Publication:
Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial

Issued Date

2020-04-25

Resource Type

Article

ISSN

1474547X
01406736

DOI

10.1016/S0140-6736(20)30552-3

Other identifier(s)

2-s2.0-85083339399

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Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

The Lancet. Vol.395, No.10233 (2020), 1345-1360

Suggested Citation

Rob W. van der Pluijm, Rupam Tripura, Richard M. Hoglund, Aung Pyae Phyo, Dysoley Lek, Akhter ul Islam, Anupkumar R. Anvikar, Parthasarathi Satpathi, Sanghamitra Satpathi, Prativa Kumari Behera, Amar Tripura, Subrata Baidya, Marie Onyamboko, Nguyen Hoang Chau, Yok Sovann, Seila Suon, Sokunthea Sreng, Sivanna Mao, Savuth Oun, Sovannary Yen, Chanaki Amaratunga, Kitipumi Chutasmit, Chalermpon Saelow, Ratchadaporn Runcharern, Weerayuth Kaewmok, Nhu Thi Hoa, Ngo Viet Thanh, Borimas Hanboonkunupakarn, James J. Callery, Akshaya Kumar Mohanty, James Heaton, Myo Thant, Kripasindhu Gantait, Tarapada Ghosh, Roberto Amato, Richard D. Pearson, Christopher G. Jacob, Sónia Gonçalves, Mavuto Mukaka, Naomi Waithira, Charles J. Woodrow, Martin P. Grobusch, Michele van Vugt, Rick M. Fairhurst, Phaik Yeong Cheah, Thomas J. Peto, Lorenz von Seidlein, Mehul Dhorda, Richard J. Maude, Markus Winterberg, Nguyen Thanh Thuy-Nhien, Dominic P. Kwiatkowski, Mallika Imwong, Podjanee Jittamala, Khin Lin, Tin Maung Hlaing, Kesinee Chotivanich, Rekol Huy, Caterina Fanello, Elizabeth Ashley, Mayfong Mayxay, Paul N. Newton, Tran Tinh Hien, Neena Valecha, Frank Smithuis, Sasithon Pukrittayakamee, Abul Faiz, Olivo Miotto, Joel Tarning, Nicholas P.J. Day, Nicholas J. White, Arjen M. Dondorp, Aung Pyae Phyo, Neena Valeche, Nicholas PJ Day Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial. The Lancet. Vol.395, No.10233 (2020), 1345-1360. doi:10.1016/S0140-6736(20)30552-3 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/54601

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Title

Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial

Author(s)

Rob W. van der Pluijm
 Rupam Tripura
 Richard M. Hoglund
 Aung Pyae Phyo
 Dysoley Lek
 Akhter ul Islam
 Anupkumar R. Anvikar
 Parthasarathi Satpathi
 Sanghamitra Satpathi
 Prativa Kumari Behera
 Amar Tripura
 Subrata Baidya
 Marie Onyamboko
 Nguyen Hoang Chau
 Yok Sovann
 Seila Suon
 Sokunthea Sreng
 Sivanna Mao
 Savuth Oun
 Sovannary Yen
 Chanaki Amaratunga
 Kitipumi Chutasmit
 Chalermpon Saelow
 Ratchadaporn Runcharern
 Weerayuth Kaewmok
 Nhu Thi Hoa
 Ngo Viet Thanh
 Borimas Hanboonkunupakarn
 James J. Callery
 Akshaya Kumar Mohanty
 James Heaton
 Myo Thant
 Kripasindhu Gantait
 Tarapada Ghosh
 Roberto Amato
 Richard D. Pearson
 Christopher G. Jacob
 Sónia Gonçalves
 Mavuto Mukaka
 Naomi Waithira
 Charles J. Woodrow
 Martin P. Grobusch
 Michele van Vugt
 Rick M. Fairhurst
 Phaik Yeong Cheah
 Thomas J. Peto
 Lorenz von Seidlein
 Mehul Dhorda
 Richard J. Maude
 Markus Winterberg
 Nguyen Thanh Thuy-Nhien
 Dominic P. Kwiatkowski
 Mallika Imwong
 Podjanee Jittamala
 Khin Lin
 Tin Maung Hlaing
 Kesinee Chotivanich
 Rekol Huy
 Caterina Fanello
 Elizabeth Ashley
 Mayfong Mayxay
 Paul N. Newton
 Tran Tinh Hien
 Neena Valecha
 Frank Smithuis
 Sasithon Pukrittayakamee
 Abul Faiz
 Olivo Miotto
 Joel Tarning
 Nicholas P.J. Day
 Nicholas J. White
 Arjen M. Dondorp
 Aung Pyae Phyo
 Neena Valeche
 Nicholas PJ Day

Other Contributor(s)

Oxford University Clinical Research Unit
 Ispat General Hospital
 Harvard T.H. Chan School of Public Health
 University of Oxford
 National Institute of Malaria Research India
 National Institute of Allergy and Infectious Diseases
 Mahosot Hospital, Lao
 Mahidol University
 Open University
 Nuffield Department of Clinical Medicine
 Wellcome Sanger Institute
 AstraZeneca
 Universiteit van Amsterdam
 National Institute of Public Health
 Pailin Provincial Health Department
 Myanmar Oxford Clinical Research Unit
 Kinshasa Mahidol Oxford Research Unit (KIMORU)
 Asia Regional Centre
 Ramu Upazila Health Complex
 Malaria Research Group and Dev Care Foundation
 Defence Services Medical Academy
 Khun Han Hospital
 Phusing Hospital
 Ratanakiri Referral Hospital
 Sampov Meas Referral Hospital
 Agartala Medical College
 Royal Society of Thailand
 Midnapore Medical College
 National Centre for Parasitology, Entomology and Malaria Control
 Kinshasa School of Public Health
 University of Health Sciences
 IGH

