Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial

Arjen M Dondorp, Caterina I Fanello, Ilse C E Hendriksen, Ermelinda Gomes, Amir Seni, Kajal D Chhaganlal, Kalifa Bojang, Rasaq Olaosebikan, Nkechinyere Anunobi, Kathryn Maitland, Esther Kivaya, Tsiri Agbenyega, Samuel Blay Nguah, Jennifer Evans, Samwel Gesase, Catherine Kahabuka, George Mtove, Behzad Nadjm, Jacqueline Deen, Juliet Mwanga-Amumpaire, Margaret Nansumba, Corine Karema, Noella Umulisa, Aline Uwimana, Olugbenga A Mokuolu, Olanrewaju T Adedoyin, Wahab B R Johnson, Antoinette K Tshefu, Marie A Onyamboko, Tharisara Sakulthaew, Wirichada Pan Ngum, Kamolrat Silamut, Kasia Stepniewska, Charles J Woodrow, Delia Bethell, Bridget Wills, Martina Oneko, Tim E Peto, Lorenz von Seidlein, Nicholas P J Day, Nicholas J White, AQUAMAT group, Ermelinda Gomes, Amir Seni, Kajal D Chhaganlal, Ilse C E Hendriksen, Alínia José Pedro, César D R Jarach, Olivier Wingi, Ester I Fernando, Mara Zambruni, Zacarias Raimundo, Carlos J de Oliveira, Arjen Dondorp, Francisco Songane, Avertino Barreto, Marcelino Lucas, Kalifa Bojang, Rasaq Olaosebikan, Nkechinyere Anunobi, Tumani Corrah, David Conway, Sarah Rowland-Jones, Francis Akor, Joseph Okebe, Muminatou Jallow, Osaretin Chimah, Abubakar Ismaela, Mamkumba Sanneh, Saidykhan Mamodou, Fatou Jammeh, Janet Fullah, Abdou Bah, Horija Saine, Tsiri Agbenyega, Samuel Blay Nguah, Jennifer Evans, Daniel Ansong, Justice Sylverken, Alex O Akoto, Larko D Owusu, David Sambian, Michael Ntim, Kathryn Maitland, Esther Kivaya, Mohammed Abubakar, Ayub Mpoya, Charles Newton, Samson Gwer, Samuel Akech, Michael Kazungu, Michael Kihara, Molline Timbwa, Mwanamvua Boga, Samwel Gesase, Catherine Kahabuka, Martha Lemnge, Lorenz von Seidlein, Aileen Barongo, Anangisye Malabeja, Omary Abdul, Zacharia Savael, Gustav Tilaus, Laura Chuwa, Stella Kabela, Behzad Nadjm, Jacqueline Deen, Hugh Reyburn, Christopher Whitty, Ilse C E Hendriksen, Amani Shao, Selemani Mtunguja, Marwa Mwikwabe, Walli Msuya, Christina Kiemi, Edward Mtili, Lorenz von Seidlein, Emmanuel Swai, Ben Amos, Rajabu Malahiyo, Regina Malugu, Michael Mnongea, Stella Emmanuel, Nzitu J Msengi, Faraja M Mtimbo, Juma Kimera, George Mtove, Corine Karema, Noella Umulisa, Aline Uwimana, Josephine Ngalula Mulumba, Aimee Uwase, Devotha Rugandura, Claude Kawite, Deogratias Ruhangaza, Jean Claude Ndagijimana, Josephine Mukeshiyaremye, Antoinette Kayitesi, Violette Mukamugenzi, Ntwali Ndizeye, Tharcisse Munyaneza, Olugbenga A Mokuolu, Olanrewaju T Adedoyin, Wahab B R Johnson, Ayodele Ojuawo, Samuel K Ernest, Omotayo O Adesiyun, Aishatu A Abdulkarim, Abdulrasheed O Adegboye, Ashau O Timi-Oladipo, Bukola R Kelani, Oyekunle Ogunkanbi, Abdulrahreem Yusuf, Oluyemisi Adegboye, Olabode T Oyewale, Olusegun Oladele, Alice Jacob, Oluseun Faniyi, Juliet Mwanga-Amumpaire, Margaret Nansumba, Patrice Piola, Pierre Debeaudrap, Yap