Pre-referral rectal artesunate to prevent death and disability in severe malaria: a placebo-controlled trial

M F Gomes, M A Faiz, J O Gyapong, M Warsame, T Agbenyega, A Babiker, F Baiden, E B Yunus, F Binka, C Clerk, P Folb, R Hassan, M A Hossain, O Kimbute, A Kitua, S Krishna, C Makasi, N Mensah, Z Mrango, P Olliaro, R Peto, T J Peto, M R Rahman, I Ribeiro, R Samad, N J White, Study 13 Research Group, Abul Faiz, Emran Bin Yunus, Md Ridwanur Rahman, Md Amir Hossain, Rasheda Samad, A M Bangali, Rafiqul Hassan, Rajib Palit, Md Sazzad Hossain Chowdhury, Alamgir Rashid Chowdhury, Arman Hossain, Md Golam Kibria, Tafsir Ahmed Chowdhury, A Uye Maung, Nasiruddin Bhuiyan, Sonet Dipta Nath, Ashraful Islam, Ranjan Chowdhury, Ajoy Ghose, M Rashid, Md Badiur Rahman, Narayan Proshad, Dulal C Paul, Ratan Chowdhury, Anil Baran Paul, Ajit Kumar Bhattacharjee, Baker Siddique, Md Danesh Chowdhury, Abul Kashem, Parimal Sharma, Niranjan Das, Md Yunus, Abul Kashem, Priya Ranjan Paul, Alhaj Nurul Alam, Md Amanul Hoque, Md Ali, Md Nurul Islam, Kallol Barua, Md Soaib, Ranadhir Barua, Manik Chandra Dhar, Md Amanat Ullah, Md Abdul Monaf, Md Syed Siraje, Mamtaz Ahmed, Ashutosh Shil, Nurul Islam, Bangkim Barua, Mong Ting Aung, Farid Alam, Monoranjan Barua, Mahbubul Mawla, M Ibrahim Azad, Manohari Dutta, Siddique Ahmed, Tarun Barua, Anil Kumar Barua, Sunil Kumar Bardan, Suibai Aung Marma, Mayshan Marma, Chaila Mong Chak, Hla Mong Chin Marma, Md Alam, Akter Ahmed, Abul Kalam Azad, Pallab Barua, Akter Hossain, Proshenjit Barua, Amir Ali, Madhu Sudan Dev, Mozaffar Ahmed, Awlad Hossain, Protiva Rani Chy, Md Safiqul Mostafa Chowdhury, Md Nizam Uddin, Yeasmin Zahan, Dolly Biswas, Golapy Kulentunu, Protiva Rani Chowdhury, Habiba Jannat, Nazem Uddin, Eliyas Ahmed, John Gyapong, Fred Binka, Christine Clerk, Frank Baiden, Rita Baiden, Seth Owusu Agyei, Nathan Mensah, Abraham Hodgson, Oscar Bangre, Fabian Achana, Samuel Chatio, Roberto Abakeh, Isaac Apuri, James Atintono, Monica Kaba, William Kwarah, Jacob Wedam, Louisa Abukari, Clara Awampaga, Abdulai Santama, Bugri Gumah Akalifa, Abdul-Wahab Hamid, Marian Warsame, Andrew Kitua, Zakayo Mrango, Tom Peto, Charles Makasi, Omari Kimbute, Samuel Mwankusye, Steven Mduma, Joseph Shishira, Mansour H Msabaha, Francis Mulokozi, Goodluck Motta, Jackson Mkwao, Elia Msegu, Elias Ndahani, Emmanuel Massawe, Rahim Mohamed, Henerico Ernest, Benson Bundala, Andrew Mkomwa, Daudi Twaha, Daniel Chochole, John Masimba, Revocatus Nyekabora, Kamuabwa L Rufulenge, Nasemba Njema, Grace Chiduo, Juliana Kitua, Avit Kapinga, Irene Kisongele, Nahda Juma, Steven Ngatunga, Fred Clement, Isabela Ribeiro, Jayme Fernandes, Rory Collins, Tim Peto, Lindiwe Makubalo, Abdel Babiker, Nicholas J White, Tsiri Agbenyega, Melba Gomes, M F Gomes, M A Faiz, J O Gyapong, M Warsame, T Agbenyega, A Babiker, F Baiden, E B Yunus, F Binka, C Clerk, P Folb, R Hassan, M A Hossain, O Kimbute, A Kitua, S Krishna, C Makasi, N Mensah, Z Mrango, P Olliaro, R Peto, T J Peto, M R Rahman, I Ribeiro, R Samad, N J White, Study 13 Research Group, Abul Faiz, Emran Bin Yunus, Md Ridwanur Rahman, Md Amir Hossain, Rasheda Samad, A M Bangali, Rafiqul Hassan, Rajib Palit, Md Sazzad Hossain Chowdhury, Alamgir Rashid Chowdhury, Arman Hossain, Md Golam Kibria, Tafsir Ahmed Chowdhury, A Uye Maung, Nasiruddin Bhuiyan, Sonet Dipta Nath, Ashraful Islam, Ranjan Chowdhury, Ajoy Ghose, M Rashid, Md Badiur Rahman, Narayan Proshad, Dulal C Paul, Ratan Chowdhury, Anil Baran Paul, Ajit Kumar Bhattacharjee, Baker Siddique, Md Danesh Chowdhury, Abul Kashem, Parimal Sharma, Niranjan Das, Md Yunus, Abul Kashem, Priya Ranjan Paul, Alhaj Nurul Alam, Md Amanul Hoque, Md Ali, Md Nurul Islam, Kallol Barua, Md Soaib, Ranadhir Barua, Manik Chandra Dhar, Md Amanat Ullah, Md Abdul Monaf, Md Syed Siraje, Mamtaz Ahmed, Ashutosh Shil, Nurul Islam, Bangkim Barua, Mong Ting Aung, Farid Alam, Monoranjan Barua, Mahbubul Mawla, M Ibrahim Azad, Manohari Dutta, Siddique Ahmed, Tarun Barua, Anil Kumar Barua, Sunil Kumar Bardan, Suibai Aung Marma, Mayshan Marma, Chaila Mong Chak, Hla Mong Chin Marma, Md Alam, Akter Ahmed, Abul Kalam Azad, Pallab Barua, Akter Hossain, Proshenjit Barua, Amir Ali, Madhu Sudan Dev, Mozaffar Ahmed, Awlad Hossain, Protiva Rani Chy, Md Safiqul Mostafa Chowdhury, Md Nizam Uddin, Yeasmin Zahan, Dolly Biswas, Golapy Kulentunu, Protiva Rani Chowdhury, Habiba Jannat, Nazem Uddin, Eliyas Ahmed, John Gyapong, Fred Binka, Christine Clerk, Frank Baiden, Rita Baiden, Seth Owusu Agyei, Nathan Mensah, Abraham Hodgson, Oscar Bangre, Fabian Achana, Samuel Chatio, Roberto Abakeh, Isaac Apuri, James Atintono, Monica Kaba, William Kwarah, Jacob Wedam, Louisa Abukari, Clara Awampaga, Abdulai Santama, Bugri Gumah Akalifa, Abdul-Wahab Hamid, Marian Warsame, Andrew Kitua, Zakayo Mrango, Tom Peto, Charles Makasi, Omari Kimbute, Samuel Mwankusye, Steven Mduma, Joseph Shishira, Mansour H Msabaha, Francis Mulokozi, Goodluck Motta, Jackson Mkwao, Elia Msegu, Elias Ndahani, Emmanuel Massawe, Rahim Mohamed, Henerico Ernest, Benson Bundala, Andrew Mkomwa, Daudi Twaha, Daniel Chochole, John Masimba, Revocatus Nyekabora, Kamuabwa L Rufulenge, Nasemba Njema, Grace Chiduo, Juliana Kitua, Avit Kapinga, Irene Kisongele, Nahda Juma, Steven Ngatunga, Fred Clement, Isabela Ribeiro, Jayme Fernandes, Rory Collins, Tim Peto, Lindiwe Makubalo, Abdel Babiker, Nicholas J White, Tsiri Agbenyega, Melba Gomes

