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）是一种毁灭性疾病，具有高死亡风险和严重的神经系统疾病，主要影响幼儿。治疗儿童儿童TBM的最佳方案和最佳药物剂量尚不清楚，因为只有一项儿童TBM治疗的临床试验。在最近的两项针对成年TBM患者的临床试验中，在治疗早期静脉注射更高剂量的利福平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结局，因为疾病谱不同-死亡率较低，神经发育发病率增加-并且实现与改善结局相关的成人目标所需的剂量尚未得到证实。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TBM来说可能仍然太低。乙胺丁醇（E），推荐作为TBM方案中的第四种药物（与H，R和吡嗪酰胺（Z）），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，已证实对结核分枝杆菌的活性，最近接受其治疗潜伏性或活动性多药耐药结核病的儿童的安全性和PK数据。本提案的目的是评估TBM儿童在早期接受高剂量IV R（联合或不联合L治疗8周）作为TBM多药治疗的一部分的药代动力学（PK）、安全性和治疗结局。将通过印度浦那的Byramji Jeejeebhoy政府医学院、印度钦奈的国家结核病研究所和合作临床中心（儿童健康研究所和Kanchi Kamakoti查尔兹信托医院）以及马拉维布兰太尔的马拉维-利物浦-威康信托临床研究计划中心招募6个月至8岁的结核病儿童。对于TB治疗的强化阶段（前8周），120名受试者将以1：1：1的比例随机接受标准剂量HRZE治疗8周（对照组）、HRivZE（IV R替代口服R治疗2周，使用来自儿童的现有PK数据和来自患有TBM的成人的PK/药效学数据的建模来估计最佳IV R剂量）或HRivZL（R IV治疗2周加左氧氟沙星（每日20 mg/kg）替代乙胺丁醇治疗8周）。将进行血浆和稀疏CSF采样，并测定H、R和L的血浆和CSF PK。将使用分级结局指标（死亡/重度神经功能残疾、中度残疾、轻度残疾或无神经功能残疾）和神经认知测试探索治疗-效应关系。将对样本进行生物库，用于未来的生物标志物研究。本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.