 mg in the form of Artekin given once a day for 3 days (Group B) to determine safety, efficacy, and tolerability. One hundred and eighty patients were randomly enrolled at the ratio of 1:2 into groups A:B. All patients had rapid initial clinical and parasitological responses. There were no significant differences in fever clearance time or parasite clearance time between both groups. The 28-day cure rates were high, at 100% and 99%, in groups A and B, respectively. We conclude that Artekin was as effective and well-tolerated as artesunate-mefloquine, and can be used alternatively as the current treatment for multidrug-resistant P. falciparum malaria. Numerous trials have demonstrated high efficacy and safety of artemisinin-based combination therapy (ACT) under supervised treatment. In contrast, effectiveness studies comparing different types of ACT applied unsupervised are scarce. The aim of this study was to compare effectiveness, tolerability and acceptance of artesunate plus amodiaquine (ASAQ) against that of artemether-lumefantrine (AL) in Ghanaian children with uncomplicated Plasmodium falciparum malaria.
                A randomized open-label trial was conducted at two district hospitals in the Ashanti region, Ghana, an area of intense malaria transmission. A total of 246 children under five years of age were randomly assigned to either ASAQ (Arsucam) or AL (Coartem). Study participants received their first weight-adjusted dose under supervision. After the parent/guardian was advised of times and mode of administration the respective three-day treatment course was completed unobserved at home. Follow-up visits were performed on days 3, 7, 14 and 28 to evaluate clinical and parasitological outcomes, adverse events, and haematological recovery. Length polymorphisms of variable regions of msp1 and msp2 were determined to differentiate recrudescences from reinfections. Acceptance levels of both treatment regimens were assessed by means of standardized interviews.
                Adequate clinical and parasitological responses after AL and ASAQ treatment were similar (88.3% and 91.7%, respectively). Interestingly, more late clinical failures until day 28 occurred in AL-treated children than in those who received ASAQ (17.5% and 7.3%, respectively; Hazard Ratio 2.41, 95% CI 1.00-5.79, p < 0.05).Haematological recovery and drug tolerability were not found to be significantly different in both study arms. The acceptance of treatment with ASAQ was higher than that with AL (rank-scores 10.6 and 10.3, respectively; p < 0.05).
                Unobserved AL and ASAQ treatment showed high adequate clinical and parasitological responses, though AL was inferior in preventing late clinical failures. One hundred and two children aged 0-10 years with cerebral malaria (Blantyre coma score of 2 or less) were randomly treated either with intramuscular arteether (3.2 mg/kg on Day 0, followed by 1.6 mg/kg on Days 1 to 4) or intravenous (i.v.) quinine dihydrochloride (20 mg of the salt/kg, followed by 10 mg of the salt/kg every 8 hr up to Day 6). Treatment with oral quinine sulfate (10 mg/kg every 8 hr) was substituted for i.v. quinine when the patient was able to take oral medicine. All patients were followed up in the hospital for 7 days; thereafter, they were treated as outpatients on Days 14, 21, and 28. Mortality rate, the main efficacy parameter, was 11.8% lower in the arteether treatment group than in the quinine group (15.7% versus 27.4%); however, the difference was not significant (P = 0.25). Means for fever clearance time, coma resolution time, and parasite clearance time were similar in the 2 treatment groups (42.2 +/- 34.9 hr; 34.8 +/- 18.8 hr, and 46.3 +/- 28.5 hr, respectively for arteether, versus 45.0 +/- 26.7 hr; 30.3 +/- 18.9 hr, and 40.7 +/- 18.9 hr, respectively, for quinine). At 28 days, the cure rates were 73.2% and 64.9% for the arteether and quinine treatment groups, respectively. Arteether is safe and therapeutically at least as effective as quinine for the treatment of cerebral malaria in children in Cameroon. Because of its ease of administration, arteether appears to be suited for use in the rural zones where monitoring facilities do not exist. To test the hypothesis that artesunate plus amodiaquine (ASAQ) is as effective as artemether-lumefantrine (AL) in the treatment of acute uncomplicated malaria in Nigerian children.
                In an open label, randomized controlled clinical trial, children aged 6 months to 10 years were randomized to receive artesunate (4 mg/kg daily) plus amodiaquine (10 mg/kg daily) or AL (5-14 kg, one tablet; 15-24 kg, two tablets and 25-34 kg, three tablets twice daily). Both drug regimens were given for 3 days and follow-up was for 28 days.
