title: Safety and efficacy of pyronaridine-artesunate in uncomplicated acute malaria: an integrated analysis of individual patient data from six randomized clinical trials.
abstract: BACKGROUND
  Pyronaridine-artesunate (PA) is indicated for the treatment of acute uncomplicated Plasmodium falciparum and Plasmodium vivax malaria.
  
  
  METHODS
  Individual patient data on safety outcomes were integrated from six randomized clinical trials conducted in Africa and Asia in patients with microscopically confirmed P. falciparum (five studies) or P. vivax (one study) malaria. Efficacy against P. falciparum was evaluated across three Phase III clinical trials.
  
  
  RESULTS
  The safety population included 2,815 patients randomized to PA, 1,254 to comparators: mefloquine + artesunate (MQ + AS), artemether-lumefantrine (AL), or chloroquine. All treatments were generally well tolerated. Adverse events occurred in 57.2% (1,611/2,815) of patients with PA versus 51.5% (646/1,254) for comparators, most commonly (PA; comparators): headache (10.6%; 9.9%), cough (5.9%; 5.6%) and anaemia (4.5%; 2.9%). Serious averse events were uncommon for all treatments (0-0.7%). Transient increases in alanine aminotransferase and aspartate aminotransferase were observed with PA but did not lead to any clinical sequelae. For P. falciparum malaria, day-28 PCR-corrected adequate clinical and parasitological response with PA was 93.6% ([1,921/2,052] 95% CI 92.6, 94.7) in the intent-to-treat population and 98.5% ([1,852/1,880] 95% CI 98.0, 99.1) in the per-protocol population. Median parasite clearance time was 24.1 h with PA, 31.9 h with MQ + AS, and 24.0 h with AL. Median fever clearance time was 15.5 h with PA, 15.8 h with MQ + AS, and 14.0 h with AL. By day 42, P. falciparum gametocytes had declined to near zero for all treatments.
  
  
  CONCLUSIONS
  Pyronaridine-artesunate was well tolerated with no safety concerns with the exception of mostly mild transient rises in transaminases. Efficacy was high and met the requirements for use as first-line therapy. Pyronaridine-artesunate should be considered for inclusion in malaria treatment programmes.
  
  
  BACKGROUND
  Clinicaltrials.gov: NCT00331136; NCT00403260; NCT00422084; NCT00440999; NCT00541385; NCT01594931.
authors: Medicines for Malaria Venture (MMV), International Center Cointrin, Route de Pré-Bois 20, PO Box 1826, CH-1215, Geneva 15, Switzerland. duparcs@mmv.org
authors: Stephan
authors: S
authors: Duparc
authors: Isabelle
authors: I
authors: Borghini-Fuhrer
authors: Carl J
authors: CJ
authors: Craft
authors: Sarah
authors: S
authors: Arbe-Barnes
authors: Robert M
authors: RM
authors: Miller
authors: Chang-Sik
authors: CS
authors: Shin
authors: Lawrence
authors: L
authors: Fleckenstein
mesh_terms: D000293:Adolescent; D000328:Adult; D000349:Africa; D000962:Antimalarials / Q000008:administration & dosage* / Q000009:adverse effects*; D037621:Artemisinins / Q000008:administration & dosage* / Q000009:adverse effects*; D000077332:Artesunate; D001208:Asia; D002648:Child; D002675:Child, Preschool; D017326:Clinical Trials, Phase III as Topic; D004338:Drug Combinations; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology; D005260:Female; D006801:Humans; D007223:Infant; D008288:Malaria / Q000188:drug therapy*; D016778:Malaria, Falciparum / Q000188:drug therapy; D016780:Malaria, Vivax / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009287:Naphthyridines / Q000008:administration & dosage* / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D009287:Naphthyridines; D000077332:Artesunate; C027871:pyronaridine