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.

中文翻译：

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以青蒿素为基础的三联疗法与以青蒿素为基础的联合疗法治疗单纯性恶性疟：一项多中心、开放标签、随机临床试验。

背景技术 恶性疟原​​虫中的青蒿素和伴侣耐药性是疟疾控制和消除的主要威胁。以青蒿素为基础的三重联合疗法 (TACT) 将现有的联合配制的 ACT 与缓慢消除的第二种伙伴药物相结合，可能提供有效的治疗并延缓抗疟药物耐药性的出现。方法 在这项多中心、开放标签、随机试验中，我们在 8 个国家的 18 家医院和健康诊所招募了单纯性恶性疟患者。符合条件的患者年龄为 2-65 岁，单独患有急性、单纯性恶性疟或与非恶性疟混合，体温 37·5°C 或更高，或在过去 24 小时内有发热史。患者被随机分配（1:1）到使用区组随机化的两种治疗中的一种，取决于他们的位置：在泰国、柬埔寨、越南和缅甸，患者被分配到双氢青蒿素-哌喹或双氢青蒿素-哌喹加甲氟喹；在柬埔寨的三个地点，他们被分配到青蒿琥酯-甲氟喹或双氢青蒿素-哌喹加甲氟喹；在老挝、缅甸、孟加拉国、印度和刚果民主共和国，他们被分配到蒿甲醚-苯芴醇或蒿甲醚-苯芴醇加阿莫地喹组。所有药物均为口服给药，剂量因药物组合和部位而异。每周对患者进行为期 42 天的随访。主要终点是疗效，定义为 42 天 PCR 校正的足够临床和寄生虫学反应。主要分析是意向治疗。对随机分配接受治疗的所有患者进行了研究药物安全性和耐受性的详细评估。该研究已在 ClinicalTrials.gov 注册，NCT02453308，并且已完成。结果 2015 年 8 月 7 日至 2018 年 2 月 8 日，1100 名患者接受了双氢青蒿素-哌喹 (183 [17%])、双氢青蒿素-哌喹加甲氟喹 (269 [24%])、青蒿琥酯-甲氟喹 (73 [7%]) ])、蒿甲醚-苯芴醇 (289 [26%]) 或蒿甲醚-苯芴醇加阿莫地喹 (286 [26%])。中位年龄为 23 岁（IQR 13 至 34），1100 名患者中有 854 名（78%）为男性。在柬埔寨、泰国和越南，双氢青蒿素-哌喹加甲氟喹后的 42 天 PCR 校正效果为 98%（152 人中的 149 人；95% CI 94 至 100），双氢青蒿素-哌喹后为 48%（141 人中的 67 人；95 % CI 39 至 56；风险差异 51%，95% CI 42 至 59；p<0·0001)。双氢青蒿素-哌喹联合甲氟喹在缅甸三个地点的疗效分别为 91%（46 人中的 42 人；95% CI 79 至 98），而双氢青蒿素 - 哌喹后的疗效为 100%（42 人中的 42 人；95% CI 92 至 100）（风险差异9%, 95% CI 1 至 17；p=0·12)。双氢青蒿素-哌喹加甲氟喹的 42 天 PCR 校正疗效（96% [68 of 71；95% CI 88 至 99]）不劣于青蒿琥酯-甲氟喹（95% [69 of 73；95% CI 87 至 99]）在柬埔寨的三个地点（风险差异 1%；95% CI -6 至 8；p=1·00）。蒿甲醚-苯芴醇加阿莫地喹的 42 天 PCR 校正总疗效（98% [286 人中的 281 人；95% CI 97 至 99]）与蒿甲醚-苯芴醇的效果相似（97% [289 人中的 279 人；95% CI 94 至 98]；风险差异 2%，95% CI -1 至 4；p=0·30)。两种 TACT 均耐受良好，尽管使用双氢青蒿素-哌喹联合甲氟喹（794 人中的 30 [3·8%]）比使用双氢青蒿素-哌喹（543 人中的 8 [1·5%]；p=0·012）更频繁地出现早期呕吐（1 小时内） . 蒿甲醚-苯芴醇加阿莫地喹（22 [1·3%] of 1703）和蒿甲醚-苯芴醇（11 [0·6%]，1721 人）后呕吐很少见。在蒿甲醚-苯芴醇中添加阿莫地喹可延长心电图校正 QT 间期（与基线 8·8 ms [SD 18·6] 对比 0·9 ms [16·1] 的基线相比，52 小时时的平均增加；p<0·01）但在双氢青蒿素-哌喹中加入甲氟喹没有（双氢青蒿素-哌喹平均增加 22·1 ms [SD 19·2]，而双氢青蒿素-哌喹加甲氟喹增加 20·8 ms [SD 17·8]；p=0·50） . 解释 双氢青蒿素-哌喹加甲氟喹和蒿甲醚-苯芴醇加阿莫地喹 TACTs 对简单的恶性疟原虫疟疾有效、耐受性良好且安全，包括在青蒿素和 ACT 伴侣耐药的地区。资助英国国际发展部、惠康信托基金、比尔和梅琳达盖茨基金会、英国医学研究委员会和美国国立卫生研究院。