SummaryBackgroundArtemether–lumefantrine and artesunate–amodiaquine are used as first-line artemisinin-based combination therapies (ACTs) in west Africa. Pyronaridine–artesunate and dihydroartemisinin–piperaquine are potentially useful for diversification of ACTs in this region, but further safety and efficacy data are required on malaria retreatment.MethodsWe did a randomised, multicentre, open-label, longitudinal, controlled phase 3b/4 clinical trial at seven tertiary centres in Burkina Faso, Guinea, and Mali. Eligible participants for first malaria episode and all retreatment episodes were adults and children aged 6 months and older with microscopically confirmed Plasmodium spp malaria (>0 to <200 000 parasites per μL of blood) and fever or history of fever in the previous 24 h. Individuals with severe or complicated malaria, an alanine aminotransferase concentration of more than twice the upper limit of normal, or a QTc greater than 450 ms were excluded. Using a randomisation list for each site, masked using sealed envelopes, participants were assigned to either pyronaridine–artesunate or dihydroartemisinin–piperaquine versus either artesunate–amodiaquine or artemether–lumefantrine. Block sizes were two or four if two treatments were allocated, and three or six if three treatments were allocated. Microscopists doing the parasitological assessments were masked to treatment allocation. All treatments were once-daily or twice-daily tablets or granules given orally and dosed by bodyweight over 3 days at the study centre. Patients were followed up as outpatients up to day 42, receiving clinical assessments on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42. Two primary outcomes were compared for non-inferiority: the 2-year incidence rate of all microscopically confirmed, complicated and uncomplicated malaria episodes in patients in the intention-to-treat population (ITT; non-inferiority margin 20%); and adequate clinical and parasitological response (ACPR) in uncomplicated malaria across all episodes (unadjusted and PCR-adjusted for Plasmodium falciparum and unadjusted for other Plasmodium spp) in the per-protocol population on days 28 and 42 (non-inferiority margin 5%). Safety was assessed in all participants who received one dose of study drug. This study is registered at the Pan African Clinical Trials Registry (PACTR201105000286876).FindingsBetween Oct 24, 2011, and Feb 1, 2016, we assigned 4710 eligible participants to the different treatment strategies: 1342 to pyronaridine–artesunate, 967 to artemether–lumefantrine, 1061 to artesunate–amodiaquine, and 1340 to dihydroartemisinin–piperaquine. The 2-year malaria incidence rate in the ITT population was non-inferior for pyronaridine–artesunate versus artemether–lumefantrine (1·77, 95% CI 1·63–1·93 vs 1·87, 1·72–2·03; rate ratio [RR] 1·05, 95% CI 0·94–1·17); and versus artesunate–amodiaquine (1·39, 95% CI 1·22–1·59 vs 1·35, 1·18–1·54; RR 0·97, 0·87–1·07). Similarly, this endpoint was non-inferior for dihydroartemisinin–piperaquine versus artemether–lumefantrine (1·16...
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SummaryBackgroundSparse data on the safety of pyronaridine-artesunate after repeated treatment of malaria episodes restrict its clinical use. We therefore compared the safety of pyronaridine-artesunate after treatment of the first episode of malaria versus re-treatment in a substudy analysis.MethodsThis planned substudy analysis of the randomised, open-label West African Network for Clinical Trials of Antimalarial Drugs (WANECAM) phase 3b/4 trial was done at six health facilities in Mali, Burkina Faso, and Guinea in patients (aged ≥6 months and bodyweight ≥5 kg) with uncomplicated microscopically confirmed Plasmodium spp malaria (parasite density <200 000 per μL blood) and fever or history of fever. The primary safety endpoint was incidence of hepatotoxicity: alanine aminotransferase of greater than five times the upper limit of normal (ULN) or Hy's criteria (alanine aminotransferase or aspartate aminotransferase greater than three times the ULN and total bilirubin more than twice the ULN) after treatment of the first episode of malaria and re-treatment (≥28 days after first treatment) with pyronaridine-artesunate. Pyronaridine-artesunate efficacy was compared with artemether-lumefantrine with the adequate clinical and parasitological response (ACPR) in an intention-to-treat analysis. WANECAM is registered with PACTR.org, number PACTR201105000286876.FindingsFollowing first treatment, 13 (1%) of 996 patients had hepatotoxicity (including one [<1%] possible Hy's law case) versus two (1%) of 311 patients on re-treatment (neither a Hy's law case). No evidence was found that pyronaridine-artesunate re-treatment increased safety risk based on laboratory values, reported adverse event frequencies, or electrocardiograph findings. For all first treatment or re-treatment episodes, pyronaridine-artesunate (n=673) day 28 crude ACPR was 92·7% (95% CI 91·0–94·3) versus 80·4% (77·8–83·0) for artemether-lumefantrine (n=671). After exclusion of patients with PCR-confirmed new infections, ACPR was similar on treatment and re-treatment and greater than 95% at day 28 and greater than 91% at day 42 in both treatment groups.InterpretationThe findings that pyronaridine-artesunate safety and efficacy were similar on first malaria treatment versus re-treatment of subsequent episodes lend support for the wider access to pyronaridine-artesunate as an alternative artemisinin-based combination treatment for malaria in sub-Saharan Africa.FundingEuropean and Developing Countries Clinical Trial Partnership, Medicines for Malaria Venture (Geneva, Switzerland), UK Medical Research Council, Swedish International Development Cooperation Agency, German Ministry for Education and Research, University Claude Bernard (Lyon, France), Malaria Research and Training Centre (Bamako, Mali), Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso), Institut de Recherche en Sciences de la Santé (Bobo-Dioulasso, Burkina Faso), and Centre National de Formation et de Recherche en Santé Rurale (Republic of Guinea).
