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

van der Pluijm, Rob W; Tripura, Rupam; Hoglund, Richard M; Pyae Phyo, Aung; Lek, Dysoley; Ul Islam, Akhter; Anvikar, Anupkumar R; Satpathi, Parthasarathi; Satpathi, Sanghamitra; Behera, Prativa Kumari; Tripura, Amar; Baidya, Subrata; Onyamboko, Marie; Chau, Nguyen Hoang; Sovann, Yok; Suon, Seila; Sreng, Sokunthea; Mao, Sivanna; Oun, Savuth; Yen, Sovannary; Amaratunga, Chanaki; Chutasmit, Kitipumi; Saelow, Chalermpon; Runcharern, Ratchadaporn; Kaewmok, Weerayuth; Hoa, Nhu Thi; Thanh, Ngo Viet; Hanboonkunupakarn, Borimas; Callery, James J; Mohanty, Akshaya Kumar; Heaton, James; Thant, Myo; Gantait, Kripasindhu; Ghosh, Tarapada; Amato, Roberto; Pearson, Richard D; Jacob, Christopher G; Gonçalves, Sónia; Mukaka, Mavuto; Waithira, Naomi; Woodrow, Charles J; Grobusch, Martin P; van Vugt, Michele; Fairhurst, Rick M; Cheah, Phaik Yeong; Peto, Thomas J; von Seidlein, Lorenz; Dhorda, Mehul; Maude, Richard J; Winterberg, Markus; Thuy-Nhien, Nguyen Thanh; Kwiatkowski, Dominic P; Imwong, Mallika; Jittamala, Podjanee; Lin, Khin; Hlaing, Tin Maung; Chotivanich, Kesinee; Huy, Rekol; Fanello, Caterina; Ashley, Elizabeth; Mayxay, Mayfong; Newton, Paul N; Hien, Tran Tinh; Valecha, Neena; Smithuis, Frank; Pukrittayakamee, Sasithon; Faiz, Abul; Miotto, Olivo; Tarning, Joel; Day, Nicholas P J; White, Nicholas J and Dondorp, Arjen M (2020). Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial. The Lancet, 395(10233)



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 [25%]), 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.

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