title: 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.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Shin Poong Pharmaceutical and the Medicines for Malaria Venture.
authors.affiliation: Ecole de Santé Publique, Faculté de Médecine, Université de Kinshasa, Kinshasa, Democratic Republic of the Congo.
authors.forename: Antoinette K
authors.initials: AK
authors.lastname: Tshefu
authors.forename: Oumar
authors.initials: O
authors.lastname: Gaye
authors.forename: Kassoum
authors.initials: K
authors.lastname: Kayentao
authors.forename: Ricardo
authors.initials: R
authors.lastname: Thompson
authors.forename: Kirana M
authors.initials: KM
authors.lastname: Bhatt
authors.forename: Sanie S S
authors.initials: SS
authors.lastname: Sesay
authors.forename: Dorina G
authors.initials: DG
authors.lastname: Bustos
authors.forename: Emiliana
authors.initials: E
authors.lastname: Tjitra
authors.forename: George
authors.initials: G
authors.lastname: Bedu-Addo
authors.forename: Isabelle
authors.initials: I
authors.lastname: Borghini-Fuhrer
authors.forename: Stephan
authors.initials: S
authors.lastname: Duparc
authors.forename: Chang Sik
authors.initials: CS
authors.lastname: Shin
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fleckenstein
mesh_terms: D000293:Adolescent; D000328:Adult; D000349:Africa; D000962:Antimalarials / Q000008:administration & dosage*; D000077549:Artemether; D037621:Artemisinins / Q000008:administration & dosage*; D000077332:Artesunate; D001208:Asia; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D004338:Drug Combinations; D004983:Ethanolamines / Q000008:administration & dosage*; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage*; D006801:Humans; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009287:Naphthyridines / Q000008:administration & dosage*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D009287:Naphthyridines; D000077332:Artesunate; D000077549:Artemether; D000078102:Lumefantrine; C027871:pyronaridine