Innovative PK/PD Approaches to Optimize TBM Treatment in Children (PATCH Study)

描述（由申请人提供）：结核性脑膜炎（TBM）是一种具有高死亡率和严重神经系统发病率的毁灭性疾病，主要影响幼儿。儿童TBM治疗的最佳方案和最佳药物剂量尚不清楚，因为迄今为止只有一项儿童TBM治疗的临床试验。在最近的两项针对TBM成人患者的临床试验中，在治疗早期给予高剂量的利福平静脉注射或每天口服氟喹诺酮，持续8周，可显著降低死亡率和严重残疾。目前尚不清楚这些策略是否可以改善儿童的预后，因为疾病谱系不同-死亡率较低，神经发育发病率风险增加-并且达到成人目标所需的剂量与改善预后相关尚未得到证实。最近，世界卫生组织建议增加一线结核病药物的剂量，包括异烟肼(H)和利福平(R)，用于儿童，认识到以前推荐的剂量通常是亚治疗剂量，但利福平(R)的剂量，驱动结核病治疗反应的药物，对于结核性结核病可能仍然太低。乙胺丁醇(E)被推荐为结核病治疗方案中的第四种药物（与H、R和吡嗪酰胺(Z)一起），其对脑脊液（CSF）的渗透性较差，可能不如左氧氟沙星(L)有效，左氧氟沙星是一种广泛使用的口服药物，具有良好的CSF渗透性，已被证明具有抗结核分枝杆菌的活性，最近从接受其治疗潜伏或活动性多药耐药结核病的儿童中获得的安全性和PK数据。本提案的目的是评估TBM儿童在治疗早期接受高剂量IV R（含或不含L） 8周作为TBM多药治疗的一部分的药代动力学（PK）、安全性和治疗结果。患有TBM的6个月至8岁儿童将通过印度浦那的Byramji Jeejeebhoy政府医学院招募；印度金奈国家结核病研究所和合作临床站点（儿童健康研究所和Kanchi Kamakoti儿童信托医院）；马拉维-利物浦-威康信托临床研究项目位于马拉维布兰太尔。对结核病治疗的强化阶段(前八周),120名参与者将随机比接收标准剂量HRZE 8周(对照组),HRivZE (IV代替口头R两周,使用建模与优化4 R剂量估计现有的PK数据从儿童和PK /药效学数据从成人与TBM),或HRivZL (R IV两周+左氧氟沙星在每日剂量为20毫克/公斤代替乙胺丁醇8周)。将进行血浆和稀疏脑脊液取样，并确定H、R和L的血浆和脑脊液PK。治疗效果之间的关系将通过分级结果测量（死亡/严重神经系统残疾、中度残疾、轻度残疾或无神经系统残疾）和神经认知测试来探讨。标本将被存入生物库，用于未来的生物标志物研究。该试验将产生至关重要的数据，为TBM儿童的药物选择和给药策略提供信息，并将适用于全球TBM儿童。

DESCRIPTION (provided by applicant): TB meningitis (TBM) is a devastating illness with high risk of mortality and severe neurologic morbidity predominantly affecting young children. The best regimen and optimal drug doses for treatment of pediatric TBM in children are unknown, as only one clinical trial of pediatric TBM treatment has ever been conducted. In two recent clinical trials in adults with TBM, higher-dose rifampin given IV early in treatment or an oral fluoroquinolone given daily for 8 weeks significantly reduced mortality and severe disability. It i unclear whether these strategies may improve outcomes in children, as the disease spectrum is different -- lower mortality and added risk of neurodevelopmental morbidity -- and the doses needed to achieve adult targets associated with improved outcomes have not been proven. Recently, the World Health Organization recommended an increase in the doses of first-line TB drugs, including isoniazid (H) and rifampin (R), for children, recognizing that previously-recommended doses were often sub-therapeutic, but the dose of rifampin (R), the drug that drives treatment response in TB, is likely still too low for TBM. Ethambutol (E), recommended as a fourth drug in TBM regimens (with H, R, and pyrazinamide (Z)), has poor penetration into cerebrospinal fluid (CSF) and may be less effective than levofloxacin (L), a widely-available oral drug with excellent CSF penetration, proven activity against Mycobacterium tuberculosis, and recent promising safety and PK data from children receiving it for latent or active multidrug-resistant TB. The goal of this proposal is to evaluate the pharmacokinetics (PK), safety, and treatment outcomes among children with TBM receiving higher-dose IV R given early in treatment with or without L for eight weeks as part of multidrug treatment for TBM. Children ages 6 months to 8 years with TBM will be recruited through Byramji Jeejeebhoy Government Medical College in Pune, India; the National Institute for Research in TB and collaborating clinical sites (Institute of Child Health and the Kanchi Kamakoti CHILDS Trust Hospital) in Chennai, India; and the Malawi- Liverpool-Wellcome Trust Clinical Research Programme site in Blantyre, Malawi. For the intensive phase of TB treatment (first 8 weeks), 120 participants will be randomized 1:1:1 to receive standard dose HRZE for 8 weeks (control arm), HRivZE (IV R substituted for oral R for two weeks, with optimal IV R dose estimated using modeling of existing PK data from children and PK/pharmacodynamic data from adults with TBM), or HRivZL (R IV for two weeks plus levofloxacin at a dose of 20 mg/kg daily substituted for ethambutol for 8 weeks). Plasma and sparse CSF sampling will be performed, and plasma and CSF PK for H, R, and L will be determined. Treatment-effect relationships will be explored using a graded outcome measure (death/severe neurologic disability, moderate disability, mild disability, or no neurologic disability) and neurocognitive testing. Specimens will be biobanked for future biomarker studies. This trial will yield critically important data to inform drug selection and dosing strategies for children with TBM and will be applicable to children with TBM globally.