Chlorproguanil-dapsone-artesunate versus artemether-lumefantrine: a randomized, double-blind phase III trial in African children and adolescents with uncomplicated Plasmodium falciparum malaria.
BACKGROUND
Chlorproguanil-dapsone-artesunate (CDA) was developed as an affordable, simple, fixed-dose artemisinin-based combination therapy for use in Africa. This trial was a randomized parallel-group, double-blind, double-dummy study to compare CDA and artemether-lumefantrine (AL) efficacy in uncomplicated Plasmodium falciparum malaria and further define the CDA safety profile, particularly its hematological safety in glucose-6-phosphate dehydrogenase (G6PD) -deficient patients.


RESULTS
The trial was conducted at medical centers at 11 sites in five African countries between June 2006 and August 2007. 1372 patients (> or =1 to <15 years old, median age 3 years) with acute uncomplicated P. falciparum malaria were randomized (2:1) to receive CDA 2/2.5/4 mg/kg once daily for three days (N = 914) or six-doses of AL over three days (N = 458). Non-inferiority of CDA versus AL for efficacy was evaluated in the Day 28 per-protocol (PP) population using parasitological cure (polymerase chain reaction [PCR]-corrected). Cure rates were 94.1% (703/747) for CDA and 97.4% (369/379) for AL (treatment difference -3.3%, 95%CI -5.6, -0.9). CDA was non-inferior to AL, but there was simultaneous superiority of AL (upper 95%CI limit <0). Adequate clinical and parasitological response at Day 28 (uncorrected for reinfection) was 79% (604/765) with CDA and 83% (315/381) with AL. In patients with a G6PD-deficient genotype (94/603 [16%] hemizygous males, 22/598 [4%] homozygous females), CDA had the propensity to cause severe and clinically concerning hemoglobin decreases: the mean hemoglobin nadir was 75 g/L (95%CI 71, 79) at Day 7 versus 97 g/L (95%CI 91, 102) for AL. There were three deaths, unrelated to study medication (two with CDA, one with AL).


CONCLUSIONS
Although parasitologically effective at Day 28, the hemolytic potential of CDA in G6PD-deficient patients makes it unsuitable for use in a public health setting in Africa.


BACKGROUND
ClinicalTrials.Gov NCT00344006.
Premji
Zul
Z
Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania. zpremji@muhas.ac.tz
Umeh
Rich E
RE
Owusu-Agyei
Seth
S
Esamai
Fabian
F
Ezedinachi
Emmanuel U
EU
Oguche
Stephen
S
Borrmann
Steffen
S
Sowunmi
Akintunde
A
Duparc
Stephan
S
Kirby
Paula L
PL
Pamba
Allan
A
Kellam
Lynda
L
Guiguemdé
Robert
R
Greenwood
Brian
B
Ward
Stephen A
SA
Winstanley
Peter A
PA
D000293:Adolescent; D000349:Africa; D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000008:administration & dosage / Q000627:therapeutic use*; D000077332:Artesunate; D002648:Child; D003622:Dapsone / Q000008:administration & dosage / Q000627:therapeutic use*; D004311:Double-Blind Method; D004983:Ethanolamines / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D010349:Patient Compliance; D002727:Proguanil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
D000962:Antimalarials; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; D000077332:Artesunate; C007030:chlorproguanil; D003622:Dapsone; D000078102:Lumefantrine; D002727:Proguanil
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