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.

项目摘要 在东亚和大洋洲，间日疟原虫是疟疾最常见的病因。复发率超过一半 间日疟是间日疟的主要传染源。复发是发病的主要原因， 尤其是儿童和孕妇。近年来，有针对性地消灭疟疾已经使 恶性疟原虫疟疾在这些人口稠密地区，但间日疟原虫疟疾迅速重新出现 因为复发。预防复发（根治）需要给予8-氨基喹啉， 直到最近还意味着7-14天的伯氨喹疗程。Tafenoquine是最近注册的缓慢消除的8- 氨基喹啉具有提供单剂量自由基固化的实质操作优点。然而，在这方面， III期随机对照试验显示，目前推荐的300 mg成人剂量（约5 mg/kg） 他非诺喹对间日疟的根治性疗效较低。他非诺喹剂量高达14 mg/kg， 在成人和G6 PD活性>70%的儿童中证明安全且耐受性良好。我们找到了 来自III期预注册试验的参与者（N= 1102）数据（DETECTIVE和GATHER;见 参考书目，参考文献22-24）。个体患者数据荟萃分析（参见参考文献32）显示 显然，a）剂量反应曲线在当前推荐剂量（5 mg/kg）附近陡峭，B） 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）， 次给药结束因此，将剂量增加一半（即，至7.5mg/kg）预计将导致总体>90%的 P.间日疟复发为了验证这一预测，我们建议进行一项多中心双盲随机 在大湄公河次区域的五个国家进行临床试验。目的1比较根治性疗效 当前他非诺喹剂量的50%和更高剂量的50%（例如，300 mg vs 450 mg（≥ 35 kg的成人） G6 PD活性> 70%的急性间日疟患儿。 复发将根据寄生虫基因分型和至 事件信息。为了检测可能被他非诺喹抑制的极低密度间日疟原虫寄生虫血症， 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和探索潜在的他非诺喹代谢物。CYP 2D 6基因分型 高铁血红蛋白血症的突变和测量结果将作为暴露相关的自由基， 疗效目的3评估更高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、血细胞比容和升高的血液高铁血红蛋白浓度。 本研究将为指导他非诺喹治疗间日疟提供明确的依据。 有效、安全且耐受性良好的单剂量抗复发治疗剂将显著改善患者的复发。 治疗间日疟和加速消灭疟疾。