Boum 2nd, Mehul Dhorda, Eleanor Turyakira, Elias Kumbakumba, Eunice Nyesigire, Peters Kalubi, Santorino Data, Naome Natukunda, Antoney Ssegane, Nyehangane Dan, Benon Tumwebaze, Benson Twinomujuni, James Kinyatta, Suzan Esther Asaasira, Jacqueline Tumuhairwe, Sanyu Scovia, Primativa Kyohairwe, Shiela Mbabazi, Harriet Adrama, Thaddeus Turuho, Sulaiman Muwanga, John Bosco Ariyo, Peace Magezi, Agatha Twebaze, Antoinette K Tshefu, Marie A Onyamboko, Jacques K Zandibeni, Elyse K Katokale, Charlie N Kabedi, Adolphine B Nkuadiolandu, Raoul N Mpoyi, Marcelline M Sakina, Crispin K Fela, Jacqueline A Omari, Odile K Muniaka, Betty D Omba, Antoinette I Boyanga, Elisee K Biyela, Benjamin B Badjanga, Yvonne B Kambashi, Arjen M Dondorp, Tharisara Sakulthaew, Caterina I Fanello, Wirichada Pan Ngum, Kasia Stepniewska, Kamolrat Silamut, Ilse C E Hendriksen, Nuttapol Panachuenwongsakul, Montri Rijaibun, Niklas Lindegardh, Warunee Hanpithakpong, Forradee Nuchsongsin, Benjamas Intarabut, Ketsanee Srinamon, Somporn Saiwaew, Kesinee Chotivanich, Nicholas J White, Nicholas P J Day, Caterina I Fanello, Arjen M Dondorp, Ilse C E Hendriksen, Nicholas P J Day, Lorenz von Seidlein, Nicholas J White, Kalifa Bojang, Kathryn Maitland, Arjen M Dondorp, Nicholas P J Day, Nicholas J White, Brian Greenwood, Martina Oneko, Bridget Wills, Nicholas White, Charles J Woodrow, Delia Bethell, Tim E Peto, David Lalloo, Sarah Walker, Kojo Koram, Malcolm Molyneux, Grace Malenga, Arjen M Dondorp, Caterina I Fanello, Ilse C E Hendriksen, Ermelinda Gomes, Amir Seni, Kajal D Chhaganlal, Kalifa Bojang, Rasaq Olaosebikan, Nkechinyere Anunobi, Kathryn Maitland, Esther Kivaya, Tsiri Agbenyega, Samuel Blay Nguah, Jennifer Evans, Samwel Gesase, Catherine Kahabuka, George Mtove, Behzad Nadjm, Jacqueline Deen, Juliet Mwanga-Amumpaire, Margaret Nansumba, Corine Karema, Noella Umulisa, Aline Uwimana, Olugbenga A Mokuolu, Olanrewaju T Adedoyin, Wahab B R Johnson, Antoinette K Tshefu, Marie A Onyamboko, Tharisara Sakulthaew, Wirichada Pan Ngum, Kamolrat Silamut, Kasia Stepniewska, Charles J Woodrow, Delia Bethell, Bridget Wills, Martina Oneko, Tim E Peto, Lorenz von Seidlein, Nicholas P J Day, Nicholas J White, AQUAMAT group, Ermelinda Gomes, Amir Seni, Kajal D Chhaganlal, Ilse C E Hendriksen, Alínia José Pedro, César D R Jarach, Olivier Wingi, Ester I Fernando, Mara Zambruni, Zacarias Raimundo, Carlos J de Oliveira, Arjen Dondorp, Francisco Songane, Avertino Barreto, Marcelino Lucas, Kalifa Bojang, Rasaq Olaosebikan, Nkechinyere Anunobi, Tumani Corrah, David Conway, Sarah Rowland-Jones, Francis Akor, Joseph Okebe, Muminatou Jallow, Osaretin Chimah, Abubakar Ismaela, Mamkumba Sanneh, Saidykhan Mamodou, Fatou Jammeh, Janet Fullah, Abdou Bah, Horija Saine, Tsiri Agbenyega, Samuel Blay Nguah, Jennifer Evans, Daniel Ansong, Justice Sylverken, Alex O Akoto, Larko D Owusu, David