title: Combination treatments for uncomplicated falciparum malaria in Kampala, Uganda: randomised clinical trial.
abstract: BACKGROUND
  Plasmodium falciparum resistance has rendered chloroquine monotherapy ineffective in much of Africa, but data on alternative regimens are limited. We compared chloroquine+sulfadoxine-pyrimethamine, amodiaquine+sulfadoxine-pyrimethamine, and amodiaquine+artesunate for treatment of uncomplicated malaria in Kampala, Uganda.
  
  
  METHODS
  Of 1017 consecutive patients aged 6 months to 10 years with uncomplicated malaria who were screened, 418 were randomised to receive: chloroquine (25 mg/kg over 3 days) and sulfadoxine-pyrimethamine (25 mg/kg sulfadoxine, 1.25 mg/kg pyrimethamine, single dose); amodiaquine (25 mg/kg over 3 days) and sulfadoxine-pyrimethamine; or amodiaquine and artesunate (4 mg/kg daily for 3 days). Primary efficacy outcomes were 28-day clinical failure risks, adjusted and unadjusted by genotyping to distinguish new infection and recrudescence. The primary safety endpoint was incidence of serious adverse events during follow-up. Analysis was intention to treat and per protocol.
  
  
  RESULTS
  18 patients were excluded before enrollment. Of those enrolled, 384 of 400 (96%) were assigned an efficacy outcome and 396 (99%) were assessed for safety. Risk of 28-day clinical treatment failure was significantly higher with chloroquine+sulfadoxine-pyrimethamine (44/125 [35%]) than with amodiaquine+sulfadoxine-pyrimethamine (12/129 [9%]; risk difference 26% [95% CI 16-36]; p<0.0001) or amodiaquine+artesunate (3/130 [2%]; 33% [24-42]; p<0.0001). The greater risk of clinical treatment failure with amodiaquine+sulfadoxine-pyrimethamine was balanced by a lower risk of new infection, resulting in a similar need for retreatment over 28 days for amodiaquine+sulfadoxine-pyrimethamine (17/129 [13%]) and amodiaquine+artesunate (16/130 [12%]; p=0.854). Serious adverse events were uncommon with all regimens.
  
  
  CONCLUSIONS
  Risk of treatment failure with chloroquine+sulfadoxine-pyrimethamine was unacceptably high. Combinations of amodiaquine and sulfadoxine-pyrimethamine or artesunate were significantly more efficacious, and each regimen could be an appropriate alternative for treatment of uncomplicated malaria in Africa.
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA 94143, USA.
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Staedke
authors.forename: Arthur
authors.initials: A
authors.lastname: Mpimbaza
authors.forename: Moses R
authors.initials: MR
authors.lastname: Kamya
authors.forename: Bridget K
authors.initials: BK
authors.lastname: Nzarubara
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
mesh_terms: D000655:Amodiaquine / Q000008:administration & dosage / Q000009:adverse effects; D000962:Antimalarials / Q000008:administration & dosage* / Q000009:adverse effects; D037621:Artemisinins / Q000008:administration & dosage / Q000009:adverse effects; D000077332:Artesunate; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000008:administration & dosage / Q000009:adverse effects; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D011739:Pyrimethamine / Q000008:administration & dosage / Q000009:adverse effects; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000009:adverse effects; D013413:Sulfadoxine / Q000008:administration & dosage / Q000009:adverse effects; D017211:Treatment Failure; D014454:Uganda
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D012717:Sesquiterpenes; D000655:Amodiaquine; D000077332:Artesunate; D013413:Sulfadoxine; D002738:Chloroquine; D011739:Pyrimethamine