title: Safety and efficacy of re-treatments with pyronaridine-artesunate in African patients with malaria: a substudy of the WANECAM randomised trial.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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).
authors.affiliation: Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Pharmacy, University of Science, Techniques and Technologies of Bamako, Mali.
authors.forename: Issaka
authors.initials: I
authors.lastname: Sagara
authors.affiliation: Centre de Formation et de Recherche en Santé Rurale de Mafèrinyah, Conakry, Guinea.
authors.forename: Abdoul Habib
authors.initials: AH
authors.lastname: Beavogui
authors.affiliation: Institut de Recherche en Science de la Santé, Bobo Dioulasso, Burkina Faso.
authors.forename: Issaka
authors.initials: I
authors.lastname: Zongo
authors.affiliation: National Center for Research and Training on Malaria, Ouagadougou, Burkina Faso.
authors.forename: Issiaka
authors.initials: I
authors.lastname: Soulama
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Borghini-Fuhrer
authors.affiliation: Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Pharmacy, University of Science, Techniques and Technologies of Bamako, Mali.
authors.forename: Bakary
authors.initials: B
authors.lastname: Fofana
authors.affiliation: Centre de Formation et de Recherche en Santé Rurale de Mafèrinyah, Conakry, Guinea.
authors.forename: Daouda
authors.initials: D
authors.lastname: Camara
authors.affiliation: Institut de Recherche en Science de la Santé, Bobo Dioulasso, Burkina Faso.
authors.forename: Anyirékun F
authors.initials: AF
authors.lastname: Somé
authors.affiliation: National Center for Research and Training on Malaria, Ouagadougou, Burkina Faso.
authors.forename: Aboubacar S
authors.initials: AS
authors.lastname: Coulibaly
authors.affiliation: Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Pharmacy, University of Science, Techniques and Technologies of Bamako, Mali.
authors.forename: Oumar B
authors.initials: OB
authors.lastname: Traore
authors.affiliation: Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Pharmacy, University of Science, Techniques and Technologies of Bamako, Mali.
authors.forename: Niawanlou
authors.initials: N
authors.lastname: Dara
authors.affiliation: National Center for Research and Training on Malaria, Ouagadougou, Burkina Faso.
authors.forename: Moïse J T
authors.initials: MJ
authors.lastname: Kabore
authors.affiliation: Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Pharmacy, University of Science, Techniques and Technologies of Bamako, Mali.
authors.forename: Ismaila
authors.initials: I
authors.lastname: Thera
authors.affiliation: Institut de Recherche en Science de la Santé, Bobo Dioulasso, Burkina Faso.
authors.forename: Yves D
authors.initials: YD
authors.lastname: Compaore
authors.affiliation: Centre de Formation et de Recherche en Santé Rurale de Mafèrinyah, Conakry, Guinea.
authors.forename: Malick Minkael
authors.initials: MM
authors.lastname: Sylla
authors.affiliation: Institut de Recherche en Science de la Santé, Bobo Dioulasso, Burkina Faso.
authors.forename: Frederic
authors.initials: F
authors.lastname: Nikiema
authors.affiliation: Centre de Formation et de Recherche en Santé Rurale de Mafèrinyah, Conakry, Guinea.
authors.forename: Mamadou Saliou
authors.initials: MS
authors.lastname: Diallo
authors.affiliation: Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Pharmacy, University of Science, Techniques and Technologies of Bamako, Mali.
authors.forename: Alassane
authors.initials: A
authors.lastname: Dicko
authors.affiliation: Department of Physiology and Pharmacology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jose Pedro
authors.initials: JP
authors.lastname: Gil
authors.affiliation: Institute for Tropical Medicine, University of Tübingen, Tübingen, Germany; German Centre for Infection Research (DZIF), Tübingen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Borrmann
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Duparc
authors.affiliation: Aptiv Solutions, Stevenage, UK.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Miller
authors.affiliation: Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Pharmacy, University of Science, Techniques and Technologies of Bamako, Mali.
authors.forename: Ogobara K
authors.initials: OK
authors.lastname: Doumbo
authors.affiliation: Shin Poong Pharmaceutical Company, Seoul, South Korea.
authors.forename: Jangsik
authors.initials: J
authors.lastname: Shin
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Bjorkman
authors.affiliation: Institut de Recherche en Science de la Santé, Bobo Dioulasso, Burkina Faso.
authors.forename: Jean-Bosco
authors.initials: JB
authors.lastname: Ouedraogo
authors.affiliation: National Center for Research and Training on Malaria, Ouagadougou, Burkina Faso.
authors.forename: Sodiomon B
authors.initials: SB
authors.lastname: Sirima
authors.affiliation: Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Pharmacy, University of Science, Techniques and Technologies of Bamako, Mali. Electronic address: adjimde@icermali.org.
authors.forename: Abdoulaye A
authors.initials: AA
authors.lastname: Djimdé
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000962:Antimalarials / Q000008:administration & dosage* / Q000009:adverse effects*; D037621:Artemisinins / Q000008:administration & dosage / Q000627:therapeutic use*; D000077332:Artesunate; D002050:Burkina Faso; D002648:Child; D002675:Child, Preschool; D004338:Drug Combinations; D005260:Female; D016701:Guinea; D006801:Humans; D007223:Infant; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D008302:Mali; D008875:Middle Aged; D009287:Naphthyridines / Q000008:administration & dosage*; D010961:Plasmodium / Q000187:drug effects*; D019233:Retreatment; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D009287:Naphthyridines; D000077332:Artesunate; C027871:pyronaridine