title: Randomized trial of safety and effectiveness of chlorproguanil-dapsone and lumefantrine-artemether for uncomplicated malaria in children in the Gambia.
abstract: BACKGROUND
  Chlorproguanil-dapsone (Lapdap), developed as a low-cost antimalarial, was withdrawn in 2008 after concerns about safety in G6PD deficient patients. This trial was conducted in 2004 to evaluate the safety and effectiveness of CD and comparison with artemether-lumefantrine (AL) under conditions of routine use in G6PD normal and G6PD deficient patients with uncomplicated malaria in The Gambia. We also examined the effects of a common genetic variant that affects chlorproguanil metabolism on risk of treatment failure.
  
  
  METHODS
  1238 children aged 6 months to 10 years with uncomplicated malaria were randomized to receive CD or artemether-lumefantrine (AL) and followed for 28 days. The first dose was supervised, subsequent doses given unsupervised at home. G6PD genotype was determined to assess the interaction between treatment and G6PD status in their effects on anaemia. The main endpoints were clinical treatment failure by day 28, incidence of severe anaemia (Hb<5 g/dL), and haemoglobin concentration on day 3.
  
  
  RESULTS
  One third of patients treated with AL, and 6% of patients treated with CD, did not complete their course of medication. 18% (109/595) of children treated with CD and 6.1% (36/587) with AL required rescue medication within 4 weeks, risk difference 12% (95%CI 8.9%-16%). 23 children developed severe anaemia (17 (2.9%) treated with CD and 6 (1.0%) with AL, risk difference 1.8%, 95%CI 0.3%-3.4%, P = 0.02). Haemoglobin concentration on day 3 was lower among children treated with CD than AL (difference 0.43 g/dL, 95% CI 0.24 to 0.62), and within the CD group was lower among those children who had higher parasite density at enrollment. Only 17 out of 1069 children who were typed were G6PD A- deficient, of these 2/9 treated with CD and 1/8 treated with AL developed severe anaemia. 5/9 treated with CD had a fall of 2 g/dL or more in haemoglobin concentration by day 3.
  
  
  CONCLUSIONS
  AL was well tolerated and highly effective and when given under operational conditions despite poor adherence to the six-dose regimen. There were more cases of severe malaria and anaemia after CD treatment although G6PD deficiency was uncommon.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT00118794.
authors.affiliation: Medical Research Council Laboratories, Banjul, The Gambia.
authors.forename: Samuel
authors.initials: S
authors.lastname: Dunyo
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sirugo
authors.forename: Sanie
authors.initials: S
authors.lastname: Sesay
authors.forename: Cyrille
authors.initials: C
authors.lastname: Bisseye
authors.forename: Fanta
authors.initials: F
authors.lastname: Njie
authors.forename: Majidah
authors.initials: M
authors.lastname: Adiamoh
authors.forename: Davis
authors.initials: D
authors.lastname: Nwakanma
authors.forename: Mathurin
authors.initials: M
authors.lastname: Diatta
authors.forename: Ramatoulie
authors.initials: R
authors.lastname: Janha
authors.forename: Fatou
authors.initials: F
authors.lastname: Sisay Joof
authors.forename: Beth
authors.initials: B
authors.lastname: Temple
authors.forename: Paul
authors.initials: P
authors.lastname: Snell
authors.forename: David
authors.initials: D
authors.lastname: Conway
authors.forename: Robert
authors.initials: R
authors.lastname: Walton
authors.forename: Yin Bun
authors.initials: YB
authors.lastname: Cheung
authors.forename: Paul
authors.initials: P
authors.lastname: Milligan
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D065731:Cytochrome P-450 CYP2C19; D003622:Dapsone / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D004338:Drug Combinations; D004983:Ethanolamines / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005449:Fluorenes / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D005714:Gambia / Q000453:epidemiology; D005838:Genotype; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D015994:Incidence; D007223:Infant; D008288:Malaria / Q000188:drug therapy* / Q000201:enzymology / Q000453:epidemiology / Q000469:parasitology; D008297:Male; D010271:Parasites / Q000187:drug effects; D010349:Patient Compliance; D002727:Proguanil / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D006454:Hemoglobins; C519882:chloroguanil, dapsone drug combination; D003622:Dapsone; D005954:Glucosephosphate Dehydrogenase; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D002727:Proguanil