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Chlorproguanil-dapsone-artesunate versus artemether-lumefantrine: a randomized, double-blind phase III trial in African children and adolescents with uncomplicated Plasmodium falciparum malaria.

Premji, Z., Umeh, R. E., Owusu-Agyei, S., Esamai, F., Ezedinachi, E. U., Oguche, S., Borrmann, S., Sowunmi, A., Duparc, S., Kirby, P. L., Pamba, A., Kellam, L., Guiguemdé, R., Greenwood, B., Ward, S. A. and Winstanley, P. A. (2009) Chlorproguanil-dapsone-artesunate versus artemether-lumefantrine: a randomized, double-blind phase III trial in African children and adolescents with uncomplicated Plasmodium falciparum malaria. PloS one, 4 (8). ISSN 1932-6203 (In Press)

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Abstract

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.

METHODS AND FINDINGS

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.

TRIAL REGISTRATION

ClinicalTrials.Gov NCT00344006.

Item Type: Article
Keywords: Chlorproguanil-dapsone-artesunate, artemether-lumefantrine, Plasmodium falciparum, malaria, Africa
Subjects: Malaria > Diagnosis & treatment
Divisions: Ifakara Health Institute > Biomedical
Depositing User: Mr Joseph Madata
Date Deposited: 24 Jul 2012 15:24
Last Modified: 16 Aug 2012 15:57
URI: http://ihi.eprints.org/id/eprint/208

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