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

24 Apr 2010

Antoinette K Tshefu, Oumar Gaye, Kassoum Kayentao, Ricardo Thompson, Kirana M Bhatt, Sanie SS Sesay, Dorina G Bustos, Emiliana Tjitra, George Bedu-Addo, Isabelle Borghini-Fuhrer, Stephan Duparc, Chang Sik Shin, Lawrence Fleckenstein

The Lancet

DOI: 10.1016/S0140-6736(10)60322-4


Background 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.

Methods 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 diff erence between groups was greater than –5%. This study is registered with ClinicalTrials.gov, number NCT00422084.

Findings 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.

Interpretation 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.

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