Abstract

Background: Most malaria deaths occur in rural areas. Rapid progression from illness to death can be interrupted by prompt, effective medication. Antimalarial treatment cannot rescue terminally ill patients but could be effective if given earlier. If patients who cannot be treated orally are several hours from facilities for injections, rectal artesunate can be given before referral and acts rapidly on parasites. We investigated whether this intervention reduced mortality and permanent disability.

Methods: In Bangladesh, Ghana, and Tanzania, patients with suspected severe malaria who could not be treated orally were allocated randomly to a single artesunate (n=8954) or placebo (n=8872) suppository by taking the next numbered box, then referred to clinics at which injections could be given. Those with antimalarial injections or negative blood smears before randomisation were excluded, leaving 12 068 patients (6072 artesunate, 5996 placebo) for analysis. Primary endpoints were mortality, assessed 7-30 days later, and permanent disability, reassessed periodically. All investigators were masked to group assignment. Analysis was by intention to treat. This study is registered in all three countries, numbers ISRCTN83979018, 46343627, and 76987662.

Results: Mortality was 154 of 6072 artesunate versus 177 of 5996 placebo (2.5%vs 3.0%, p=0.1). Two versus 13 (0.03%vs 0.22%, p=0.0020) were permanently disabled; total dead or disabled: 156 versus 190 (2.6%vs 3.2%, p=0.0484). There was no reduction in early mortality (56 vs 51 deaths within 6 h; median 2 h). In patients reaching clinic within 6 h (median 3 h), pre-referral artesunate had no significant effect on death after 6 h or permanent disability (71/4450 [1.6%] vs 82/4426 [1.9%], risk ratio 0.86 [95% CI 0.63-1.18], p=0.35). In patients still not in clinic after more than 6 h, however, half were still not there after more than 15 h, and pre-referral rectal artesunate significantly reduced death or permanent disability (29/1566 [1.9%] vs 57/1519 [3.8%], risk ratio 0.49 [95% CI 0.32-0.77], p=0.0013).