Sambian, Michael Ntim, Kathryn Maitland, Esther Kivaya, Mohammed Abubakar, Ayub Mpoya, Charles Newton, Samson Gwer, Samuel Akech, Michael Kazungu, Michael Kihara, Molline Timbwa, Mwanamvua Boga, Samwel Gesase, Catherine Kahabuka, Martha Lemnge, Lorenz von Seidlein, Aileen Barongo, Anangisye Malabeja, Omary Abdul, Zacharia Savael, Gustav Tilaus, Laura Chuwa, Stella Kabela, Behzad Nadjm, Jacqueline Deen, Hugh Reyburn, Christopher Whitty, Ilse C E Hendriksen, Amani Shao, Selemani Mtunguja, Marwa Mwikwabe, Walli Msuya, Christina Kiemi, Edward Mtili, Lorenz von Seidlein, Emmanuel Swai, Ben Amos, Rajabu Malahiyo, Regina Malugu, Michael Mnongea, Stella Emmanuel, Nzitu J Msengi, Faraja M Mtimbo, Juma Kimera, George Mtove, Corine Karema, Noella Umulisa, Aline Uwimana, Josephine Ngalula Mulumba, Aimee Uwase, Devotha Rugandura, Claude Kawite, Deogratias Ruhangaza, Jean Claude Ndagijimana, Josephine Mukeshiyaremye, Antoinette Kayitesi, Violette Mukamugenzi, Ntwali Ndizeye, Tharcisse Munyaneza, Olugbenga A Mokuolu, Olanrewaju T Adedoyin, Wahab B R Johnson, Ayodele Ojuawo, Samuel K Ernest, Omotayo O Adesiyun, Aishatu A Abdulkarim, Abdulrasheed O Adegboye, Ashau O Timi-Oladipo, Bukola R Kelani, Oyekunle Ogunkanbi, Abdulrahreem Yusuf, Oluyemisi Adegboye, Olabode T Oyewale, Olusegun Oladele, Alice Jacob, Oluseun Faniyi, Juliet Mwanga-Amumpaire, Margaret Nansumba, Patrice Piola, Pierre Debeaudrap, Yap Boum 2nd, Mehul Dhorda, Eleanor Turyakira, Elias Kumbakumba, Eunice Nyesigire, Peters Kalubi, Santorino Data, Naome Natukunda, Antoney Ssegane, Nyehangane Dan, Benon Tumwebaze, Benson Twinomujuni, James Kinyatta, Suzan Esther Asaasira, Jacqueline Tumuhairwe, Sanyu Scovia, Primativa Kyohairwe, Shiela Mbabazi, Harriet Adrama, Thaddeus Turuho, Sulaiman Muwanga, John Bosco Ariyo, Peace Magezi, Agatha Twebaze, Antoinette K Tshefu, Marie A Onyamboko, Jacques K Zandibeni, Elyse K Katokale, Charlie N Kabedi, Adolphine B Nkuadiolandu, Raoul N Mpoyi, Marcelline M Sakina, Crispin K Fela, Jacqueline A Omari, Odile K Muniaka, Betty D Omba, Antoinette I Boyanga, Elisee K Biyela, Benjamin B Badjanga, Yvonne B Kambashi, Arjen M Dondorp, Tharisara Sakulthaew, Caterina I Fanello, Wirichada Pan Ngum, Kasia Stepniewska, Kamolrat Silamut, Ilse C E Hendriksen, Nuttapol Panachuenwongsakul, Montri Rijaibun, Niklas Lindegardh, Warunee Hanpithakpong, Forradee Nuchsongsin, Benjamas Intarabut, Ketsanee Srinamon, Somporn Saiwaew, Kesinee Chotivanich, Nicholas J White, Nicholas P J Day, Caterina I Fanello, Arjen M Dondorp, Ilse C E Hendriksen, Nicholas P J Day, Lorenz von Seidlein, Nicholas J White, Kalifa Bojang, Kathryn Maitland, Arjen M Dondorp, Nicholas P J Day, Nicholas J White, Brian Greenwood, Martina Oneko, Bridget Wills, Nicholas White, Charles J Woodrow, Delia Bethell, Tim E Peto, David Lalloo, Sarah Walker, Kojo Koram, Malcolm Molyneux, Grace Malenga

