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.

Trial registration: ClinicalTrials.gov NCT00519467.

Conflict of interest statement

Competing Interests: Paula Kirby and Mary Woessner are current employees of GlaxoSmithKline, and Stephan Duparc and Colin Neate are former employees of GlaxoSmithKline.

Figures

Figure 1. Trial profile of the study and patient flow for a) adults and b) children.

ITT = intent to treat population; PP = per-protocol population.

Figure 2. Primary efficacy outcome: mean time to PC90 (±95% confidence intervals) in the Day 3 per-protocol population for (a) adults and (b) children.

*P ≤0.05 versus CPG−DDS alone; **P ≤0.01 versus CPG–DDS alone.

Figure 3. Results for Day 3 per-protocol population for mean time to PC50 and mean time to PC99 for (a) adults and (b) children.

*P ≤0.05 versus CPG−DDS alone; **P ≤0.01 versus CPG–DDS alone. Five adults (two in the CPG−DDS group, two in the +artesunate 1 mg/kg group and one in the +artesunate 2 mg/kg group) and 14 children (three from the CPG−DDS group, and five, three and three from the +artesunate 1, 2 and 4 mg/kg groups, respectively) were excluded from the mean time to PC50 analysis due to poor model fit. Seven adults (five in the CPG−DDS group, and one each in the +artesunate 1 mg/kg and 2 mg/kg groups) and five children (two from the CPG−DDS group, two from the +artesunate 1 mg/kg and one from the +artesunate 2 mg/kg group) were excluded from the mean time to PC99 analysis due to poor model fit.

Figure 4. Adults: Percentage of patients who were gametocytemic in the Day 3 per-protocol population at each scheduled assessment time.

Figure 5. Children: Percentage of patients who were gametocytemic in the Day 3 per-protocol population at each scheduled assessment time.