Interpretation: If patients with severe malaria cannot be treated orally and access to injections will take several hours, a single inexpensive artesunate suppository at the time of referral substantially reduces the risk of death or permanent disability.

Funding: UNICEF/UNDP/World Bank Special Programme for Research and Training in Tropical Diseases (WHO/TDR); WHO Global Malaria Programme (WHO/GMP); 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).

Figures

Figure 1
Figure 1
Trial profile Main 7–30 day follow-up was at a median of 14 days after randomisation. *Randomised patients were excluded only if a prerandomisation blood smear was free of malaria parasites (26% of all smears were negative for malaria); or the entry form recorded that an antimalarial drug had already just been injected. In patients with smear-negative disease who were still alive but not injected or in clinic more than 6 h after randomisation, 28/475 artesunate-allocated vs 25/472 placebo-allocated patients died or were disabled.
Figure 2
Figure 2
Death by time since randomisation and death or permanent disability at the 7–30 day follow-up
Figure 3
Figure 3
Effects of trial treatment on early mortality and, subdivided by time taken to reach clinic, later mortality or permanent disability *Median time to death. †Median time (for those with adverse outcome) to arrival at clinic, or prior death.
Figure 4
Figure 4
Effects of trial treatment in Africa and in Asia NS=not significant. *Median time to death. †Median time (for those with adverse outcome) to arrival at clinic, or prior death.
Figure 5
Figure 5
Effects of trial treatment if comatose and if not comatose *Median time to death. †Median time (for those with adverse outcome) to arrival at clinic, or prior death.

References

    1. for the Disease Control Priorities Project . Global burden of disease and risk factors. In: Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL, editors. The World Bank/Oxford University Press; New York: 2006.
    1. Newton CRJC, Krishna S. Severe falciparum malaria in children: current understanding of pathophysiology and supportive treatment. Pharmacol Ther. 1998;79:1–53.
    1. Molyneux ME. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. Q J Med. 1989;71:441–459.
    1. Carter JA, Mung'ala-Odera V, Neville BGR. Persistent neurocognitive impairments associated with severe falciparum malaria in Kenyan children. J Neurol Neurosurg Psychiatry. 2005;76:476–481.
    1. Ngoungou EB, Dulac O, Poudiougou B. Epilepsy as a consequence of cerebral malaria in area in which malaria is endemic in Mali, West Africa. Epilepsia. 2006;47:873–879.
    1. White NJ. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob Agents Chemother. 1997;41:1413–1422.
    1. Simpson JA, Agbenyega T, Barnes KI. Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients. PLoS Med. 2006;3:e444.
    1. Krishna S, Planche T, Agbenyega T. Bioavailability and preliminary clinical efficacy of intrarectal artesunate in Ghanaian children with moderate malaria. Antimicrob Agents Chemother. 2001;45:509–516.
    1. Barnes KI, Mwenechanya J, Tembo M. Efficacy of rectal artesunate compared with parenteral quinine in initial treatment of moderately severe malaria in African children and adults: a randomised study. Lancet. 2004;363:1598–1605.
    1. Brewer TG, Peggins JO, Grate SJ. Neurotoxicity in animals due to arteether and artemether. Trans R Soc Trop Med Hyg. 1994;88(suppl 1):S33–S36.
    1. Dondorp A, Nosten F, Stepniewska K, Day NP, White NJ. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005;366:717–725.
    1. White NJ. Antimalarial drug resistance and mortality in falciparum malaria. Trop Med Int Health. 1999;4:469.
    1. White NJ. Antimalarial resistance. J Clin Invest. 2004;113:1084–1092.
    1. Arrow KJ, Panosian CB, Gelband H. Saving lives, buying time: economics of malaria drugs in an age of resistance. National Academy Press; Washington: 2004.
    1. Peterson S, Nsungwa-Sabiiti J, Were W. Coping with paediatric referral—Ugandan parents' experience. Lancet. 2004;363:1955–1956.
    1. al Fadil SM, Alrahman SH, Cousens S. Integrated Management of Childhood Illness strategy: compliance with referral and follow-up recommendations in Gezira State, Sudan. Bull World Health Organ. 2003;81:708–716.
    1. Chowdhury EK, El Arifeen S, Rahman M. Care at first-level facilities for children with severe pneumonia in Bangladesh: a cohort study. Lancet. 2008;372:822–830.
    1. Yunus EB, Faiz MA, Rahman MR. Study to document pre-admission risk factors for development of severe malaria and the spectrum of it and the outcome in different categories of hospitals in malaria endemic zone of Bangladesh. J Bang Coll Phys Surg. 2004;22:83–88.

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