Pyronaridine-artesunate or dihydroartemisinin-piperaquine versus current first-line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b/4 trial.
Pyronaridine-artesunate or dihydroartemisinin-piperaquine versus current first-line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b/4 trial.
复制标题
DOI：
10.1016/s0140-6736(18)30291-5
复制
发表时间：
2018-04-07
期刊：
影响因子：
--
通讯作者：
West African Network for Clinical Trials of Antimalarial Drugs (WANECAM)
中科院分区：
文献类型：
--
作者：
West African Network for Clinical Trials of Antimalarial Drugs (WANECAM)
青蒿甲醚-鲁米芬和青蒿琥酯-阿莫地喹在西非被用作基于青蒿素的一线联合疗法(ACTS)。吡诺那定-青蒿琥酯和双氢青蒿素-哌喹可能有助于该地区药物治疗的多样化，但还需要关于疟疾再治疗的更多安全性和有效性数据。我们在布基纳法索、几内亚和马里的七个三级中心进行了一项随机、多中心、开放标签、纵向、对照的3b/4期临床试验。符合条件的首次疟疾和所有复治病例均为6个月及以上的成人和儿童，镜检确诊为疟原虫(每血中含疟原虫0~200 000)，且在过去24小时内有发热或发热史。排除有严重或合并疟疾、丙氨酸氨基转移酶浓度超过正常上限两倍或QTc值大于450ms的个体。通过使用密封信封遮盖的每个部位的随机列表，参与者被分配到咯萘啶-青蒿琥酯或双氢青蒿素-哌喹，而不是青蒿琥酯-阿莫地喹或蒿甲醚-鲁米芬。如果分配两个处理，区组大小为两个或四个，如果分配三个处理，则区组大小为三个或六个。做寄生虫学评估的显微镜专家被戴上面具进行治疗分配。所有治疗均为每日一次或每日两次的片剂或颗粒剂，在研究中心按体重口服超过3天。患者作为门诊患者被跟踪到第42天，在第0、1、2、3、7、14、21、28、35和42天接受临床评估。比较了两个非劣势的主要结果：意向治疗人群(ITT；非劣势优势20%)中所有显微镜确诊的、复杂的和不复杂的疟疾病例的两年发病率；以及在按方案人群的第28天和第42天(非劣势优势5%)，在非复杂疟疾的所有病例中充分的临床和寄生虫学反应(未对恶性疟原虫进行调整和经聚合酶链式反应(PCR)调整，以及未对其他疟原虫属进行调整)。对所有接受一剂研究药物的参与者进行安全性评估。这项研究在泛非临床试验注册中心(PACTR201105000286876)注册。在2011年10月24日至2016年2月1日期间，我们将4710名符合条件的参与者分配到不同的治疗策略中：1342人接受咯萘啶-青蒿琥酯治疗，967人接受蒿甲醚治疗，1061人接受青蒿琥酯-阿莫地喹治疗，1340人接受双氢青蒿素-哌喹治疗。在ITT人群中，青蒿琥酯与蒿甲醚相比，2年疟疾发病率并不低(1·77，95%CI 1·63-1·93 vs 1·87，1·72-2·03；发病率比[RR]1·05，95%CI 0·94-1·17)；与青蒿琥酯-阿莫地喹(1·39，95%CI 1·22-1·59 vs 1·35，1·18-1·54；RR 0·97，0·87-1·07)相比。同样，双氢青蒿素-哌喹与蒿甲醚-鲁米芬相比，这一终点并不逊色(1·16，95%CI 1·01-1·34vs 1·42 1·25-1·62；RR 1·22，95%CI 1·06-1·41)，与青蒿琥酯-阿莫地喹(1·35，1·21-1·51 vs 1·68，1·51-1·88；RR 1·25，1·02-1·50)相比。对于无并发症恶性疟，所有ACTs经PCR调整的ACPR在第28天均大于99.5%，在第42天大于98.6%；在第28天，青蒿琥酯丙酮组的未调整ACPR高于对照组(蒿甲醚-鲁米芬净为96.9%比82.3%，青蒿琥酯-阿莫地喹为95.6%比89.0%)，双氢青蒿素-哌喹为99.5%比81.6%，青蒿琥酯-阿莫地喹为99.0%比89.0%。对于非恶性疟原虫，所有研究药物的未调整ACPR在第28天大于98%，在第42天大于83%，但蒿甲醚-鲁米芬对卵形疟原虫(16例患者中有10例[62.5%])和疟疾(12例患者中9例[75.0%])除外。在研究期间发生了9例死亡，没有一例与研究治疗有关。与对照组相比，丙氨酸丙二胺-青蒿琥酯组的转氨酶大多有轻微的一过性升高，双氢青蒿素-哌喹组的QTcF也有轻微的延长。疟疾的吡罗那定-青蒿琥酯和双氢青蒿素-哌喹治疗和再治疗耐受性良好，疗效不逊于一线药物。在西非，更多地获得这些有效的治疗方法是合理的。欧洲和发展中国家临床试验伙伴关系、疟疾新药企业(瑞士日内瓦)、英国医学研究理事会、瑞典国际开发合作署、德国教育和研究部、克劳德·伯纳德大学(法国里昂)、巴马科科学、技术和技术大学(马里巴马科)、拉丁美洲和加勒比科学与技术中心(布基纳法索)、圣罗兰科学与技术研究所(布基纳法索)、博博-迪乌拉索研究所(布基纳法索)和国家信息和通信技术中心(几内亚亚共和国)。
Artemether–lumefantrine and artesunate–amodiaquine are used as first-line artemisinin-based combination therapies (ACTs) in west Africa. Pyronaridine–artesunate and dihydroartemisinin–piperaquine are potentially useful for diversification of ACTs in this region, but further safety and efficacy data are required on malaria retreatment. We did a randomised, multicentre, open-label, longitudinal, controlled phase 3b/4 clinical trial at seven tertiary centres in Burkina Faso, Guinea, and Mali. Eligible participants for first malaria episode and all retreatment episodes were adults and children aged 6 months and older with microscopically confirmed Plasmodium spp malaria (>0 to <200 000 parasites per μL of blood) and fever or history of fever in the previous 24 h. Individuals with severe or complicated malaria, an alanine aminotransferase concentration of more than twice the upper limit of normal, or a QTc greater than 450 ms were excluded. Using a randomisation list for each site, masked using sealed envelopes, participants were assigned to either pyronaridine–artesunate or dihydroartemisinin–piperaquine versus either artesunate–amodiaquine or artemether–lumefantrine. Block sizes were two or four if two treatments were allocated, and three or six if three treatments were allocated. Microscopists doing the parasitological assessments were masked to treatment allocation. All