title: Chlorproguanil-dapsone-artesunate versus artemether-lumefantrine: a randomized, double-blind phase III trial in African children and adolescents with uncomplicated Plasmodium falciparum malaria.
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.
  
  
  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.
authors.affiliation: Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania. zpremji@muhas.ac.tz
authors.forename: Zul
authors.initials: Z
authors.lastname: Premji
authors.forename: Rich E
authors.initials: RE
authors.lastname: Umeh
authors.forename: Seth
authors.initials: S
authors.lastname: Owusu-Agyei
authors.forename: Fabian
authors.initials: F
authors.lastname: Esamai
authors.forename: Emmanuel U
authors.initials: EU
authors.lastname: Ezedinachi
authors.forename: Stephen
authors.initials: S
authors.lastname: Oguche
authors.forename: Steffen
authors.initials: S
authors.lastname: Borrmann
authors.forename: Akintunde
authors.initials: A
authors.lastname: Sowunmi
authors.forename: Stephan
authors.initials: S
authors.lastname: Duparc
authors.forename: Paula L
authors.initials: PL
authors.lastname: Kirby
authors.forename: Allan
authors.initials: A
authors.lastname: Pamba
authors.forename: Lynda
authors.initials: L
authors.lastname: Kellam
authors.forename: Robert
authors.initials: R
authors.lastname: Guiguemdé
authors.forename: Brian
authors.initials: B
authors.lastname: Greenwood
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
authors.forename: Peter A
authors.initials: PA
authors.lastname: Winstanley
mesh_terms: 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
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; D000077332:Artesunate; C007030:chlorproguanil; D003622:Dapsone; D000078102:Lumefantrine; D002727:Proguanil
references.citation: Lancet. 2004 Jun 5;363(9424):1843-8
references.pmid: 15183620
references.citation: J Infect Dis. 2006 Apr 15;193(8):1151-9
references.pmid: 16544256
references.citation: Trop Med Int Health. 2008 May;13(5):635-43
references.pmid: 18346028
references.citation: East Afr Med J. 2002 Jan;79(1):42-4
references.pmid: 12380870
references.citation: Am J Trop Med Hyg. 2007 Oct;77(4):779-89
references.pmid: 17978087
references.citation: Malar J. 2006 May 16;5:43
references.pmid: 16704735
references.citation: Clin Infect Dis. 2005 Oct 15;41(8):1079-86
references.pmid: 16163624
references.citation: Hum Genet. 1994 Nov;94(5):513-7
references.pmid: 7959686
references.citation: Trans R Soc Trop Med Hyg. 2008 May;102(5):412-20
references.pmid: 18328518
references.citation: Am J Trop Med Hyg. 2006 Jun;74(6):991-8
references.pmid: 16760509
references.citation: PLoS One. 2008 Mar 05;3(3):e1779
references.pmid: 18320064
references.citation: Am J Trop Med Hyg. 2003 Feb;68(2):133-9
references.pmid: 12641400
references.citation: Br J Clin Pharmacol. 2006 Mar;61(3):289-300
references.pmid: 16487222
references.citation: Proc Natl Acad Sci U S A. 1962 Jan 15;48:9-16
references.pmid: 13868717
references.citation: Biochem J. 1990 Oct 1;271(1):157-60
references.pmid: 2222408
references.citation: Trans R Soc Trop Med Hyg. 2005 Jun;99(6):459-67
references.pmid: 15837358
references.citation: Lancet. 2005 Apr 23-29;365(9469):1474-80
references.pmid: 15850631
references.citation: Lancet. 2007 Sep 22;370(9592):1035-9
references.pmid: 17889242
references.citation: PLoS One. 2008;3(12):e4031
references.pmid: 19112496
references.citation: PLoS One. 2008 Jun 25;3(6):e2530
references.pmid: 18575626
references.citation: Lancet. 2007 Feb 10;369(9560):491-8
references.pmid: 17292769
references.citation: Trans R Soc Trop Med Hyg. 1997 Jan-Feb;91(1):68-73
references.pmid: 9093633
references.citation: Bull World Health Organ. 1966;35(2):165-79
references.pmid: 5297001
references.citation: Antimicrob Agents Chemother. 2000 Mar;44(3):697-704
references.pmid: 10681341
references.citation: Hum Hered. 1999 Jan;49(1):41-4
references.pmid: 9858856
references.citation: PLoS Med. 2005 Apr;2(4):e92
references.pmid: 15839740
references.citation: Clin Infect Dis. 2007 Dec 1;45(11):1453-61
references.pmid: 17990228
references.citation: Trans R Soc Trop Med Hyg. 1989 Mar-Apr;83(2):182-8
references.pmid: 2692227
references.citation: Blood. 1989 Nov 15;74(7):2550-5
references.pmid: 2572288