Articles www.thelancet.com Vol 375 April 24, 2010 1457 Lancet 2010; 375: 1457–67 See Editorial page 1407 See Comment page 1413 *Members listed at end of paper Ecole de Santé Publique, Faculté de Médecine, Université de Kinshasa, Kinshasa, Democratic Republic of the Congo (A K Tshefu MD); Service de Parasitologie, Faculté de Médecine, Université Cheikh Anta Diop, Dakar, Senegal (O Gaye MD); Malaria Research and Training Centre, Faculté de Médecine de Pharmacie et d’Odonto-Stomatologie, Bamako, Mali (K Kayentao MD); Chokwé Health Research and Training Centre, National Institute of Health, Chokwé, Mozambique (R Thompson PhD); UNITID College of Health Sciences University of Nairobi, Nairobi, Kenya (K M Bhatt MMED); Farafenni Field Station, Medical Research Council Laboratories, Fajara, The Gambia (S S S Sesay MD); Research Institute for Tropical Medicine, Manila, Philippines (D G Bustos MD); National Institute of Health Research and Development, Ministry of Health, Jakarta, Indonesia (E Tjitra MD); Komfo Anokye Teaching Hospital, Kumasi, Ghana (G Bedu-Addo MD); Medicines for Malaria Venture, Geneva, Switzerland (I Borghini-Fuhrer PhD, S Duparc MD); Shin Poong Pharmaceutical, Seoul, South Korea (C S Shin PhD); and University of Iowa, Iowa City, IA, USA (L Fleckenstein PharmD) Correspondence to: Dr Isabelle Borghini-Fuhrer, Medicines for Malaria Venture, International Center Cointrin, Route de Pré-Bois 20, PO Box 1826, CH-1215 Geneva 15, Switzerland borghinii@mmv.org 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 Antoinette K Tshefu, Oumar Gaye, Kassoum Kayentao, Ricardo Thompson, Kirana M Bhatt, Sanie S S Sesay, Dorina G Bustos, Emiliana Tjitra, George Bedu-Addo, Isabelle Borghini-Fuhrer, Stephan Duparc, Chang Sik Shin, Lawrence Fleckenstein, and the Pyronaridine-artesunate Study Team* Summary 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 difference 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. Funding Shin Poong Pharmaceutical and the Medicines for Malaria Venture. Introduction The development of artemisinin-based combination therapy has led to a renewed interest in antimalarial research and development. Artemether-lumefantrine is regarded as the gold standard for treatment of malaria, with good safety and generally more than 90% efficacy. 1 However, it needs to be taken twice a day, requires a fatty diet for optimum absorption, and the fairly short half-life exposes patients to the risk of early reinfection. 2 The WHO Global Malaria Programme recommends artemisinin- based combination therapy as first-line treatment for malaria, 3 and there is a need for new regimens that are affordable, convenient, effective, and safe. Pyronaridine-artesunate is being investigated as a fixed-dose (3:1 ratio) artemisinin-based combination therapy for the treatment of Plasmodium falciparum and Plasmodium vivax malaria. Pyronaridine showed potent activity against African P falciparum isolates in vitro, including chloroquine-resistant strains. 4 In animal models of malaria infection, pyronaridine and artesunate showed