title: Pyronaridine-artesunate granules versus artemether-lumefantrine crushed tablets in children with Plasmodium falciparum malaria: a randomized controlled trial.
abstract: BACKGROUND
  Children are most vulnerable to malaria. A pyronaridine-artesunate pediatric granule formulation is being developed for the treatment of uncomplicated Plasmodium falciparum malaria.
  
  
  METHODS
  This phase III, multi-center, comparative, open-label, parallel-group, controlled clinical trial included patients aged ≤12 years, bodyweight ≥5 to <25 kg, with a reported history of fever at inclusion or in the previous 24 h and microscopically-confirmed uncomplicated P. falciparum malaria. Patients were randomized (2:1) to pyronaridine-artesunate granules (60/20 mg) once daily or artemether-lumefantrine crushed tablets (20/120 mg) twice daily, both dosed by bodyweight, orally (liquid suspension) for three days.
  
  
  RESULTS
  Of 535 patients randomized, 355 received pyronaridine-artesunate and 180 received artemether-lumefantrine. Day-28 adequate clinical and parasitological response (ACPR), corrected for re-infection using polymerase chain reaction (PCR) genotyping (per-protocol population) was 97.1% (329/339; 95% CI 94.6, 98.6) for pyronaridine-artesunate; 98.8% (165/167; 95% CI 95.7, 99.9) for artemether-lumefantrine. The primary endpoint was achieved: pyronaridine-artesunate PCR-corrected day-28 ACPR was statistically significantly >90% (P < .0001). Pyronaridine-artesunate was non-inferior to artemether-lumefantrine: treatment difference -1.8% (95% CI -4.3 to 1.6). The incidence of drug-related adverse events was 37.2% (132/355) with pyronaridine-artesunate, 44.4% (80/180) with artemether-lumefantrine. Clinical biochemistry results showed similar mean changes versus baseline in the two treatment groups. From day 3 until study completion, one patient in each treatment group had peak alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN) and peak total bilirubin >2xULN (i.e. within the Hy's law definition).
  
  
  CONCLUSIONS
  The pyronaridine-artesunate pediatric granule formulation was efficacious and was non-inferior to artemether-lumefantrine. The adverse event profile was similar for the two comparators. Pyronaridine-artesunate should be considered for inclusion in paediatric malaria treatment programmes.
  
  
  BACKGROUND
  ClinicalTrials.gov: identifier NCT00541385.
authors.affiliation: Malaria Research and Training Center, Faculté de Médecine de Pharmacie et d'Odonto-Stomatologie, Bamako, Mali.
authors.forename: Kassoum
authors.initials: K
authors.lastname: Kayentao
authors.forename: Ogobara K
authors.initials: OK
authors.lastname: Doumbo
authors.forename: Louis K
authors.initials: LK
authors.lastname: Pénali
authors.forename: André T
authors.initials: AT
authors.lastname: Offianan
authors.forename: Kirana M
authors.initials: KM
authors.lastname: Bhatt
authors.forename: Joshua
authors.initials: J
authors.lastname: Kimani
authors.forename: Antoinette K
authors.initials: AK
authors.lastname: Tshefu
authors.forename: Jack H T
authors.initials: JH
authors.lastname: Kokolomami
authors.forename: Michael
authors.initials: M
authors.lastname: Ramharter
authors.forename: Pablo Martinez
authors.initials: PM
authors.lastname: de Salazar
authors.forename: Alfred B
authors.initials: AB
authors.lastname: Tiono
authors.forename: Alphonse
authors.initials: A
authors.lastname: Ouédraogo
authors.forename: Maria Dorina G
authors.initials: MD
authors.lastname: Bustos
authors.forename: Frederick
authors.initials: F
authors.lastname: Quicho
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: D000962:Antimalarials / Q000008:administration & dosage* / Q000009:adverse effects; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000008:administration & dosage*; D000077332:Artesunate; D002648:Child; D002675:Child, Preschool; D004304:Dosage Forms; D004338:Drug Combinations; D004983:Ethanolamines / Q000008:administration & dosage*; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage*; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D009287:Naphthyridines / Q000008:administration & dosage*; D059208:Parasite Load; D012008:Recurrence; D013607:Tablets; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004304:Dosage Forms; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D009287:Naphthyridines; D013607:Tablets; D000077332:Artesunate; C027871:pyronaridine