Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT)

an open-label, randomised trial

Arjen Dondorp, Caterina Fanello, Ilse 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, Jaqueline Deen, Juliet Mwanga-Amumpaire & 21 others 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 Woodrow, Nicholas Day, Nicholas J White, Bridget Wills, Martina Oneko, Delia Bethell, Tim E Petro, Lorenz Von Seidlein

    Research output: Contribution to journalArticleResearchpeer-review

    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: 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
    Original languageEnglish
    Pages (from-to)1647-1657
    Number of pages11
    JournalLancet
    Volume376
    Issue number9753
    Publication statusPublished - 8 Nov 2010

    Fingerprint

    Quinine
    Falciparum Malaria
    Odds Ratio
    Therapeutics
    Malaria
    Coma
    artesunate
    Pediatric Hospitals
    Mortality
    Africa South of the Sahara
    Random Allocation
    Hospital Mortality
    Hypoglycemia
    Meta-Analysis
    Cause of Death
    Seizures
    Research Personnel
    Outcome Assessment (Health Care)

    Cite this

    Dondorp, A., Fanello, C., Hendriksen, I., Gomes, E., Seni, A., Chhaganlal, K. D., ... Von Seidlein, L. (2010). Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet, 376(9753), 1647-1657.
    Dondorp, Arjen ; Fanello, Caterina ; Hendriksen, Ilse ; Gomes, Ermelinda ; Seni, Amir ; Chhaganlal, Kajal D ; Bojang, Kalifa ; Olaosebikan, Rasaq ; Anunobi, Nkechinyere ; Maitland, Kathryn ; Kivaya, Esther ; Agbenyega, Tsiri ; Nguah, Samuel Blay ; Evans, Jennifer ; Gesase, Samwel ; Kahabuka, Catherine ; Mtove, George ; Nadjm, Behzad ; Deen, Jaqueline ; Mwanga-Amumpaire, Juliet ; Nansumba, Margaret ; Karema, Corine ; Umulisa, Noella ; Uwimana, Aline ; Mokuolu, Olugbenga A ; Adedoyin, Olanrewaju T ; Johnson, Wahab B R ; Tshefu, Antoinette K ; Onyamboko, Marie A ; Sakulthaew, Tharisara ; Ngum, Wirichada Pan ; Silamut, Kamolrat ; Stepniewska, Kasia ; Woodrow, Charles ; Day, Nicholas ; White, Nicholas J ; Wills, Bridget ; Oneko, Martina ; Bethell, Delia ; Petro, Tim E ; Von Seidlein, Lorenz. / Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT) : an open-label, randomised trial. In: Lancet. 2010 ; Vol. 376, No. 9753. pp. 1647-1657.
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    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: 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",
    keywords = "artemether plus benflumetol, artesunate, quinine, adolescent, Africa, article, child, clinical trial, coma, controlled clinical trial, controlled study, convulsion, drug tolerability, female, human, hypersensitivity reaction, hypoglycemia, loading drug dose, malaria falciparum, male, mortality, multicenter study, neurologic disease, outcome assessment, pediatrics, preschool child, priority journal, randomized controlled trial, rash, school child, treatment outcome, unspecified side effect, Africa South of the Sahara, Antimalarials, Artemisinins, Child, Preschool, Female, Humans, Infant, Kaplan-Meier Estimate, Malaria, Falciparum, Male, Quinine, Survival Rate",
    author = "Arjen Dondorp and Caterina Fanello and Ilse Hendriksen and Ermelinda Gomes and Amir Seni and Chhaganlal, {Kajal D} and Kalifa Bojang and Rasaq Olaosebikan and Nkechinyere Anunobi and Kathryn Maitland and Esther Kivaya and Tsiri Agbenyega and Nguah, {Samuel Blay} and Jennifer Evans and Samwel Gesase and Catherine Kahabuka and George Mtove and Behzad Nadjm and Jaqueline Deen and Juliet Mwanga-Amumpaire and Margaret Nansumba and Corine Karema and Noella Umulisa and Aline Uwimana and Mokuolu, {Olugbenga A} and Adedoyin, {Olanrewaju T} and Johnson, {Wahab B R} and Tshefu, {Antoinette K} and Onyamboko, {Marie A} and Tharisara Sakulthaew and Ngum, {Wirichada Pan} and Kamolrat Silamut and Kasia Stepniewska and Charles Woodrow and Nicholas Day and White, {Nicholas J} and Bridget Wills and Martina Oneko and Delia Bethell and Petro, {Tim E} and {Von Seidlein}, Lorenz",
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    pages = "1647--1657",
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    Dondorp, A, Fanello, C, Hendriksen, I, Gomes, E, Seni, A, Chhaganlal, KD, Bojang, K, Olaosebikan, R, Anunobi, N, Maitland, K, Kivaya, E, Agbenyega, T, Nguah, SB, Evans, J, Gesase, S, Kahabuka, C, Mtove, G, Nadjm, B, Deen, J, Mwanga-Amumpaire, J, Nansumba, M, Karema, C, Umulisa, N, Uwimana, A, Mokuolu, OA, Adedoyin, OT, Johnson, WBR, Tshefu, AK, Onyamboko, MA, Sakulthaew, T, Ngum, WP, Silamut, K, Stepniewska, K, Woodrow, C, Day, N, White, NJ, Wills, B, Oneko, M, Bethell, D, Petro, TE & Von Seidlein, L 2010, 'Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial', Lancet, vol. 376, no. 9753, pp. 1647-1657.

    Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT) : an open-label, randomised trial. / Dondorp, Arjen; Fanello, Caterina; Hendriksen, Ilse; Gomes, Ermelinda; Seni, Amir; Chhaganlal, Kajal D; Bojang, Kalifa; Olaosebikan, Rasaq; Anunobi, Nkechinyere; Maitland, Kathryn; Kivaya, Esther; Agbenyega, Tsiri; Nguah, Samuel Blay; Evans, Jennifer; Gesase, Samwel; Kahabuka, Catherine; Mtove, George; Nadjm, Behzad; Deen, Jaqueline; Mwanga-Amumpaire, Juliet; Nansumba, Margaret; Karema, Corine; Umulisa, Noella; Uwimana, Aline; Mokuolu, Olugbenga A; Adedoyin, Olanrewaju T; Johnson, Wahab B R; Tshefu, Antoinette K; Onyamboko, Marie A; Sakulthaew, Tharisara; Ngum, Wirichada Pan; Silamut, Kamolrat; Stepniewska, Kasia; Woodrow, Charles; Day, Nicholas; White, Nicholas J; Wills, Bridget; Oneko, Martina; Bethell, Delia; Petro, Tim E; Von Seidlein, Lorenz.

    In: Lancet, Vol. 376, No. 9753, 08.11.2010, p. 1647-1657.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT)

    T2 - an open-label, randomised trial

    AU - Dondorp, Arjen

    AU - Fanello, Caterina

    AU - Hendriksen, Ilse

    AU - Gomes, Ermelinda

    AU - Seni, Amir

    AU - Chhaganlal, Kajal D

    AU - Bojang, Kalifa

    AU - Olaosebikan, Rasaq

    AU - Anunobi, Nkechinyere

    AU - Maitland, Kathryn

    AU - Kivaya, Esther

    AU - Agbenyega, Tsiri

    AU - Nguah, Samuel Blay

    AU - Evans, Jennifer

    AU - Gesase, Samwel

    AU - Kahabuka, Catherine

    AU - Mtove, George

    AU - Nadjm, Behzad

    AU - Deen, Jaqueline

    AU - Mwanga-Amumpaire, Juliet

    AU - Nansumba, Margaret

    AU - Karema, Corine

    AU - Umulisa, Noella

    AU - Uwimana, Aline

    AU - Mokuolu, Olugbenga A

    AU - Adedoyin, Olanrewaju T

    AU - Johnson, Wahab B R

    AU - Tshefu, Antoinette K

    AU - Onyamboko, Marie A

    AU - Sakulthaew, Tharisara

    AU - Ngum, Wirichada Pan

    AU - Silamut, Kamolrat

    AU - Stepniewska, Kasia

    AU - Woodrow, Charles

    AU - Day, Nicholas

    AU - White, Nicholas J

    AU - Wills, Bridget

    AU - Oneko, Martina

    AU - Bethell, Delia

    AU - Petro, Tim E

    AU - Von Seidlein, Lorenz

    PY - 2010/11/8

    Y1 - 2010/11/8

    N2 - 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: 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

    AB - 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: 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

    KW - artemether plus benflumetol

    KW - artesunate

    KW - quinine

    KW - adolescent

    KW - Africa

    KW - article

    KW - child

    KW - clinical trial

    KW - coma

    KW - controlled clinical trial

    KW - controlled study

    KW - convulsion

    KW - drug tolerability

    KW - female

    KW - human

    KW - hypersensitivity reaction

    KW - hypoglycemia

    KW - loading drug dose

    KW - malaria falciparum

    KW - male

    KW - mortality

    KW - multicenter study

    KW - neurologic disease

    KW - outcome assessment

    KW - pediatrics

    KW - preschool child

    KW - priority journal

    KW - randomized controlled trial

    KW - rash

    KW - school child

    KW - treatment outcome

    KW - unspecified side effect

    KW - Africa South of the Sahara

    KW - Antimalarials

    KW - Artemisinins

    KW - Child, Preschool

    KW - Female

    KW - Humans

    KW - Infant

    KW - Kaplan-Meier Estimate

    KW - Malaria, Falciparum

    KW - Male

    KW - Quinine

    KW - Survival Rate

    UR - http://www.scopus.com/inward/record.url?scp=78449267241&partnerID=8YFLogxK

    M3 - Article

    VL - 376

    SP - 1647

    EP - 1657

    JO - Lancet

    JF - Lancet

    SN - 0140-6736

    IS - 9753

    ER -

    Dondorp A, Fanello C, Hendriksen I, Gomes E, Seni A, Chhaganlal KD et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010 Nov 8;376(9753):1647-1657.