Elsevier

The Lancet

Volume 363, Issue 9424, 5 June 2004, Pages 1843-1848
The Lancet

Articles
Comparison of chlorproguanil-dapsone with sulfadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in young African children: double-blind randomised controlled trial

https://doi.org/10.1016/S0140-6736(04)16350-2Get rights and content

Summary

Background

Increasing resistance to sulfadoxine-pyrimethamine is leading to a decline in its effectiveness. We aimed to assess the safety profile of chlorproguanil-dapsone (CD), and to compare the safety and efficacy of this drug with that of sulfadoxine-pyrimethamine (SP) as treatment for uncomplicated falciparum malaria.

Methods

We undertook a double-blind, randomised trial in 1850 consecutively recruited children with uncomplicated falciparum malaria, pooling data from five African countries. Analyses were based on all randomised patients with available data.

Findings

CD was significantly more efficacious than SP (odds ratio 3·1 [95% CI 2·0–4·8]); 1313 patients (96%) given CD and 306 (89%) given SP achieved acceptable clinical and parasitological response by day 14. Adverse events were reported in 46% and 50% of patients randomised to CD and SP, respectively (treatment difference −4·4%, [95% CI −10·1 to 1·3]). Haemoglobin in the CD group was significantly lower than in the SP group at day 7, a difference of −4 g/L (95% CI −6 to −2). Mean day 14 haemoglobin (measured only for the small number of patients whose day 7 data caused concern) was 94 g/L (92–96) and 97 g/L (92–102) after CD and SP, respectively. Glucose-6-phosphate dehydrogenase deficient patients on CD had greater odds than those on SP of having a fall of 20 g/dL or more in haemoglobin when baseline temperature was high. Methaemoglobinaemia was seen in the CD group (n=320, mean 0·4% [95% CI 0·4–0·4]) before treatment, 4·2% (95% CI 3·8–4·6) (n=301) at day 3, and 0·6% (0·6–0·7) (n=300) at day 7).

Interpretation

CD had greater efficacy than SP in Africa and was well tolerated. Haematological adverse effects were more common with CD than with SP and were reversible. CD is a useful alternative where SP is failing due to resistance.

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,

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