Instituto de Medicina Tropical, Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.
Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Amazonas, Brazil.
Lancet. 2014 Mar 22;383(9922):1049-58. doi: 10.1016/S0140-6736(13)62568-4. Epub 2013 Dec 19.
Clinical effectiveness of previous regimens to treat Plasmodium vivax infection have been hampered by compliance. We aimed to assess the dose-response, safety, and tolerability of single-dose tafenoquine plus 3-day chloroquine for P vivax malaria radical cure.
In this double-blind, randomised, dose-ranging phase 2b study, men and women (aged ≥16 years) with microscopically confirmed P vivax monoinfection (parasite density >100 to <100,000 per μL blood) were enrolled from community health centres and hospitals across seven sites in Brazil, Peru, India, and Thailand. Patients with glucose-6-phosphate dehydrogenase enzyme activity of less than 70% were excluded. Eligible patients received chloroquine (days 1-3) and were randomly assigned (1:1:1:1:1:1) by a computer-generated randomisation schedule to receive single-dose tafenoquine 50 mg, 100 mg, 300 mg, or 600 mg, primaquine 15 mg for 14 days, or chloroquine alone. Randomisation was stratified by baseline parasite count (≤7500 and >7500 per μL blood). The primary efficacy endpoint was relapse-free efficacy at 6 months from initial dose (ie, clearance of initial infection without subsequent microscopically confirmed infection), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01376167.
Between Sept 19, 2011, and March 25, 2013, 329 patients were randomly assigned to a treatment group (chloroquine plus tafenoquine 50 mg [n=55], 100 mg [n=57], 300 mg [n=57], 600 mg [n=56]; or to chloroquine plus primaquine [n=50]; or chloroquine alone [n=54]). Relapse-free efficacy at 6 months was 57·7% (95% CI 43-70) with tafenoquine 50 mg, 54·1% (40-66) with tafenoquine 100 mg, 89·2% (77-95) with tafenoquine 300 mg, 91·9% (80-97) with tafenoquine 600 mg, 77·3% (63-87) with primaquine, and 37·5% (23-52) with chloroquine alone. Tafenoquine 300 mg and 600 mg had better efficacy than chloroquine alone (treatment differences 51·7% [95% CI 35-69], p<0·0001, with tafenoquine 300 mg and 54·5% [38-71], p<0·0001, with tafenoquine 600 mg), as did primaquine (treatment difference 39·9% [21-59], p=0·0004). Adverse events were similar between treatments. 29 serious adverse events occurred in 26 (8%) of 329 patients; QT prolongation was the most common serious adverse event (11 [3%] of 329), occurring in five (2%) of 225 patients receiving tafenoquine, four (8%) of 50 patients receiving primaquine, and two (4%) of 54 patients receiving chloroquine alone, with no evidence of an additional effect on QT of chloroquine plus tafenoquine coadministration.
Single-dose tafenoquine 300 mg coadministered with chloroquine for P vivax malaria relapse prevention was more efficacious than chloroquine alone, with a similar safety profile. As a result, it has been selected for further clinical assessment in phase 3.
GlaxoSmithKline, Medicines for Malaria Venture.
先前用于治疗间日疟原虫感染的临床疗效受到了依从性的影响。我们旨在评估单剂量他非诺喹加 3 天氯喹治疗间日疟原虫根治的剂量反应、安全性和耐受性。
在这项双盲、随机、剂量范围的 2b 期研究中，从巴西、秘鲁、印度和泰国的 7 个社区卫生中心和医院招募了经显微镜确认患有单纯间日疟原虫感染（寄生虫密度>100 至<100000 每μL 血液）的男性和女性（年龄≥16 岁）。排除葡萄糖-6-磷酸脱氢酶活性低于 70%的患者。符合条件的患者接受氯喹（第 1-3 天），并通过计算机生成的随机分组方案随机分配（1:1:1:1:1:1），接受单剂量他非诺喹 50mg、100mg、300mg 或 600mg，14 天的磷酸伯氨喹，或单独氯喹。随机分组按基线寄生虫计数（≤7500 和>7500 每μL 血液）分层。主要疗效终点是初始剂量后 6 个月的无复发疗效（即初始感染清除而无随后显微镜确认的感染），通过意向治疗进行分析。这项研究在 ClinicalTrials.gov 注册，编号为 NCT01376167。
在 2011 年 9 月 19 日至 2013 年 3 月 25 日期间，329 名患者被随机分配到治疗组（氯喹加他非诺喹 50mg [n=55]、100mg [n=57]、300mg [n=57]、600mg [n=56]；或氯喹加磷酸伯氨喹 [n=50]；或氯喹单独 [n=54]）。6 个月时无复发疗效分别为他非诺喹 50mg 组为 57.7%（95%CI 43-70）、他非诺喹 100mg 组为 54.1%（40-66）、他非诺喹 300mg 组为 89.2%（77-95）、他非诺喹 600mg 组为 91.9%（80-97）、磷酸伯氨喹组为 77.3%（63-87）、氯喹单独组为 37.5%（23-52）。他非诺喹 300mg 和 600mg 组的疗效优于氯喹单独组（治疗差异分别为 51.7%[95%CI 35-69]，p<0·0001，他非诺喹 300mg 和 54.5%[38-71]，p<0·0001，他非诺喹 600mg），磷酸伯氨喹组也优于氯喹单独组（治疗差异 39.9%[21-59]，p=0·0004）。各治疗组的不良反应相似。329 名患者中有 29 例（8%）发生 29 例严重不良事件；QT 延长是最常见的严重不良事件（329 例中有 11 例[3%]），225 例接受他非诺喹治疗的患者中有 5 例（2%）、50 例接受磷酸伯氨喹治疗的患者中有 4 例（8%）、54 例接受氯喹单独治疗的患者中有 2 例（4%），没有证据表明氯喹加他非诺喹联合用药对 QT 有额外的影响。
单剂量他非诺喹 300mg 联合氯喹预防间日疟原虫复发的疗效优于氯喹单独治疗，安全性相似。因此，它已被选中用于 3 期临床试验的进一步评估。
葛兰素史克公司，疟疾药物促进协会。
