Chlorproguanil Hydrochloride/Dapsone

Intermittent Preventive Treatment of malaria in infants is a promising strategy to reduce incidence of clinical malaria in children under the age of 1 year. It is likely to be implemented as a malaria control strategy in Tanzania using sulfadoxine/pyremethamine SP. SP is failing as a first line treatment for clinical episodes of malaria and government policy is driving a change to use Artemesin Combination Therapy (ACT). The main ongoing Kilimanjaro IPTi study is looking at alternatives to SP for use in IPTi. Currently, as there is no evidence for the use of other drugs for IPT, SP will be continued for IPT in pregnancy and in infants. This study proposes to measure the efficacy of SP and chlorproguanil/dapsone (CD), in symptomatic 6- 59 month old children using standard methodology. These are both study drugs in the main IPTi study. This will help us to see how the efficacies of SP and CD in sick children relate to the efficacies for treating asymptomatic children with IPTi. In addition this proposal aims to test the efficacy of SP given to 2-10 month old asymptomatic infants (the target group for IPTi). Evidence suggests that asymptomatic malaria infections with low parasitaemia have a higher cure rate than symptomatic infections with high parasitaemia even when markers of resistance are highly prevalent. This second study aims to quantify this difference and will produce evidence to help policy makers know when drugs used for IPTi should be changed. Both studies will be open label and run concurrently in Hale, Korogwe district near to the main Kilimanjaro IPTi site in Tanzania.

CDA is a combination of chlorproguanil, dapsone and artesunate, being developed in a public-private partnership with the Medicines for Malaria Venture (MMV), World Health Organisation (WHO-TDR) and academic partners from the London School of Hygiene and Tropical Medicine, University of Liverpool and the Liverpool School of Tropical Medicine as a treatment for acute uncomplicated P. falciparum malaria.
The combination of chlorproguanil HCl (CPG) and dapsone (DDS) as chlorproguanil-dapsone has already been shown to be efficacious against P.falciparum in adults and children in Sub-Sahara Africa. The addition of artesunate to LAPDAP has been demonstrated to increase the parasite kill rate as demonstrated in the phase II study, and reduce the chance of any parasites escaping treatment over the 3-day course. The addition of artesunate is also anticipated to have the population benefit of protection against the development of resistant strains of P.falciparum, although it will not be possible to demonstrate this in a clinical trial. One further population benefit of the artemisinin drugs are their ability to suppress the sexual forms of the parasite (gametocytes), which should reduce infectivity after antimalarial treatment and potentially lower transmission rates with widespread use, including the spread of any parasites resistant to the partner drug.
The aims of this phase III study are to compare the efficacy of a fixed ratio combination tablet of CDA to chlorproguanil-dapsone, and collect supporting safety data. This will be a multi-centre, double-blind, double-dummy, randomised trial, in children, adolescents and adults, with chlorproguanil-dapsone as a comparator.