ArticlesComparison of chlorproguanil-dapsone with sulfadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in young African children: double-blind randomised controlled trial
Introduction
Sulfadoxine-pyrimethamine (SP) is now the first choice drug for uncomplicated falciparum malaria in much of Africa,1 but it exerts high selection pressure for resistance2, 3 and might not remain useful for long.4 Africa includes most of the world's poorest countries, and the cost of antimalarial drugs is of major importance.5 Although other effective drugs are available, their high cost severely impairs widespread use.
Chlorproguanil-dapsone (CD) selects resistance less readily than SP,6 and has clinical use in cases when SP has failed.7, 8 CD (Lapdap™) has been developed as a fixed-ratio formulation and is available to the public sector at low cost (less than 50 US cents for a 3-day adult treatment course). Previous clinical trials of CD9, 10, 11 have focused more on efficacy than safety. Here, we describe a multi-centre phase III clinical trial of the registered tablet formulation. The primary aim of the study was to evaluate the safety profile of CD, and the secondary aim was to compare the 14-day efficacy of CD and SP in uncomplicated falciparum malaria.
Section snippets
Methods
This was a double-blind study in which patients randomly allocated to CD also took SP-placebo and vice-versa. It was undertaken at: Kisarawe, Tanzania (ethics approval was from the Muhimbili University College of Health Sciences Academic Board), Kilifi, Kenya (Kenya Medical Research Institute ethics committee), Blantyre, Malawi (College of Medicine Research ethics committee), Ibadan, Nigeria (Joint University of Ibadan/University College Hospital institutional review committee), and Lambaréné,
Role of the funding source
Funding for this study was from a ‘Product Development Team’ (PDT), which was equally funded by GlaxoSmithKline (GSK), WHO, and the UK Department for International Development (DFID), each of which participated in PDT meetings. The study protocol was developed by academic members of the PDT, assisted by GSK and WHO personnel. Clinical trial materials were provided by GSK. Both WHO and GSK undertook monitoring of trial sites. Data entry and analysis was done centrally for all five sites by
Results
250 children were randomised from Gabon and 400 each from the other centres. The study was prematurely terminated in Gabon because all other sites had finished recruitment, and enough patients had been recruited for the primary aim of assessing the safety profile of CD. All 1850 randomised patients were included in the intention-to-treat (ITT) population (table 1), although not all individuals had all data available at all timepoints. Figure 1 shows the numbers withdrawn from the study
Discussion
We used the standard dose of SP in this trial, and the CD dose was fixed according to previous investigations. The “paediatric formulation” of CD, used here, has been developed as a tablet instead of a liquid for two main reasons. First, in an African rural setting, dosing accuracy is greater with solid formulations20 and second, solid formulations are less expensive to manufacture and transport.
At day 14, the overall efficacy of CD was greater than that of SP in all five study sites. In Gabon,
References (30)
- et al.
Treatment of plasmodium falciparum malaria with pyrimethamine-sulfadoxine: selective pressure for resistance is a function of long elimination half-life
Trans R Soc Trop Med Hyg
(1993) - et al.
The efficacy of antifolate combinations in Africa: a predictive model based on pharmacodynamic and pharmacokinetic analyses
Parasitol Today
(1997) - et al.
Estimating the needs for artesunate-based combination therapy for malaria case-management in Africa
Trends Parasitol
(2003) - et al.
Drug resistant falciparum malaria in Tanzania: chlorproguanil-dapsone is effective treatment for infections resistant to pyrimethamine-sulfadoxine
Lancet
(2001) - et al.
Chlorproguanil-dapsone versus sulfadoxine-pyrimethamine for sequential episodes of uncomplicated falciparum malaria in Kenya and Malawi: a randomised clinical trial
Lancet
(2002) - et al.
Chlorproguanil-dapsone for uncomplicated falciparum malaria in young children: pharmacokinetics and therapeutic range
Trans R Soc Trop Med Hyg
(1997) - et al.
Molecular analysis of recrudescent parasites in a Plasmodium falciparum drug efficacy trial in Gabon
Trans R Soc Trop Med Hyg
(1997) - et al.
High-throughput sequence typing of T-cell epitope polymorphisms in Plasmodium falciparum circumsporozoite protein
Mol Biochem Parasitol
(2000) - et al.
Molecular heterogeneity of glucose-6-phosphate dehydrogenase A-
Blood
(1989) The use of antimalarial drugs: report of a WHO informal consultation, Nov 13–17, 2000—WHO/CDS/RBM/2001.33
(2000)
The evolution of drug-resistant malaria: the role of drug elimination half-life
Philos Trans R Soc Lond B Biol Sci
Molecular evidence of greater selective pressure for drug resistance exerted by the long acting antifolate pyrimethamine/sulfadoxine compared with the shorter acting chlorproguanil-dapsone on Kenyan Plasmodium falciparum
J Infect Dis
Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria
J Infect Dis
Chlorproguanil-dapsone: an effective treatment for uncomplicated falciparum malaria
Anti Microb Ag Chemother
Assessment of therapeutic efficacy of antimalarial drugs for uncomplicated falciparum malaria in areas with intense transmission—WHO/MAL/96.1077
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