Abstract

Background: Severe malaria is a major cause of childhood death and often the main reason for paediatric hospital admission in sub-Saharan Africa. Quinine is still the established treatment of choice, although evidence from Asia suggests that artesunate is associated with a lower mortality. We compared parenteral treatment with either artesunate or quinine in African children with severe malaria.

Methods: This open-label, randomised trial was undertaken in 11 centres in nine African countries. Children (<15 years) with severe falciparum malaria were randomly assigned to parenteral artesunate or parenteral quinine. Randomisation was in blocks of 20, with study numbers corresponding to treatment allocations kept inside opaque sealed paper envelopes. The trial was open label at each site, and none of the investigators or trialists, apart from for the trial statistician, had access to the summaries of treatment allocations. The primary outcome measure was in-hospital mortality, analysed by intention to treat. This trial is registered, number ISRCTN50258054.

Findings: 5425 children were enrolled; 2712 were assigned to artesunate and 2713 to quinine. All patients were analysed for the primary outcome. 230 (8·5%) patients assigned to artesunate treatment died compared with 297 (10·9%) assigned to quinine treatment (odds ratio [OR] stratified for study site 0·75, 95% CI 0·63-0·90; relative reduction 22·5%, 95% CI 8·1-36·9; p=0·0022). Incidence of neurological sequelae did not differ significantly between groups, but the development of coma (65/1832 [3·5%] with artesunate vs 91/1768 [5·1%] with quinine; OR 0·69 95% CI 0·49-0·95; p=0·0231), convulsions (224/2712 [8·3%] vs 273/2713 [10·1%]; OR 0·80, 0·66-0·97; p=0·0199), and deterioration of the coma score (166/2712 [6·1%] vs 208/2713 [7·7%]; OR 0·78, 0·64-0·97; p=0·0245) were all significantly less frequent in artesunate recipients than in quinine recipients. Post-treatment hypoglycaemia was also less frequent in patients assigned to artesunate than in those assigned to quinine (48/2712 [1·8%] vs 75/2713 [2·8%]; OR 0·63, 0·43-0·91; p=0·0134). Artesunate was well tolerated, with no serious drug-related adverse effects.

Interpretation: Artesunate substantially reduces mortality in African children with severe malaria. These data, together with a meta-analysis of all trials comparing artesunate and quinine, strongly suggest that parenteral artesunate should replace quinine as the treatment of choice for severe falciparum malaria worldwide.

Funding: The Wellcome Trust.

Copyright © 2010 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Trial profile *663 in Beira, 442 in Kilifi, 436 in Kumasi, 921 in Muheza, 540 in Korogwe, 502 in Banjul, 450 in Ilorin, 386 in Rwanda, 663 in Mbarara, and 422 in Kinshasa. †Two patients also had other criteria.
Figure 2
Figure 2
Kaplan-Meier curves comparing survival in African children with severe falciparum malaria treated with either parenteral artesunate or quinine The numbers in parentheses are the deaths during the indicated time. In eight patients the exact time of death during the night was missing and was estimated as 2359 h.
Figure 3
Figure 3
Treatment effect in protocol-specified subgroups The forest plot shows odds ratios and 95% CIs. The size of the squares is proportional to the size, and therefore weight, of the subgroup. The diamonds show the combined differences. The efficacy of antimalarial pretreatment was classified before study unblinding (webappendix p 12). Hyperparasitaemia means greater than 10% of red cells parasitised. OR=odds ratio. GCS=Glasgow coma scale. BCS=Blantyre coma scale. BE=base excess. *Site mortality classified as low if the site mortality rate was lower than the overall study mortality rate, and high if the site mortality rate was higher than the overall study mortality rate. †Classified according to centre policy (ten sites); classified according to individual data (one site). ‡Decompensated or compensated shock. I2 denotes the percentage of total variation across sites resulting from heterogeneity rather than chance, with the p value of significance.
Figure 4
Figure 4
Neurological sequelae at discharge and after 28 days (range 3–8 weeks) in children with severe falciparum malaria *Some patients had severe impairment in more than one domain.
Figure 5
Figure 5
Meta-analysis of all randomised controlled trials that have compared parenteral artesunate and parenteral quinine in severe malaria The solid vertical line represents equality of the two groups; the dashed line is the overall treatment difference. The horizontal lines and the width of the diamonds show the CIs for the odds ratios. The size of the squares is proportional to the size, and therefore weight, of the trial. OR=odds ratio. *99% CIs for totals.

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Source: PubMed

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