Abstract

© 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license Background: Artemisinin and partner-drug resistance in Plasmodium falciparum are major threats to malaria control and elimination. Triple artemisinin-based combination therapies (TACTs), which combine existing co-formulated ACTs with a second partner drug that is slowly eliminated, might provide effective treatment and delay emergence of antimalarial drug resistance. Methods: In this multicentre, open-label, randomised trial, we recruited patients with uncomplicated P falciparum malaria at 18 hospitals and health clinics in eight countries. Eligible patients were aged 2–65 years, with acute, uncomplicated P falciparum malaria alone or mixed with non-falciparum species, and a temperature of 37·5°C or higher, or a history of fever in the past 24 h. Patients were randomly assigned (1:1) to one of two treatments using block randomisation, depending on their location: in Thailand, Cambodia, Vietnam, and Myanmar patients were assigned to either dihydroartemisinin–piperaquine or dihydroartemisinin–piperaquine plus mefloquine; at three sites in Cambodia they were assigned to either artesunate–mefloquine or dihydroartemisinin–piperaquine plus mefloquine; and in Laos, Myanmar, Bangladesh, India, and the Democratic Republic of the Congo they were assigned to either artemether–lumefantrine or artemether–lumefantrine plus amodiaquine. All drugs were administered orally and doses varied by drug combination and site. Patients were followed-up weekly for 42 days. The primary endpoint was efficacy, defined by 42-day PCR-corrected adequate clinical and parasitological response. Primary analysis was by intention to treat. A detailed assessment of safety and tolerability of the study drugs was done in all patients randomly assigned to treatment. This study is registered at ClinicalTrials.gov, NCT02453308, and is complete. Findings: Between Aug 7, 2015, and Feb 8, 2018, 1100 patients were given either dihydroartemisinin–piperaquine (183 [17%]), dihydroartemisinin–piperaquine plus mefloquine (269 [24%]), artesunate–mefloquine (73 [7%]), artemether–lumefantrine (289 [26%]), or artemether–lumefantrine plus amodiaquine (286 [26%]). The median age was 23 years (IQR 13 to 34) and 854 (78%) of 1100 patients were male. In Cambodia, Thailand, and Vietnam the 42-day PCR-corrected efficacy after dihydroartemisinin–piperaquine plus mefloquine was 98% (149 of 152; 95% CI 94 to 100) and after dihydroartemisinin–piperaquine was 48% (67 of 141; 95% CI 39 to 56; risk difference 51%, 95% CI 42 to 59; p<0·0001). Efficacy of dihydroartemisinin–piperaquine plus mefloquine in the three sites in Myanmar was 91% (42 of 46; 95% CI 79 to 98) versus 100% (42 of 42; 95% CI 92 to 100) after dihydroartemisinin–piperaquine (risk difference 9%, 95% CI 1 to 17; p=0·12). The 42-day PCR corrected efficacy of dihydroartemisinin–piperaquine plus mefloquine (96% [68 of 71; 95% CI 88 to 99]) was non-inferior to that of artesunate–mefloquine (95% [69 of 73; 95% CI 87 to 99]) in three sites in Cambodia (risk difference 1%; 95% CI −6 to 8; p=1·00). The overall 42-day PCR-corrected efficacy of artemether–lumefantrine plus amodiaquine (98% [281 of 286; 95% CI 97 to 99]) was similar to that of artemether–lumefantrine (97% [279 of 289; 95% CI 94 to 98]; risk difference 2%, 95% CI −1 to 4; p=0·30). Both TACTs were well tolerated, although early vomiting (within 1 h) was more frequent after dihydroartemisinin–piperaquine plus mefloquine (30 [3·8%] of 794) than after dihydroartemisinin–piperaquine (eight [1·5%] of 543; p=0·012). Vomiting after artemether–lumefantrine plus amodiaquine (22 [1·3%] of 1703) and artemether–lumefantrine (11 [0·6%] of 1721) was infrequent. Adding amodiaquine to artemether–lumefantrine extended the electrocardiogram corrected QT interval (mean increase at 52 h compared with baseline of 8·8 ms [SD 18·6] vs 0·9 ms [16·1]; p<0·01) but adding mefloquine to dihydroartemisinin–piperaquine did not (mean increase of 22·1 ms [SD 19·2] for dihydroartemisinin–piperaquine vs 20·8 ms [SD 17·8] for dihydroartemisinin–piperaquine plus mefloquine; p=0·50). Interpretation: Dihydroartemisinin–piperaquine plus mefloquine and artemether–lumefantrine plus amodiaquine TACTs are efficacious, well tolerated, and safe treatments of uncomplicated P falciparum malaria, including in areas with artemisinin and ACT partner-drug resistance. Funding: UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and US National Institutes of Health.

Keyword(s)

Medicine

Availability

URI

https://repository.li.mahidol.ac.th/handle/20.500.14594/54601

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Scopus 2020