                A total of 132 children (66 in each group) were randomized to receive either ASAQ or AL. Day 28 cure rates in the per protocol (PP) population were 93% for ASAQ and 95% for AL (OR = 0.71, 95% CI = 0.12-3.99, rho = 0.66). Using Kaplan-Meier product-limit estimates of failure, the median survival time for ASAQ was 21 days and for AL 28 days (P = 0.294). PCR corrected day 28 cure rate for PP populations were 98.4% for ASAQ and 100% for AL. Both drugs were well-tolerated.
                ASAQ is as effective as AL and both combinations were efficacious and safe. An open randomized comparison of two-fixed dose artemisinin derivative-containing combination regimens was conducted in adults with acute uncomplicated multidrug resistant falciparum malaria in Thailand. DNP, a combination of dihydroartemisinin with napthoquine and trimethoprim developed recently in China, has been evaluated in China, Vietnam, Cambodia and Thailand. This study was performed to compare the safety, tolerability and efficacy of DNP and artemether-lumefantrine/Coartem. One hundred and thirty eligible uncomplicated falciparum malaria patients were enrolled into the study. Patients were randomly assigned in a 2:1 ratio into group A, which received DNP one tablet twice a day for one day; and group B, which received Coartem/Riamet four tablets twice a day for 3 days. The cure rates at 28-day were 99% and 97% in group A and group B, respectively. No serious adverse events occurred. We concluded that both DNP and Coartem/ Riamet were safe, well tolerated and highly efficacious in the treatment of acute uncomplicated falciparum malaria in Thailand. A randomized, comparative clinical trial for assessment of the efficacy of two antimalarial regimens, artemether alone and the sequential regimen artemethermefloquine, was carried out in 109 Thai male patients with acute uncomplicated, multidrug resistant falciparum malaria who were admitted to the Bangkok Hospital for Tropical Diseases. Fifty-three patients received oral artemether at a total dose of 700 mg (300 mg initially, followed by 100 mg daily for 4 days), and 56 patients received the sequential regimen of artemether-mefloquine (300 mg oral artemether initially, followed by 750 mg oral mefloquine after 24 h). Patients in both groups had a rapid initial response to treatment, with a median parasite clearance time of 40 h compared with 43.5 h for the sequential regimen. Median fever clearance times were 42.5 h and 32.5 h for artemether and the sequential regimen respectively. Parasitaemia reoccurred in patients of both groups during the follow up period, six in the artemether and three in the sequential regimen (cure rates were 88 and 94%). No serious adverse effects were observed in either group of patients. Clinical trial registries are in widespread use to promote transparency around trials and their results.
                To describe characteristics of drug trials listed in ClinicalTrials.gov and examine whether the funding source of these trials is associated with favorable published outcomes.
                An observational study of safety and efficacy trials for anticholesteremics, antidepressants, antipsychotics, proton-pump inhibitors, and vasodilators conducted between 2000 and 2006.
                ClinicalTrials.gov, a Web-based registry of clinical trials launched in 1999.
                Publications resulting from the trials for the 5 drug categories of interest were identified, and data were abstracted on the trial record and publication, including timing of registration, elements of the study design, funding source, publication date, and study outcomes. Assessments were based on the primary funding categories of industry, government agencies, and nonprofit or nonfederal organizations.
                Among 546 drug trials, 346 (63%) were primarily funded by industry, 74 (14%) by government sources, and 126 (23%) by nonprofit or nonfederal organizations. Trials funded by industry were more likely to be phase 3 or 4 trials (88.7%; P < 0.001 across groups), to use an active comparator in controlled trials (36.8%; P = 0.010 across groups), to be multicenter (89.0%; P < 0.001 across groups), and to enroll more participants (median sample size, 306 participants; P < 0.001 across groups). Overall, 362 (66.3%) trials had published results. Industry-funded trials reported positive outcomes in 85.4% of publications, compared with 50.0% for government-funded trials and 71.9% for nonprofit or nonfederal organization-funded trials (P < 0.001). Trials funded by nonprofit or nonfederal sources with industry contributions were also more likely to report positive outcomes than those without industry funding (85.0% vs. 61.2%; P = 0.013). Rates of trial publication within 24 months of study completion ranged from 32.4% among industry-funded trials to 56.2% among nonprofit or nonfederal organization-funded trials without industry contributions (P = 0.005 across groups).
                The publication status of a trial could not always be confirmed, which could result in misclassification. Additional information on study protocols and comprehensive trial results were not available to further explore underlying factors for the association between funding source and outcome reporting.
                In this sample of registered drug trials, those funded by industry were less likely to be published within 2 years of study completion and were more likely to report positive outcomes than were trials funded by other sources.
                National Library of Medicine and National Institute of Child Health and Human Development, National Institutes of Health.
More trials with a larger number of participants are needed before a firm conclusion about the efficacy and safety of arteether can be reached.