Efficacy and safety of a fixed-dose oral combination of pyronaridine-artesunate compared with artemether-lumefantrine in children and adults with uncomplicated Plasmodium falciparum malaria: a randomised non-inferiority trial.
There is a need for new artemisinin-based combination therapies that are convenient, effective, and safe. We compared the efficacy and safety of pyronaridine-artesunate with that of artemether-lumefantrine for treatment of uncomplicated P falciparum malaria.
This phase 3, parallel-group, double-blind, randomised, non-inferiority trial was undertaken in seven sites in Africa and three sites in southeast Asia. In a double-dummy design, patients aged 3-60 years with uncomplicated P falciparum malaria were randomly assigned in a 2:1 ratio to receive pyronaridine-artesunate once a day or artemether-lumefantrine twice a day, orally for 3 days, plus respective placebo. Randomisation was done by computer-generated randomisation sequence in blocks of nine by study centre. Intervention tablets contained 180 mg pyronaridine and 60 mg artesunate; control tablets contained 20 mg artemether and 120 mg lumefantrine. Both treatments were given according to bodyweight. The primary efficacy outcome was PCR-corrected adequate clinical and parasitological response (ACPR) rate at day 28 in the per-protocol population. Non-inferiority was shown if the lower limit of the two-sided 95% CI for the difference between groups was greater than -5%. This study is registered with ClinicalTrials.gov, number NCT00422084.
1272 patients were randomly assigned to treatment (pyronaridine-artesunate, n=849; artemether-lumefantrine, n=423). The per-protocol population consisted of 784 patients in the pyronaridine-artesunate group and 386 patients in the artemether-lumefantrine group. PCR-corrected ACPR rate at day 28 was 99.5% (780 patients; 95% CI 98.7-99.9) in the pyronaridine-artesunate group and 99.2% (383 patients; 95% CI 97.7-99.8) in the artemether-lumefantrine group (treatment difference 0.3%, 95% CI -0.7 to 1.8; p=0.578). There were 509 (60.0%) adverse events in 849 patients assigned to pyronaridine-artesunate and 241 (57.0%) in 423 patients assigned to artemether-lumefantrine. The most frequent drug-related adverse event was eosinophilia (pyronaridine-artesunate, 53 events [6.2%]; artemether-lumefantrine 24 events [5.7%]). 21 (2.5%) patients in the pyronaridine-artesunate group and seven (1.7%) in the artemether-lumefantrine group discontinued study drugs or were withdrawn from the study. Mild and transient increases in alanine aminotransferase and aspartate aminotransferase concentrations were seen in the pyronaridine-artesunate group but not in the artemether-lumefantrine group.
Efficacy of pyronaridine-artesunate was non-inferior to that of artemether-lumefantrine for treatment of uncomplicated falciparum malaria. Pyronaridine-artesunate should be considered for inclusion in malaria treatment programmes.
Shin Poong Pharmaceutical and the Medicines for Malaria Venture.
Tshefu AK
，Gaye O
，Kayentao K
，Thompson R
，Bhatt KM
，Sesay SS
，Bustos DG
，Tjitra E
，Bedu-Addo G
，Borghini-Fuhrer I
，Duparc S
，Shin CS
，Fleckenstein L
，Pyronaridine-artesunate Study Team
... -
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Pyronaridine-artesunate or dihydroartemisinin-piperaquine versus current first-line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b/4 trial.
Artemether-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.
We 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).
Between 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, 95% CI 1·01-1·34 vs 1·42 1·25-1·62; RR 1·22, 95% CI 1·06-1·41) and versus artesunate-amodiaquine (1·35, 1·21-1·51 vs 1·68, 1·51-1·88; RR 1·25, 1·02-1·50). For uncomplicated P falciparum malaria, PCR-adjusted ACPR was greater than 99·5% at day 28 and greater than 98·6% at day 42 for all ACTs; unadjusted ACPR was higher for pyronaridine-artesunate versus comparators at day 28 (96·9% vs 82·3% for artemether-lumefantrine and 95·6% vs 89·0% for artesunate-amodiaquine) and for dihydroartemisinin-piperaquine versus comparators (99·5% vs 81·6% for artemether-lumefantrine and 99·0% vs 89·0% for artesunate-amodiaquine). For non-falciparum species, unadjusted ACPR was greater than 98% for all study drugs at day 28 and at day 42 was greater than 83% except for artemether-lumefantrine against Plasmodium ovale (in ten [62·5%] of 16 patients) and against Plasmodium malariae (in nine [75·0%] of 12 patients). Nine deaths occurred during the study, none of which were related to the study treatment. Mostly mild transient elevations in transaminases occurred with pyronaridine-artesunate versus comparators, and mild QTcF prolongation with dihydroartemisinin-piperaquine versus comparators.
Pyronaridine-artesunate and dihydroartemisinin-piperaquine treatment and retreatment of malaria were well tolerated with efficacy that was non-inferior to first-line ACTs. Greater access to these efficacious treatments in west Africa is justified.
The European and Developing Countries Clinical Trial Partnership, Medicines for Malaria Venture (Geneva, Switzerland), the UK Medical Research Council, the Swedish International Development Cooperation Agency, German Ministry for Education and Research, University Claude Bernard (Lyon, France), University of Science, Techniques and Technologies of Bamako (Bamako, Mali), the 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).
West African Network for Clinical Trials of Antimalarial Drugs (WANECAM)
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Safety and efficacy of re-treatments with pyronaridine-artesunate in African patients with malaria: a substudy of the WANECAM randomised trial.
Sparse 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.
This 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.
Following 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.
The 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.
European 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).
Sagara I
，Beavogui AH
，Zongo I
，Soulama I
，Borghini-Fuhrer I
，Fofana B
，Camara D
，Somé AF
，Coulibaly AS
，Traore OB
，Dara N
，Kabore MJ
，Thera I
，Compaore YD
，Sylla MM
，Nikiema F
，Diallo MS
，Dicko A
，Gil JP
，Borrmann S
，Duparc S
，Miller RM
，Doumbo OK
，Shin J
，Bjorkman A
，Ouedraogo JB
，Sirima SB
，Djimdé AA
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