Abstract
BackgroundChlorproguanil-dapsone (Lapdap), developed as a low-cost antimalarial, was withdrawn in 2008 after concerns about safety in G6PD deficient patients. This trial was conducted in 2004 to evaluate the safety and effectiveness of CD and comparison with artemether-lumefantrine (AL) under conditions of routine use in G6PD normal and G6PD deficient patients with uncomplicated malaria in The Gambia. We also examined the effects of a common genetic variant that affects chlorproguanil metabolism on risk of treatment failure.Methods1238 children aged 6 months to 10 years with uncomplicated malaria were randomized to receive CD or artemether-lumefantrine (AL) and followed for 28 days. The first dose was supervised, subsequent doses given unsupervised at home. G6PD genotype was determined to assess the interaction between treatment and G6PD status in their effects on anaemia. The main endpoints were clinical treatment failure by day 28, incidence of severe anaemia (Hb<5 g/dL), and haemoglobin concentration on day 3.FindingsOne third of patients treated with AL, and 6% of patients treated with CD, did not complete their course of medication. 18% (109/595) of children treated with CD and 6.1% (36/587) with AL required rescue medication within 4 weeks, risk difference 12% (95%CI 8.9%–16%). 23 children developed severe anaemia (17 (2.9%) treated with CD and 6 (1.0%) with AL, risk difference 1.8%, 95%CI 0.3%–3.4%, P = 0.02). Haemoglobin concentration on day 3 was lower among children treated with CD than AL (difference 0.43 g/dL, 95% CI 0.24 to 0.62), and within the CD group was lower among those children who had higher parasite density at enrolment. Only 17 out of 1069 children who were typed were G6PD A- deficient, of these 2/9 treated with CD and 1/8 treated with AL developed severe anaemia. 5/9 treated with CD had a fall of 2 g/dL or more in haemoglobin concentration by day 3.InterpretationAL was well tolerated and highly effective and when given under operational conditions despite poor adherence to the six-dose regimen. There were more cases of severe malaria and anaemia after CD treatment although G6PD deficiency was uncommon.Trial RegistrationClinicaltrials.gov NCT00118794
Highlights
Chlorproguanil-dapsone (CD) was developed as a low-cost treatment for uncomplicated malaria [1]
Two trials of CD combined with artesunate (CDA) [8.9], showed clearly that malaria patients with glucose-6phosphate dehydrogenase (G6PD) A- deficiency who were treated with CDA were more likely to develop severe anaemia following treatment than G6PD deficient patients treated with SP+AQ [8] or AL [9] and in light of these findings further development of CDA (Dacart) was stopped and CD (Lapdap) was withdrawn by GSK [2]
Using DNA extracted from blood spots, the dihydrofolate reductase (DHFR) codon 51, 59 and 108 alleles were genotyped by polymerase chain reaction (PCR) amplification followed by analysis restriction fragment length polymorphism (PCR-RFLP) [14]
Summary
Chlorproguanil-dapsone (CD) was developed as a low-cost treatment for uncomplicated malaria [1]. In a phase 3 trial in children, 96% showed clinical and parasitological cure by day 14 after the start of treatment, but children with G6PD A- deficiency were more likely to have a fall of haemoglobin of 2 g/dL or more by day 3 if they had been treated with CD, and this association was more marked if baseline temperature was high [6] Following this trial, a series of studies was planned to evaluate the safety and effectiveness of CD in operational settings in order to evaluate the extent to which the risks associated with the use of the drug in settings without G6PD screening might outweigh the benefits to malaria treatment [7] of which the present study conducted in 2004 was the only one to be completed. We examined the effects of a common genetic variant that affects chlorproguanil metabolism on risk of treatment failure
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