Abstract
BackgroundCritical to the development of new drugs for treatment of malaria is the capacity to safely evaluate their activity in human subjects. The approach that has been most commonly used is testing in subjects with natural malaria infection, a methodology that may expose symptomatic subjects to the risk of ineffective treatment. Here we describe the development and pilot testing of a system to undertake experimental infection using blood stage Plasmodium falciparum parasites (BSP). The objectives of the study were to assess the feasibility and safety of induced BSP infection as a method for assessment of efficacy of new drug candidates for the treatment of P. falciparum infection.Methods and FindingsA prospective, unblinded, Phase IIa trial was undertaken in 19 healthy, malaria-naïve, male adult volunteers who were infected with BSP and followed with careful clinical and laboratory observation, including a sensitive, quantitative malaria PCR assay. Volunteers were randomly allocated to treatment with either of two licensed antimalarial drug combinations, artemether–lumefantrine (A/L) or atovaquone-proguanil (A/P). In the first cohort (n = 6) where volunteers received ∼360 BSP, none reached the target parasitemia of 1,000 before the day designated for antimalarial treatment (day 6). In the second and third cohorts, 13 volunteers received 1,800 BSP, with all reaching the target parasitemia before receiving treatment (A/L, n = 6; A/P, n = 7) The study demonstrated safety in the 19 volunteers tested, and a significant difference in the clearance kinetics of parasitemia between the drugs in the 13 evaluable subjects, with mean parasite reduction ratios of 759 for A/L and 17 for A/P (95% CI 120–4786 and 7–40 respectively; p<0.01).ConclusionsThis system offers a flexible and safe approach to testing the in vivo activity of novel antimalarials.Trial Registration:ClinicalTrials.gov NCT01055002
Highlights
Significant advances have been made recently in the control of malaria [1,2], with reductions in the incidence and prevalence of infection as well as in malaria-associated mortality
While the reduction in burden of malaria is likely to be due to multiple factors, including the increasing use of insecticide-treated bed nets, the replacement of ineffective antimalarials with artemisinin combination therapy (ACT) has been recognized as a major factor in reducing the burden of malaria [2]
The study was conducted in accordance with the Declaration of Helsinki principles for the conduct of clinical trials and the International Committee of Harmonization Good Clinical Practice Guidelines as recognized by the Australian Therapeutic Goods Administration (TGA)
Summary
Significant advances have been made recently in the control of malaria [1,2], with reductions in the incidence and prevalence of infection as well as in malaria-associated mortality. While the reduction in burden of malaria is likely to be due to multiple factors, including the increasing use of insecticide-treated bed nets, the replacement of ineffective antimalarials with artemisinin combination therapy (ACT) has been recognized as a major factor in reducing the burden of malaria [2]. The concerning reports of slow clearance of P. falciparum parasitemia following artemisinin therapy in southeast Asia [3] reinforce the requirement to develop new antimalarials to replace drugs losing their efficacy [4]. The approach that has been most commonly used is testing in subjects with natural malaria infection, a methodology that may expose symptomatic subjects to the risk of ineffective treatment. We describe the development and pilot testing of a system to undertake experimental infection using blood stage Plasmodium falciparum parasites (BSP). The objectives of the study were to assess the feasibility and safety of induced BSP infection as a method for assessment of efficacy of new drug candidates for the treatment of P. falciparum infection
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