Optimizing the dose of tafenoquine for the radical cure of Plasmodium vivax malaria in Southeast Asia

项目总结 在东亚和大洋洲，间日疟原虫是导致疟疾的最常见原因。超过一半的人会复发 这些感染构成了间日疟的主要负担。复发是发病的主要原因， 尤其是在儿童和孕妇中。近年来，有针对性地消除疟疾降低了 恶性疟疾在这些人口稠密的地区，但间日疟迅速卷土重来 因为旧病复发。预防复发(根治性治疗)需要服用8-氨基喹啉-这是 直到最近，这意味着7-14天的伯喹疗程。他芬诺喹是一种最近注册的缓慢淘汰的8- 氨基喹啉具有提供单剂量根治的实质性操作优势。然而， 第三阶段随机对照试验表明，目前推荐的300毫克成人剂量(~5毫克/公斤) 他芬诺喹对间日疟根治性疗效较差。剂量达14毫克/公斤的他非诺喹 在G6PD活性为70%的成人和儿童中证明是安全的和良好的耐受性。我们得到了那个人 参与者(N=1102)来自阶段3注册前试验的数据(检测和收集；见 参考文献，参考文献22-24)。个人患者数据荟萃分析(见参考文献32)显示 显然，a)剂量反应曲线在当前推荐剂量(5 mg/kg)附近是陡峭的，而b) 间日疟原虫复发(&lt；4个月)的优势比为0.69(95%可信区间0.64比0.75；p=10-21) 剂量。因此，将剂量增加一半(即至7.5毫克/公斤)预计将导致总体&gt；90%的减少。 间日疟原虫复发。为了验证这一预测，我们建议进行多中心双盲随机 在大湄公河次区域的五个国家进行临床试验。目的1比较根治性治疗的疗效 目前剂量的他非诺喹和50%更高的剂量(例如，人≥35千克的300毫克和450毫克)在成人中 和儿童急性间日疟和葡萄糖-6-磷酸脱氢酶(G6PD)活性&GT；70%。 复发和再感染将根据寄生虫的基因分型和时间进行概率区分 活动信息。为了检测可能被他苯喹抑制的极低密度间日疟原虫， 将进行超灵敏聚合酶链式反应(UPCR)。目标2评估血浆、尿液和红血球 血细胞他非诺喹浓度，并探索潜在的他非诺喹代谢物。CYP2D6基因分型 突变和高铁血红蛋白血症的测量将被纳入为自由基的暴露相关因素 疗效显著。目的3评价大剂量他非诺喹的安全性和耐受性。耐受性， 将监测胃肠道症状、红细胞压积和高铁血红蛋白浓度升高。 本研究将为指导他非诺喹根治间日疟提供确凿的证据。 一种有效、安全和耐受性良好的单剂抗复发治疗将显著改善 治疗间日疟，加快消除疟疾。

PROJECT SUMMARY In East Asia and Oceania Plasmodium vivax is the most common cause of malaria. Relapses occur in over half the infections and comprise the main burden of P. vivax malaria. Relapses are the major cause of morbidity, particularly in children and pregnant women. In recent years targeted malaria elimination has driven down Plasmodium falciparum malaria in these populous regions, but P. vivax malaria has re-emerged rapidly because of relapse. Preventing relapse (radical cure) requires administration of an 8-aminoquinoline – which until recently meant a 7-14 day course of primaquine. Tafenoquine is a recently registered slowly eliminated 8- aminoquinoline with the substantial operational advantage of providing single dose radical cure. However, Phase 3 randomized controlled trials showed that the currently recommended 300mg adult dose (~ 5mg/kg) of tafenoquine had low radical curative efficacy against P. vivax malaria. Tafenoquine doses up to 14mg/kg have proved safe and well tolerated in adults and children with >70% G6PD activity. We obtained the individual participant (N= 1102) data from the Phase 3 pre-registration trials (DETECTIVE and GATHER; see Bibliography, references 22-24). Individual patient data meta-analysis (see Bibliography, reference 32) shows clearly that a) the dose response curve is steep around the currently recommended dose (5mg/kg) and b) the odds ratio for P. vivax recurrence (<4 months) is 0.69 (95% CI 0.64 to 0.75; p=10-21) for each mg/kg increase in dose. Thus, increasing the dose by half (i.e., to 7.5mg/kg) is predicted to result in an overall >90% reduction of P. vivax recurrence. To test this prediction, we propose conducting a multi-center double-blind randomized clinical trial in five countries in the Greater Mekong sub-Region. Aim 1 compares the radical curative efficacies of the current tafenoquine dose and a 50% higher dose (e.g., 300mg versus 450mg in persons ≥35kg) in adults and children with acute vivax malaria and glucose-6-phosphate dehydrogenase (G6PD) activity >70%. Relapses will be distinguished from reinfections probabilistically based on parasite genotyping and time to event information. To detect very low-density P. vivax parasitemias which might be suppressed by tafenoquine, ultrasensitive polymerase chain reaction (uPCR) will be performed. Aim 2 assesses plasma, urine, and red blood cell tafenoquine concentrations and explores potential tafenoquine metabolites. Genotyping for CYP2D6 mutations and measurements of methemoglobinemia will be included as exposure correlates of radical curative efficacy. Aim 3 assesses safety and tolerability of the higher tafenoquine dose. Tolerability, gastrointestinal symptoms, hematocrit, and elevated blood methemoglobin concentrations will be monitored. This study will provide definitive evidence to guide tafenoquine dosing for the radical cure of P. vivax malaria. An efficacious, safe and well tolerated single dose anti-relapse therapeutic will substantially improve the treatment of P. vivax malaria and accelerate malaria elimination.