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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
Authors: 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
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
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
Keywords: Medicine
Issue Date: 25-Apr-2020
Citation: The Lancet. Vol.395, No.10233 (2020), 1345-1360
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, 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.
ISSN: 1474547X
Appears in Collections:Scopus 2020

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