Rob W. van der PluijmRupam TripuraRichard M. HoglundAung Pyae PhyoDysoley LekAkhter ul IslamAnupkumar R. AnvikarParthasarathi SatpathiSanghamitra SatpathiPrativa Kumari BeheraAmar TripuraSubrata BaidyaMarie OnyambokoNguyen Hoang ChauYok SovannSeila SuonSokunthea SrengSivanna MaoSavuth OunSovannary YenChanaki AmaratungaKitipumi ChutasmitChalermpon SaelowRatchadaporn RuncharernWeerayuth KaewmokNhu Thi HoaNgo Viet ThanhBorimas HanboonkunupakarnJames J. CalleryAkshaya Kumar MohantyJames HeatonMyo ThantKripasindhu GantaitTarapada GhoshRoberto AmatoRichard D. PearsonChristopher G. JacobSónia GonçalvesMavuto MukakaNaomi WaithiraCharles J. WoodrowMartin P. GrobuschMichele van VugtRick M. FairhurstPhaik Yeong CheahThomas J. PetoLorenz von SeidleinMehul DhordaRichard J. MaudeMarkus WinterbergNguyen Thanh Thuy-NhienDominic P. KwiatkowskiMallika ImwongPodjanee JittamalaKhin LinTin Maung HlaingKesinee ChotivanichRekol HuyCaterina FanelloElizabeth AshleyMayfong MayxayPaul N. NewtonTran Tinh HienNeena ValechaFrank SmithuisSasithon PukrittayakameeAbul FaizOlivo MiottoJoel TarningNicholas P.J. DayNicholas J. WhiteArjen M. DondorpAung Pyae PhyoNeena ValecheNicholas PJ DayOxford University Clinical Research UnitIspat General HospitalHarvard T.H. Chan School of Public HealthUniversity of OxfordNational Institute of Malaria Research IndiaNational Institute of Allergy and Infectious DiseasesMahosot Hospital, LaoMahidol UniversityOpen UniversityNuffield Department of Clinical MedicineWellcome Sanger InstituteAstraZenecaUniversiteit van AmsterdamNational Institute of Public HealthPailin Provincial Health DepartmentMyanmar Oxford Clinical Research UnitKinshasa Mahidol Oxford Research Unit (KIMORU)Asia Regional CentreRamu Upazila Health ComplexMalaria Research Group and Dev Care FoundationDefence Services Medical AcademyKhun Han HospitalPhusing HospitalRatanakiri Referral HospitalSampov Meas Referral HospitalAgartala Medical CollegeRoyal Society of ThailandMidnapore Medical CollegeNational Centre for Parasitology, Entomology and Malaria ControlKinshasa School of Public HealthUniversity of Health SciencesIGH2020-05-052020-05-052020-04-25The Lancet. Vol.395, No.10233 (2020), 1345-13601474547X014067362-s2.0-85083339399https://repository.li.mahidol.ac.th/handle/20.500.14594/54601© 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.Mahidol UniversityMedicineArticleSCOPUS10.1016/S0140-6736(20)30552-3