Primaquine to reduce transmission of Plasmodium falciparum malaria in Mali: a single-blind, dose-ranging, adaptive randomised phase 2 trial
Primaquine to reduce transmission of Plasmodium falciparum malaria in Mali: a single-blind, dose-ranging, adaptive randomised phase 2 trial
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DOI：
10.1016/s1473-3099(15)00479-x
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发表时间：
2016-06-01
影响因子：
56.3
通讯作者：
Gosling, Roly
中科院分区：
文献类型：
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作者：
Dicko, Alassane;Brown, Joelle M.;Gosling, Roly
背景单一的小剂量伯氨喹与以青蒿素为基础的联合疗法相结合，可能会阻止恶性疟疾向蚊子的传播。我们的目标是确定四个小剂量的伯喹联合双氢青蒿素-哌喹治疗马里男性患者的活性和安全性。方法在这个第二阶段的单盲、剂量范围、适应性随机试验中，我们在马里韦莱塞布古的疟疾研究和培训中心(MRTC)现场招募了患有单纯性恶性疟疾的男孩和男性。所有受试者均经镜检证实为配子阳性携带者，葡萄糖-6-磷酸脱氢酶(G6PD)功能正常。第一阶段，受试者按1：1：1随机分为3个剂量组：0 mg/kg(对照组)、0.125 mg/kg、0.5 mg/kg。随机化是用计算机生成的随机化列表(六个区块大小)进行的，并用密封的不透明信封隐藏。在第二阶段，不同的参与者按顺序被分配到0.25 mg/kg伯喹或0.0625 mg/kg伯喹。伯氨喹片剂溶于溶液中，单次口服。受试者还接受了为期3天的双氢青蒿素-哌喹疗程，按体重给予(每片320毫克双氢青蒿素和40毫克哌喹)。结果评估员被屏蔽进行治疗分配，但参与者被允许了解小组分配。感染性通过膜喂养试验进行评估，并在第一阶段的开始部分进行了优化。主要的疗效终点是在对传染性分析进行优化后完成研究、进行了治疗前传染性测量和至少一次后续传染性测量并给予正确剂量的伯克喹的参与者中，在伯克喹治疗后2天内蚊子传染性的平均人内百分比变化。安全终点是在28天的研究跟踪期间，至少有一次随访的参与者的人内血红蛋白浓度的平均变化。这项研究在ClinicalTrials.gov注册，编号NCT01743820。结果在2013年1月2日至2014年11月27日期间，我们招募了81名参与者。在初级分析样本(n=71)中，与对照组(n=14)相比，伯氨喹0.25 mg/kg剂量组(n=15)和0.5 mg/kg剂量组(n=14)的受试者在第2天的人内传染性平均下降幅度显著低于对照组(n=14)，分别为92.6%(95%CI 78.3-100；p=0.0014)和75.0%(45.7-100；p=0.014)；11.3%[-27.4%至50.0])。被分配到0.0625 mg/kg剂量组(n=16)和0.125 mg/kg剂量组(n=12；54.9%[13.4-96.3]；p=0.096)的参与者的减少量与对照组(n=16)和0.125 mg/kg剂量组(n=12；54.9%[13.4-96.3p=0.096])没有显著差异。在随访期间，在血红蛋白分析(n=70)中，任何个体都没有记录到具有临床意义或统计学意义的血红蛋白下降。没有严重不良事件的报告，不良事件在治疗组之间没有差异。解释：单次剂量的伯氨喹0.25 mg/kg与双氢青蒿素-哌喹一起服用，对于预防G6PD缺乏的男孩和男性恶性疟传播是安全有效的。未来的研究应该评估单剂伯喹在G6PD缺陷者中的安全性，以确定伯喹的治疗范围，以便能够安全地推出伯喹的社区干预措施。
Background Single low doses of primaquine, when added to artemisinin-based combination therapy, might prevent transmission of Plasmodium falciparum malaria to mosquitoes. We aimed to establish the activity and safety of four low doses of primaquine combined with dihydroartemisinin-piperaquine in male patients in Mali.Methods In this phase 2, single-blind, dose-ranging, adaptive randomised trial, we enrolled boys and men with uncomplicated P falciparum malaria at the Malaria Research and Training Centre (MRTC) field site in Ouelessebougou, Mali. All participants were confirmed positive carriers of gametocytes through microscopy and had normal function of glucose-6-phosphate dehydrogenase (G6PD) on colorimetric quantification In the first phase, participants were randomly assigned (1:1:1) to one of three primaquine doses: 0 mg/kg (control), 0.125 mg/kg, and 0.5 mg/kg. Randomisation was done with a computer-generated randomisation list (in block sizes of six) and concealed with sealed, opaque envelopes. In the second phase, different participants were sequentially assigned (1:1) to 0.25 mg/kg primaquine or 0.0625 mg/kg primaquine. Primaquine tablets were dissolved into a solution and administered orally in a single dose. Participants were also given a 3 day course of dihydroartemisinin-piperaquine, administered by weight (320 mg dihydroartemisinin and 40 mg piperaquine per tablet). Outcome assessors were masked to treatment allocation, but participants were permitted to find out group assignment. Infectivity was assessed through membrane feeding assays, which were optimised through the beginning part of phase one. The primary efficacy endpoint was the mean within-person percentage change in mosquito infectivity 2 days after primaquine treatment in participants who completed the study after optimisation of the infectivity assay, had both a pre-treatment infectivity measurement and at least one follow-up infectivity measurement, and who were given the correct primaquine dose. The safety endpoint was the mean within-person change in haemoglobin concentration during 28 days of study follow-up in participants with at least one follow-up visit. This study is registered with ClinicalTrials.gov, number NCT01743820.Findings Between Jan 2,2013, and Nov 27,2014, we enrolled 81 participants. In the primary analysis sample (n=71), participants in the 0.25 mg/kg primaquine dose group (n=15) and 0.5 mg/kg primaquine dose group (n=14) had significantly lower mean within-person reductions in infectivity at day 2-92.6% (95% CI 78.3-100; p=0.0014) for the 0.25 mg/kg group; and 75.0% (45.7-100; p=0.014) for the 0.5 mg/kg primaquine group compared with those in the control group (n=14; 11.3% [-27.4 to 50.0]). Reductions were not significantly different from control for participants assigned to the 0.0625 mg/kg dose group (n=16; 41.9% [1.4-82.5]; p=0.16) and the 0.125 mg/kg dose group (n=12; 54.9% [13.4-96.3]; p=0.096). No clinically meaningful or statistically significant drops in haemoglobin were recorded in any individual in the haemoglobin analysis (n=70) during follow-up. No serious adverse events were reported and adverse events did not differ between treatment groups.Interpretation A single dose of 0.25 mg/kg primaquine, given alongside dihydroartemisinin-piperaquine, was safe and efficacious for the prevention of P falciparum malaria transmission in boys and men who are not deficient in G6PD. Future studies should assess the safety of single-dose primaquine in G6PD-deficient individuals to define the therapeutic range of primaquine to enable the safe roll-out of community interventions with primaquine.