Combination therapy for uncomplicated falciparum malaria in Ugandan children: a randomized trial

JAMA. 2007 May 23;297(20):2210-9. doi: 10.1001/jama.297.20.2210.


Context: Combination therapy is now widely advocated as first-line treatment for uncomplicated malaria in Africa. However, it is not clear which treatment regimens are optimal or how to best assess comparative efficacies in highly endemic areas.

Objective: To compare the efficacy and safety of 3 leading combination therapies for the treatment of uncomplicated malaria.

Design, setting, and participants: Single-blind randomized clinical trial, conducted between November 2004 and June 2006, of treatment for all episodes of uncomplicated malaria in children in an urban community in Kampala, Uganda. A total of 601 healthy children (aged 1-10 years) were randomly selected and were followed up for 13 to 19 months, receiving all medical care at the study clinic.

Interventions: Study participants were randomized to receive 1 of 3 combination therapies (amodiaquine plus sulfadoxine-pyrimethamine, amodiaquine plus artesunate, or artemether-lumefantrine) when diagnosed with their first episode of uncomplicated malaria. The same assigned treatment was given for all subsequent episodes.

Main outcome measure: 28-Day risk of parasitological failure (unadjusted and adjusted by genotyping to distinguish recrudescence from new infection) for each episode of uncomplicated malaria treated with study drugs.

Results: Of enrolled children, 329 of 601 were diagnosed with at least 1 episode of uncomplicated malaria, and 687 episodes of Plasmodium falciparum malaria were treated with study drugs. The 28-day risk of treatment failure (unadjusted by genotyping) for individual episodes of malaria were 26.1% (95% CI, 21.1%-32.1%) for amodiaquine plus sulfadoxine-pyrimethamine, 17.4% (95% CI, 13.1%-23.1%) for amodiaquine plus artesunate, and 6.7% (95% CI, 3.9%-11.2%) for artemether-lumefantrine (P<.05 for all pairwise comparisons). When only recrudescent treatment failures were considered, the risks of failure were 14.1% (95% CI, 10.3%-19.2%), 4.6% (95% CI, 2.5%-8.3%), and 1.0% (95% CI, 0.3%-4.0%) for the same order of study drugs, respectively (P< or =.008 for all pairwise comparisons, except amodiaquine plus artesunate vs artemether-lumefantrine, P = .05). There were no deaths or cases of severe malaria. Significant reductions in anemia (9.3% [95% CI, 7.0%-12.0%] at enrollment vs 0.6% [95% CI, 0.1%-2.2%] during the last 2 months of follow-up; P<.001) and asymptomatic parasitemia (18.6% [95% CI, 15.5%-22.1%] at enrollment vs 2.3% [95% CI, 1.5%-3.5%] during the last 2 months of follow-up; P<.001) were observed according to routine testing.

Conclusions: Artemether-lumefantrine was the most efficacious treatment for uncomplicated malaria in the study population. With all study regimens, the provision of prompt and reasonably effective facility-based treatment was associated with good outcomes in long-term health measures.

Trial registration: Identifier: ISRCTN37517549.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amodiaquine / therapeutic use
  • Animals
  • Antimalarials / therapeutic use*
  • Artemether, Lumefantrine Drug Combination
  • Artemisinins / therapeutic use
  • Artesunate
  • Child
  • Child, Preschool
  • Drug Combinations
  • Drug Therapy, Combination
  • Ethanolamines / therapeutic use
  • Fluorenes / therapeutic use
  • Humans
  • Infant
  • Longitudinal Studies
  • Malaria, Falciparum / diagnosis
  • Malaria, Falciparum / drug therapy*
  • Parasitemia / diagnosis
  • Plasmodium falciparum / isolation & purification
  • Pyrimethamine / therapeutic use
  • Sesquiterpenes / therapeutic use
  • Single-Blind Method
  • Sulfadoxine / therapeutic use
  • Treatment Outcome
  • Uganda
  • Urban Population


  • Antimalarials
  • Artemether, Lumefantrine Drug Combination
  • Artemisinins
  • Drug Combinations
  • Ethanolamines
  • Fluorenes
  • Sesquiterpenes
  • Amodiaquine
  • fanasil, pyrimethamine drug combination
  • Artesunate
  • Sulfadoxine
  • Pyrimethamine

Associated data

  • ISRCTN/ISRCTN37517549