From Universidad Peruana Cayetano Heredia, Lima, Peru (A.L.-C., R.C., M.C.); Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Manaus (M.V.G.L., F.V., W.M.M., M.A.M.B., M.R.F.C.), and Fundação Oswaldo Cruz, Manguinhos, Rio de Janeiro (M.V.G.L.) - both in Brazil; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam (T.T.H., C.H.N.); Universidad de Antioquia, Medellin (I.D.V.), Centro de Investigaciones Clinicas S.A.S de Cali, Cali (M.F.V.), and IMAT Oncomedica, Monteria (S.A.) - all in Colombia; Umphang Hospital, Tak (C.N.-l., R.P.), and Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot (C.S.C., F.H.N., G.B.) - both in Thailand; the Centre for Tropical Medicine and Global Health (C.S.C., F.H.N., G.B.) and the Oxford Centre for Clinical Tropical Medicine (B.A.), Nuffield Department of Medicine, University of Oxford, Oxford, GlaxoSmithKline, Stockley Park West (G.C., V.M.R., S.W.J., E.H., D.D.C., K.M., G.C.K.W.K., J.A.G.), and GlaxoSmithKline, Stevenage (L.K.) - all in the United Kingdom; Medicines for Malaria Venture, Geneva (S.D.); and GlaxoSmithKline, Collegeville, PA (V.M.W., J.J.B.).
N Engl J Med. 2019 Jan 17;380(3):229-241. doi: 10.1056/NEJMoa1802537.
Tafenoquine, a single-dose therapy for Plasmodium vivax malaria, has been associated with relapse prevention through the clearance of P. vivax parasitemia and hypnozoites, termed "radical cure."
We performed a phase 3, prospective, double-blind, double-dummy, randomized, controlled trial to compare tafenoquine with primaquine in terms of safety and efficacy. The trial was conducted at seven hospitals or clinics in Peru, Brazil, Colombia, Vietnam, and Thailand and involved patients with normal glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and female patients with moderate G6PD enzyme deficiency; all patients had confirmed P. vivax parasitemia. The patients were randomly assigned, in a 2:1 ratio, to receive a single 300-mg dose of tafenoquine or 15 mg of primaquine once daily for 14 days (administered under supervision); all patients received a 3-day course of chloroquine and were followed for 180 days. The primary safety outcome was a protocol-defined decrease in the hemoglobin level (>3.0 g per deciliter or ≥30% from baseline or to a level of <6.0 g per deciliter). Freedom from recurrence of P. vivax parasitemia at 6 months was the primary efficacy outcome in a planned patient-level meta-analysis of the current trial and another phase 3 trial of tafenoquine and primaquine (per-protocol populations), and an odds ratio for recurrence of 1.45 (tafenoquine vs. primaquine) was used as a noninferiority margin.
A protocol-defined decrease in the hemoglobin level occurred in 4 of 166 patients (2.4%; 95% confidence interval [CI], 0.9 to 6.0) in the tafenoquine group and in 1 of 85 patients (1.2%; 95% CI, 0.2 to 6.4) in the primaquine group, for a between-group difference of 1.2 percentage points (95% CI, -4.2 to 5.0). In the patient-level meta-analysis, the percentage of patients who were free from recurrence at 6 months was 67.0% (95% CI, 61.0 to 72.3) among the 426 patients in the tafenoquine group and 72.8% (95% CI, 65.6 to 78.8) among the 214 patients in the primaquine group. The efficacy of tafenoquine was not shown to be noninferior to that of primaquine (odds ratio for recurrence, 1.81; 95% CI, 0.82 to 3.96).
Among patients with normal G6PD enzyme activity, the decline in hemoglobin level with tafenoquine did not differ significantly from that with primaquine. Tafenoquine showed efficacy for the radical cure of P. vivax malaria, although tafenoquine was not shown to be noninferior to primaquine. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; GATHER ClinicalTrials.gov number, NCT02216123 .).
替法诺喹是一种用于治疗间日疟原虫疟疾的单剂量疗法，通过清除间日疟原虫寄生虫血症和休眠子，被称为“根治性治疗”，从而预防复发。
我们进行了一项 3 期、前瞻性、双盲、双模拟、随机、对照试验，比较替法诺喹与伯氨喹在安全性和疗效方面的差异。该试验在秘鲁、巴西、哥伦比亚、越南和泰国的 7 家医院或诊所进行，涉及葡萄糖-6-磷酸脱氢酶（G6PD）酶活性正常和女性中度 G6PD 酶缺乏的患者；所有患者均有明确的间日疟原虫寄生虫血症。患者按 2:1 的比例随机分配，接受单次 300mg 替法诺喹或每日 15mg 伯氨喹治疗 14 天（在监督下给药）；所有患者均接受 3 天氯喹治疗，并随访 180 天。主要安全性结局是方案定义的血红蛋白水平下降（每升下降>3.0 克或基线下降≥30%，或降至每升<6.0 克）。在计划的患者水平荟萃分析中，主要疗效结局是 6 个月时无复发的间日疟原虫寄生虫血症，该分析纳入了当前试验和另一项替法诺喹和伯氨喹的 3 期试验（按方案人群）；替法诺喹与伯氨喹相比，复发的优势比为 1.45（替法诺喹比伯氨喹），这被用作非劣效性边界。
替法诺喹组 166 例患者中有 4 例（2.4%；95%置信区间[CI]，0.9 至 6.0）和伯氨喹组 85 例患者中有 1 例（1.2%；95%CI，0.2 至 6.4）发生方案定义的血红蛋白水平下降，两组间差异为 1.2 个百分点（95%CI，-4.2 至 5.0）。在患者水平的荟萃分析中，替法诺喹组 426 例患者中有 67.0%（95%CI，61.0 至 72.3）和伯氨喹组 214 例患者中有 72.8%（95%CI，65.6 至 78.8）在 6 个月时无复发。替法诺喹的疗效未显示优于伯氨喹（复发的优势比，1.81；95%CI，0.82 至 3.96）。
在 G6PD 酶活性正常的患者中，替法诺喹组的血红蛋白水平下降与伯氨喹组无显著差异。替法诺喹对根治间日疟原虫疟疾有效，尽管替法诺喹未显示优于伯氨喹。（由葛兰素史克和疟疾药物倡议资助；GATHER 临床试验.gov 编号，NCT02216123）。
