title: The efficacy and safety of a new fixed-dose combination of amodiaquine and artesunate in young African children with acute uncomplicated Plasmodium falciparum.
abstract: BACKGROUND
  Artesunate (AS) plus amodiaquine (AQ) is one artemisinin-based combination (ACT) recommended by the WHO for treating Plasmodium falciparum malaria. Fixed-dose AS/AQ is new, but its safety and efficacy are hitherto untested.
  
  
  METHODS
  A randomized, open-label trial was conducted comparing the efficacy (non-inferiority design) and safety of fixed (F) dose AS (25 mg)/AQ (67.5 mg) to loose (L) AS (50 mg) + AQ (153 mg) in 750, P. falciparum-infected children from Burkina Faso aged 6 months to 5 years. Dosing was by age. Primary efficacy endpoint was Day (D) 28, PCR-corrected, parasitological cure rate. Recipients of rescue treatment were counted as failures and new infections as cured. Documented, common toxicity criteria (CTC) graded adverse events (AEs) defined safety.
  
  
  RESULTS
  Recruited and evaluable children numbered 750 (375/arm) and 682 (90.9%), respectively. There were 8 (AS/AQ) and 6 (AS+AQ) early treatment failures and one D7 failure (AS+AQ). Sixteen (AS/AQ) and 12 (AS+AQ) patients had recurrent parasitaemia (PCR new infections 10 and 6, respectively). Fourteen patients per arm required rescue treatment for vomiting/spitting out study drugs. Efficacy rates were 92.1% in both arms: AS/AQ = 315/342 (95% CI: 88.7-94.7) vs. AS+AQ = 313/340 (95% CI: 88.6-94.7). Non-inferiority was demonstrated at two-sided alpha = 0.05: Delta (AS+AQ - AS/AQ) = 0.0% (95% CI: -4.1% to 4.0%). D28, Kaplan Meier PCR-corrected cure rates (all randomized children) were similar: 93.7% (AS/AQ) vs. 93.2% (AS+AQ) Delta = -0.5 (95% CI -4.2 to 3.0%). By D2, both arms had rapid parasite (F & L, 97.8% aparasitaemic) and fever (97.2% [F], 96.0% [L] afebrile) clearances.Both treatments were well tolerated. Drug-induced vomiting numbered 8/375 (2.1%) and 6/375 (1.6%) in the fixed and loose arms, respectively (p = 0.59). One patient developed asymptomatic, CTC grade 4 hepatitis (AST 1052, ALT 936). Technical difficulties precluded the assessment and risk of neutropaenia for all patients.
  
  
  CONCLUSIONS
  Fixed dose AS/AQ was efficacious and well tolerated. These data support the use of this new fixed dose combination for treating P. falciparum malaria with continued safety monitoring.
  
  
  BACKGROUND
  Current Controlled Trials ISRCTN07576538.
authors.affiliation: Centre National de Recherche et de Formation sur le Paludisme (CNRFP), BP 2208, Ouagadougou, Burkina Faso. s.sirima.cnlp@fasonet.bf
authors.forename: Sodiomon B
authors.initials: SB
authors.lastname: Sirima
authors.forename: Alfred B
authors.initials: AB
authors.lastname: Tiono
authors.forename: Adama
authors.initials: A
authors.lastname: Gansané
authors.forename: Amidou
authors.initials: A
authors.lastname: Diarra
authors.forename: Amidou
authors.initials: A
authors.lastname: Ouédraogo
authors.forename: Amadou T
authors.initials: AT
authors.lastname: Konaté
authors.forename: Jean René
authors.initials: JR
authors.lastname: Kiechel
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Morgan
authors.forename: Piero L
authors.initials: PL
authors.lastname: Olliaro
authors.forename: Walter R J
authors.initials: WR
authors.lastname: Taylor
mesh_terms: D000655:Amodiaquine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D037621:Artemisinins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002050:Burkina Faso; D002675:Child, Preschool; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D018512:Parasitemia / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; C515299:amodiaquine, artesunate drug combination; D000655:Amodiaquine