treatments were once-daily or twice-daily tablets or granules given orally and dosed by bodyweight over 3 days at the study centre. Patients were followed up as outpatients up to day 42, receiving clinical assessments on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42. Two primary outcomes were compared for non-inferiority: the 2-year incidence rate of all microscopically confirmed, complicated and uncomplicated malaria episodes in patients in the intention-to-treat population (ITT; non-inferiority margin 20%); and adequate clinical and parasitological response (ACPR) in uncomplicated malaria across all episodes (unadjusted and PCR-adjusted for Plasmodium falciparum and unadjusted for other Plasmodium spp) in the per-protocol population on days 28 and 42 (non-inferiority margin 5%). Safety was assessed in all participants who received one dose of study drug. This study is registered at the Pan African Clinical Trials Registry (PACTR201105000286876). Between Oct 24, 2011, and Feb 1, 2016, we assigned 4710 eligible participants to the different treatment strategies: 1342 to pyronaridine–artesunate, 967 to artemether–lumefantrine, 1061 to artesunate–amodiaquine, and 1340 to dihydroartemisinin–piperaquine. The 2-year malaria incidence rate in the ITT population was non-inferior for pyronaridine–artesunate versus artemether–lumefantrine (1·77, 95% CI 1·63–1·93 vs 1·87, 1·72–2·03; rate ratio [RR] 1·05, 95% CI 0·94–1·17); and versus artesunate–amodiaquine (1·39, 95% CI 1·22–1·59 vs 1·35, 1·18–1·54; RR 0·97, 0·87–1·07). Similarly, this endpoint was non-inferior for dihydroartemisinin–piperaquine versus artemether–lumefantrine (1·16, 95% CI 1·01–1·34 vs 1·42 1·25–1·62; RR 1·22, 95% CI 1·06–1·41) and versus artesunate–amodiaquine (1·35, 1·21–1·51 vs 1·68, 1·51–1·88; RR 1·25, 1·02–1·50). For uncomplicated P falciparum malaria, PCR-adjusted ACPR was greater than 99·5% at day 28 and greater than 98·6% at day 42 for all ACTs; unadjusted ACPR was higher for pyronaridine–artesunate versus comparators at day 28 (96·9% vs 82·3% for artemether–lumefantrine and 95·6% vs 89·0% for artesunate–amodiaquine) and for dihydroartemisinin-piperaquine versus comparators (99·5% vs 81·6% for artemether–lumefantrine and 99·0% vs 89·0% for artesunate–amodiaquine). For non-falciparum species, unadjusted ACPR was greater than 98% for all study drugs at day 28 and at day 42 was greater than 83% except for artemether–lumefantrine against Plasmodium ovale (in ten [62·5%] of 16 patients) and against Plasmodium malariae (in nine [75·0%] of 12 patients). Nine deaths occurred during the study, none of which were related to the study treatment. Mostly mild transient elevations in transaminases occurred with pyronaridine–artesunate versus comparators, and mild QTcF prolongation with dihydroartemisinin-piperaquine versus comparators. Pyronaridine–artesunate and dihydroartemisinin–piperaquine treatment and retreatment of malaria were well tolerated with efficacy that was non-inferior to first-line ACTs. Greater access to these efficacious treatments in west Africa is justified. The European and Developing Countries Clinical Trial Partnership, Medicines for Malaria Venture (Geneva, Switzerland), the UK Medical Research Council, the Swedish International Development Cooperation Agency, German Ministry for Education and Research, University Claude Bernard (Lyon, France), University of Science, Techniques and Technologies of Bamako (Bamako, Mali), the Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso), Institut de Recherche en Sciences de la Santé (Bobo-Dioulasso, Burkina Faso), and Centre National de Formation et de Recherche en Santé Rurale (Republic of Guinea).