TY - JOUR
T1 - Chlorproguanil - Dapsone - Artesunate versus artemether - Lumefantrine
T2 - A randomized, double-blind phase III trial in African children and adolescents with uncomplicated Plasmodium falciparum malaria
AU - Premji, Zul
AU - Umeh, Rich E.
AU - Owusu-Agyei, Seth
AU - Esamai, Fabian
AU - Ezedinachi, Emmanuel U.
AU - Oguche, Stephen
AU - Borrmann, Steffen
AU - Sowunmi, Akintunde
AU - Duparc, Stephan
AU - Kirby, Paula L.
AU - Pamba, Allan
AU - Kellam, Lynda
AU - Guiguemdé, Robert
AU - Greenwood, Brian
AU - Ward, Stephen A.
AU - Winstanley, Peter A.
N1 - Funding Information:
The authors are grateful to Professor Lucio Luzzatto for his review of the manuscript and helpful comments. Naomi Richardson of Magenta Communications Ltd developed a first draft of this paper from the approved study report and collated author contributions and was funded by GlaxoSmithKline PLC. The authors would like to thank all those who were involved in the clinical trial teams at Bobo-Dioulasso in Burkina Faso, Kintampo in Ghana, Eldoret, Kilifi and Pingilikani in Kenya, Ibadan, Enugu, Jos and Calabar in Nigeria, and Bagamoyo and Kiwangwa in Tanzania. The investigators would also like to gratefully acknowledge the children and their parents who agreed to take part in this study. Steffen Borrmann is supported by a Deutsche Forschungsgemeinschaft (DFG) Junior Group grant (SFB 544, A7).
PY - 2009/8/19
Y1 - 2009/8/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=68949200963&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0006682
DO - 10.1371/journal.pone.0006682
M3 - Article
C2 - 19690618
AN - SCOPUS:68949200963
SN - 1932-6203
VL - 4
JO - PLoS ONE
JF - PLoS ONE
IS - 8
M1 - e6682
ER -
