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

描述(由申请人提供)：结核病脑膜炎(TBM)是一种破坏性疾病，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TBM的最佳方案和最佳药物剂量尚不清楚，因为仅进行过一次儿童TBM治疗的临床试验。在最近的两项成人TBM临床试验中，在治疗早期给予较高剂量的利福平或连续8周每天口服氟喹诺酮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，因为疾病谱不同--死亡率较低，神经发育障碍的风险增加--而且实现与改善预后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儿童一线结核病药物的剂量，包括异烟肼(H)和利福平(R)，认识到以前推荐的剂量通常是亚治疗剂量，但推动结核病治疗反应的药物利福平(R)的剂量可能仍然太低。乙胺丁醇(E)被推荐作为TBM方案的第四种药物(与H、R和吡津酰胺(Z)一起使用)，它在脑脊液中的渗透性较差，可能不如左氧氟沙星(L)，左氧氟沙星是一种广泛存在的口服药物，具有良好的脑脊液渗透性，已被证明对结核分枝杆菌具有活性，而且最近有望获得来自儿童接受其治疗潜伏期或活动期多药耐药结核病的安全性和PK数据。这项建议的目标是评估作为创伤性脑损伤多药治疗的一部分，早期使用或不使用L治疗8周的脑膜炎患儿的药代动力学(PK)、安全性和治疗结果。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站点(儿童健康研究所和坎奇·卡马科蒂儿童信托医院)以及马拉维-利物浦-惠康信托基金临床研究计划站点招募6个月至8岁的患有TBM的儿童。在结核病强化治疗阶段(前8周)，120名参与者将被随机分为三组，分别接受标准剂量的HRZE治疗8周(对照组)、HRivZE(静脉注射R替代口服R治疗两周，根据现有儿童PK数据和成人TBM患者的PK/药效学数据建模估计最佳静脉注射R剂量)或HRivZL(静脉注射治疗两周加左氧氟沙星，每日剂量20 mg/kg，替代乙胺丁醇，为期8周)。将进行血浆和稀疏脑脊液采样，并测定H、R和L的血浆和脑脊液PK。将使用分级结果测量(死亡/严重神经残疾、中度残疾、轻度残疾或无神经残疾)和神经认知测试来探索治疗效果关系。标本将被生物库储存，用于未来的生物标记物研究。这项试验将产生至关重要的数据，为儿童脑瘫的药物选择和剂量策略提供信息，并将适用于全球脑瘫儿童。

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.