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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

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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, Stephen ORCID: https://orcid.org/0000-0003-2331-3192 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, Vol 4, Issue 8, e6682.

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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 (≥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,-20.9). 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. © Premji et al.

Item Type: Article
Subjects: WC Communicable Diseases > Tropical and Parasitic Diseases > WC 770 Therapy
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
WC Communicable Diseases > WC 20 Research (General)
WS Pediatrics > By Age Groups > WS 430 Infancy
QV Pharmacology > QV 38 Drug action.
QV Pharmacology > QV 4 General works
QX Parasitology > QX 20 Research (General)
WB Practice of Medicine > Therapeutics > WB 330 Drug therapy
QX Parasitology > Protozoa > QX 135 Plasmodia
WS Pediatrics > By Age Groups > WS 460 Adolescence (General)
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1371/journal.pone.0006682
Depositing User: Mary Creegan
Date Deposited: 25 Feb 2010 13:23
Last Modified: 06 Feb 2018 12:59
URI: http://archive.lstmed.ac.uk/id/eprint/366

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