Whatever the parenteral formulation of quinine, the blood concentration-time profiles of quinine were similar after intrarectal administration. Intrarectal administration of hydrochloride salt solution is a possible mode of quinine delivery in remote rural areas of Africa.
BackgroundAccording to the guidelines of the Burkina Faso National Malaria Control Programme, artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) are the first-line drugs for uncomplicated malaria treatments. However, in some contexts where individuals will experience more than 1 episode of clinical malaria per year, it is unknown to what extent giving any of these ACTs repeatedly is safe. In the framework of the activities of the West African Network for Antimalarial Drugs (WANECAM) network, we have compared the efficacy and tolerability of repeated use of dihydroartemisinin-piperaquine (DHA-PQ) or artesunate-pyronaridine (PYR) with artesunate-amodiaquine (ASAQ).MethodsA randomised open-label parallel 3 arms trial was conducted to compare the efficacy of a three-day regimen of DHA-PQ and PYR with ASAQ. The trial involved children and adults with uncomplicated falciparum malaria. Participants were randomly assigned to one of the three treatment arms at the first clinical episode. During the subsequent clinical episodes, the same drug was administered. Follow-up duration was 42 days for each episode. Study duration was two years for each participant. Primary endpoints were the incidence rate of uncomplicated malaria over a period of 2 years and PCR corrected/uncorrected ACPR at day 28 and day 42. Safety parameters were also assessed.ResultsOf the 763 patients enrolled, the incidence rate of clinical malaria was 1.4, 1.2, and 1.5 episodes / person-year at risk in the ASAQ, DHA-PQ and PYRAMAX arms, respectively. The PCR-uncorrected efficacy at day 28 versus day 42 was: ASAQ 93.4%vs79.5%; PYR 98.1%vs74.8%; and DHA-PQ 99.5%vs95.2%. Bronchitis, rhinitis, abdominal pain, cough, QTc prolongation, headache, and vomiting were registered as the main adverse events in each of the three groups.ConclusionsThe findings from our study support the current recommendations for using artemisinin-based combinations in the treatment of uncomplicated malaria in areas of high malaria transmission such as Burkina Faso.
BackgroundMalaria elimination and its ultimate eradication will require drugs targeting all stages of the parasite’s life cycle. Yet, very few drugs are known to be effective on the sexual stages (gametocytes) of Plasmodium falciparum. Artemisinin-based combination therapy (ACT) has been shown to have some early-stage gametocytocidal effects on in vitro and in feeding experiments. However, field studies showed that artesunate reduces but does not prevent post-treatment transmission of P. falciparum to mosquitos.Methods763 children and adult patients with acute uncomplicated Plasmodium sp. malaria were included in a phase IIIb/IV comparative, randomised, multi-centre, open label, parallel 3-arm clinical trial to assess safety and efficacy of repeated administration of pyronaridine-artesunate, dihydroartemisinin-piperaquine or artemether-lumefantrine or artesunate-amodiaquine over a two-year period. Drugs were given based on the body weight and volunteers were followed up for 42 days. Clinical signs and symptoms were recorded and filter paper and blood smears collected during each visit. Malaria parasites were assessed and parasite density development stages determined by light microscopy.Results P. falciparum gametocyte was 1.9%, during the two years of follow-up. From the three treatment arms, artesunate-amodiaquine was the arm bearing more P. falciparum gametocyte with 68.7%, dihydroartemisinin-piperaquine accounted for 6.3% and pyronaridine-artesunate for 25%. P. falciparum gametocyte was more pronounced in populations having parasite density ≤1 00 000 parasites/µl compared to above parasitaemia.ConclusionRepeated ACTs treatment didn’t clear P. falciparum gametocyte in a population infected with uncomplicated malaria.
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