title: Clinical tolerability of artesunate-amodiaquine versus comparator treatments for uncomplicated falciparum malaria: an individual-patient analysis of eight randomized controlled trials in sub-Saharan Africa.
abstract: BACKGROUND
  The widespread use of artesunate-amodiaquine (ASAQ) for treating uncomplicated malaria makes it important to gather and analyse information on its tolerability.
  
  
  METHODS
  An individual-patient tolerability analysis was conducted using data from eight randomized controlled clinical trials conducted at 17 sites in nine sub-Saharan countries comparing ASAQ to other anti-malarial treatments. All patients who received at least one dose of the study drug were included in the analysis. Differences in adverse event (AE) and treatment emergent adverse event (TEAE) were analysed by Day 28.
  
  
  RESULTS
  Of the 6,179 patients enrolled (74% <5 years of age), 50% (n = 3,113) received ASAQ, 20% (n = 1,217) another ACT, and 30% (n = 1,849) a non-ACT (combination or single-agent) treatment. Overall, 8,542 AEs were recorded. The proportion of patients experiencing at least one gastro-intestinal AE on ASAQ was 43% (and higher than that with artemether-lumefantrine and dihydroartemisinin-piperaquine at two sites), and was 23% for any other AEs (not different from other treatments). Specifically, the risk of diarrhoea, vomiting, cough and weakness was lower with artemether-lumefantrine; artemether-lumefantrine and dihydroartemisinin-piperaquine carried a higher risk of pruritus, chloroquine-SP had a higher risk of nausea. Parasitological recurrence increased the risk of occurrence of any AE. No other difference was detected. Comparing AE to TEAE in patients who had pre-treatment occurrence and grades of intensity recorded, AEs were significantly more related to the pre-treatment prevalence of the symptom (p = 0.001, Fisher test); AEs overestimated TEAEs by a factor ranging from none to five-fold. The overall incidence of serious AEs (SAEs) with ASAQ was nine per 1,000 (29/3,113) and mortality was one per 1,000 (three deaths, none drug-related); both were similar to other treatments.
  
  
  CONCLUSIONS
  ASAQ was comparatively well-tolerated. Safety information is important, and must be collected and analysed in a standardized way. TEAEs are a more objective measure of treatment-induced toxicity.
authors.affiliation: Drugs for Neglected Diseases Initiative (DNDi), Geneva, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Zwang
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.forename: Abdoulaye
authors.initials: A
authors.lastname: Djimdé
authors.forename: Corine
authors.initials: C
authors.lastname: Karema
authors.forename: Andreas
authors.initials: A
authors.lastname: Mårtensson
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Ndiaye
authors.forename: Sodiomon B
authors.initials: SB
authors.lastname: Sirima
authors.forename: Piero
authors.initials: P
authors.lastname: Olliaro
mesh_terms: D000293:Adolescent; D000328:Adult; D017954:Africa South of the Sahara; D000655:Amodiaquine / Q000008:administration & dosage* / Q000009:adverse effects*; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000009:adverse effects*; D037621:Artemisinins / Q000008:administration & dosage* / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; C515299:amodiaquine, artesunate drug combination; D000655:Amodiaquine