Placebo-controlled trials are controversial when individuals might be denied existing beneficial medical interventions. In the case of malaria, most patients die in rural villages without healthcare facilities. An artesunate suppository that can be given by minimally skilled persons might be of value when patients suddenly become too ill for oral treatment but are several hours from a facility that can give injectable treatment for severe disease. In such situations, by default, no treatment is (or can be) given until the patient reaches a facility, making the placebo control design clinically relevant; alternative bioequivalence designs at the facility would misrepresent reality and risk incorrect conclusions. We describe the ethical issues underpinning a placebo-controlled trial in severe malaria. To protect patients and minimise risk, all patients were referred immediately to hospital so that each had a higher chance of prompt treatment through participation. There was no difference between artesunate and placebo in patients who reached clinic rapidly; among those who could not, a single artesunate suppository significantly reduced death or permanent disability, a finding of direct and indirect benefit to patients in participating villages and elsewhere.
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Funding The clinical study forming the basis for this paper was supported financially by the Unicef/UNDP/World Bank Special Programme for Research & Training in Tropical Diseases (WHO/TDR), the Global Malaria Programme (WHO/GMP), the Sall Family Foundation, the European Union (QLRT-2000-01430), the UK Medical Research Council, USAID, Irish Aid, the Karolinska Institute, and the University of Oxford Clinical Trial Service Unit (CTSU).
Competing interests AF and FB are on the WHO Antimalarial Treatment Guidelines Committee.
Ethics approval Ethics approval was provided by the ethics committees of Bangladesh, Ghana, United Republic of Tanzania and WHO.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
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