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

优化他非诺喹的剂量以根治东南亚间日疟原虫疟疾

• 批准号: 10703688
• 负责人: Cindy S Chu
• 金额: $ 106.79万
• 依托单位: UNIVERSITY OF OXFORD
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-08 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703688
• 关键词: Acceleration; Acute; Adult; Aftercare; Aminoquinolines; Anemia; Antimalarials; Asia; Bibliography; Blood; CYP2D6 gene; Child; Chloroquine; Clinical Trials; Country; Data; Developmental Delay Disorders; Dose; Double-Blind Method; Drug Interactions; Enrollment; Erythrocytes; Event; Falciparum Malaria; Far East; Fetal Growth Retardation; Genotype; Glucosephosphate Dehydrogenase; Goals; Guidelines; Hematocrit procedure; Hemoglobin; Human; Incidence; Individual; Infection; Liver; Malaria; Measurement; Measures; Meta-Analysis; Metadata; Methemoglobin; Methemoglobinemia; Monitor; Morbidity - disease rate; Mutation; Oceania; Odds Ratio; Parasitemia; Parasites; Participant; Patients; Persons; Pharmaceutical Preparations; Phase; Plasma; Plasmodium vivax; Polymerase Chain Reaction; Pregnant Women; Primaquine; Primary Infection; Production; Randomized, Controlled Trials; Recommendation; Recurrence; Relapse; Research; Safety; Schedule; Southeastern Asia; Statistical Models; Testing; Therapeutic; Time; Treatment Failure; Urine; Visit; Vivax Malaria; Whole Blood; artemether; benflumetol; density; design; detection method; gastrointestinal symptom; genome sequencing; improved; individual patient; neonatal death; pharmacometrics; policy recommendation; randomized, clinical trials; relapse prevention; response; safety assessment; transmission process

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.

项目概要 在东亚和大洋洲，间日疟原虫是导致一半以上疟疾复发的最常见原因。 感染并构成间日疟原虫疟疾的主要负担，复发是发病的主要原因， 特别是在儿童和孕妇中，近年来有针对性的疟疾消除工作有所减少。 这些人口稠密地区出现恶性疟疾，但间日疟疾又迅速卷土重来 因为预防复发（根治）需要服用 8-氨基喹啉 - 这 直到最近，伯氨喹的疗程为 7-14 天，他非诺喹是最近注册的缓慢淘汰的 8- 药物。 氨基喹啉具有提供单剂量根治性治疗的显着操作优势。 3期随机对照试验表明，目前推荐的成人剂量为300mg（~5mg/kg） 他非诺喹对间日疟原虫疟疾的根治疗效较低，他非诺喹剂量高达 14 毫克/公斤。 经证明，对于 G6PD 活性 >70% 的成人和儿童来说是安全且耐受性良好的。 来自 3 期预注册试验（DETECTIVE 和 GATHER；参见 参考文献，参考文献 22-24）个体患者数据荟萃分析（参见参考文献，参考文献 32）显示。 显然，a) 剂量反应曲线在当前推荐剂量 (5mg/kg) 附近很陡峭，b) 每增加 mg/kg 剂量，间日疟原虫复发（<4 个月）的比值比为 0.69（95% CI 0.64 至 0.75；p=10-21） 因此，将剂量增加一半（即至 7.5mg/kg）预计将导致总体减少 >90%。 为了检验这一预测，我们建议进行多中心双盲随机试验。 在大湄公河次区域五个国家进行的临床试验目标 1 比较了根治性疗效。 成人目前他非诺喹剂量的基础上增加 50% 的剂量（例如，≥35kg 的人为 300mg 与 450mg） 以及患有急性间日疟且葡萄糖-6-磷酸脱氢酶 (G6PD) 活性 > 70% 的儿童。 将根据寄生虫基因分型和时间来区分复发和再感染。 检测可能被他非诺喹抑制的极低密度间日疟原虫血症， 将进行超灵敏聚合酶链反应 (uPCR)，目标 2 评估血浆、尿液和红细胞。 血细胞他非诺喹浓度并探索 CYP2D6 的潜在他非诺喹代谢物。 高铁血红蛋白血症的突变和测量将被纳入自由基暴露的相关性 目标 3 评估较高剂量他非诺喹的安全性和耐受性。 将监测胃肠道症状、血细胞比容和血液高铁血红蛋白浓度升高。 这项研究将为指导他非诺喹的剂量以根治间日疟疾提供明确的证据。 有效、安全且耐受性良好的单剂量抗复发治疗将显着改善 治疗间日疟并加速消除疟疾。