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The use of placebo in a trial of rectal artesunate as initial treatment for severe malaria patients en route to referral clinics: ethical issues
  1. Andrew Kitua1,
  2. Peter Folb2,
  3. Marian Warsame3,
  4. Fred Binka4,
  5. Abul Faiz5,
  6. Isabela Ribeiro6,
  7. Tom Peto7,
  8. John Gyapong8,
  9. Emran Bin Yunus9,
  10. Ridwan Rahman10,
  11. Frank Baiden11,
  12. Christine Clerk12,
  13. Zakayo Mrango13,
  14. Charles Makasi13,
  15. Omari Kimbute13,
  16. Amir Hossain9,
  17. Rasheda Samad9,
  18. Melba Gomes1
  1. 1Unicef/UNDP/World Bank/WHO Special Programme for Research & training in Tropical Diseases, World Health Organization, Geneva, Switzerland
  2. 2Medical Research Council, Cape Town, South Africa
  3. 3Global Malaria Programme, World Health Organization, Geneva, Switzerland
  4. 4School of Public Health, University of Ghana, Accra, Ghana
  5. 5Sir Salimullah Medical College, Dhaka, Bangladesh
  6. 6DNDi, Rio de Janeiro, Brazil
  7. 7London School of Hygiene & Tropical Medicine, London, UK
  8. 8Health Research Unit, Ghana Health Service, Accra, Ghana
  9. 9Chittagong Medical College, Chittagong, Bangladesh
  10. 10Shaheed Suhrawardy Medical College, Dhaka, Bangladesh
  11. 11Kintampo Health Research Centre, Ghana
  12. 12Dodowa Health Research Centre, Dodowa, Ghana
  13. 13National Institute of Medical Research, Tanzania
  1. Correspondence to Dr Melba Gomes, UNICEF/UNDP/World Bank/WHO Special Programme for Research & Training in Tropical Diseases, World Health Organization, 1211 Avenue Appia, Geneva 27, Geneva, Switzerland; gomesm{at}who.int.

Abstract

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.

  • Healthcare for specific diseases/groups

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Footnotes

  • 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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