title: Open-label comparative clinical study of chlorproguanil-dapsone fixed dose combination (Lapdap) alone or with three different doses of artesunate for uncomplicated Plasmodium falciparum malaria.
abstract: The objective of this study was to determine the appropriate dose of artesunate for use in a fixed dose combination therapy with chlorproguanil-dapsone (CPG-DDS) for the treatment of uncomplicated falciparum malaria.
  
  
  METHODS
  Open-label clinical trial comparing CPG-DDS alone or with artesunate 4, 2, or 1 mg/kg at medical centers in Blantyre, Malawi and Farafenni, The Gambia. The trial was conducted between June 2002 and February 2005, including 116 adults (median age 27 years) and 107 children (median age 38 months) with acute uncomplicated Plasmodium falciparum malaria. Subjects were randomized into 4 groups to receive CPG-DDS alone or plus 4, 2 or 1 mg/kg of artesunate once daily for 3 days. Assessments took place on Days 0-3 in hospital and follow-up on Days 7 and 14 as out-patients. Efficacy was evaluated in the Day 3 per-protocol (PP) population using mean time to reduce baseline parasitemia by 90% (PC90). A number of secondary outcomes were also included. Appropriate artesunate dose was determined using a pre-defined decision matrix based on primary and secondary outcomes. Treatment emergent adverse events were recorded from clinical assessments and blood parameters. Safety was evaluated in the intent to treat (ITT) population.
  
  
  RESULTS
  In the Day 3 PP population for the adult group (N = 85), mean time to PC90 was 19.1 h in the CPG-DDS group, significantly longer than for the +artesunate 1 mg/kg (12.5 h; treatment difference -6.6 h [95%CI -11.8, -1.5]), 2 mg/kg (10.7 h; -8.4 h [95%CI -13.6, -3.2]) and 4 mg/kg (10.3 h; -8.7 h [95%CI -14.1, -3.2]) groups. For children in the Day 3 PP population (N = 92), mean time to PC90 was 21.1 h in the CPG-DDS group, similar to the +artesunate 1 mg/kg group (17.7 h; -3.3 h [95%CI -8.6, 2.0]), though the +artesunate 2 mg/kg and 4 mg/kg groups had significantly shorter mean times to PC90 versus CPG-DDS; 14.4 h (treatment difference -6.4 h [95%CI -11.7, -1.0]) and 12.8 h (-7.4 h [95%CI -12.9, -1.8]), respectively. An analysis of mean time to PC90 for the Day 14 PP and ITT populations was consistent with the primary analysis. Treatment emergent, drug-related adverse events were experienced in 35.3% (41/116) of adults and 70.1% (75/107) of children; mostly hematological and gastroenterological. The nature and incidence of adverse events was similar between the groups. No dose-related changes in laboratory parameters were observed. Nine serious adverse events due to any cause occurred in five subjects including two cases of hemolysis believed to be associated with drug treatment (one adult, one child). One adult died of anaphylactic shock, not associated with investigational therapy.
  
  
  CONCLUSIONS
  CPG-DDS plus artesunate demonstrated advantages over CPG-DDS alone for the primary efficacy endpoint (mean time to PC90) except in children for the 1 mg/kg artesunate dose. Based on a pre-defined decision matrix, the primary endpoint in the child group supported an artesunate dose of 4 mg/kg. Secondary endpoints also supported a 4 mg/kg artesunate dose to take forward into the remainder of the development program.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00519467.
authors.affiliation: Department of Pharmacology & Therapeutics, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Wootton
authors.forename: Hyginus
authors.initials: H
authors.lastname: Opara
authors.forename: Giancarlo A
authors.initials: GA
authors.lastname: Biagini
authors.forename: Maxwell K
authors.initials: MK
authors.lastname: Kanjala
authors.forename: Stephan
authors.initials: S
authors.lastname: Duparc
authors.forename: Paula L
authors.initials: PL
authors.lastname: Kirby
authors.forename: Mary
authors.initials: M
authors.lastname: Woessner
authors.forename: Colin
authors.initials: C
authors.lastname: Neate
authors.forename: Maggie
authors.initials: M
authors.lastname: Nyirenda
authors.forename: Hannah
authors.initials: H
authors.lastname: Blencowe
authors.forename: Queen
authors.initials: Q
authors.lastname: Dube-Mbeye
authors.forename: Thomas
authors.initials: T
authors.lastname: Kanyok
authors.forename: Stephen
authors.initials: S
authors.lastname: Ward
authors.forename: Malcolm
authors.initials: M
authors.lastname: Molyneux
authors.forename: Sam
authors.initials: S
authors.lastname: Dunyo
authors.forename: Peter A
authors.initials: PA
authors.lastname: Winstanley
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D019306:Artemisia / Q000737:chemistry; D037621:Artemisinins / Q000627:therapeutic use*; D000077332:Artesunate; D002648:Child; D002675:Child, Preschool; D003622:Dapsone / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D005714:Gambia; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy*; D008295:Malawi; D008297:Male; D008875:Middle Aged; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000302:isolation & purification; D002727:Proguanil / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018401:Sample Size; D012717:Sesquiterpenes / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D012717:Sesquiterpenes; C519882:chloroguanil, dapsone drug combination; D000077332:Artesunate; D003622:Dapsone; D002727:Proguanil