Study protocol for a phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis [LASER-TBM].
Study protocol for a phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis [LASER-TBM].
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增加剂量利福平和辅助利奈唑胺（联合或不联合阿司匹林）治疗 HIV 相关结核性脑膜炎的安全性和耐受性的 2A 期试验研究方案 [LASER-TBM]。
DOI：
10.12688/wellcomeopenres.16783.1
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发表时间：
2021
影响因子：
--
通讯作者：
Wilkinson RJ
中科院分区：
文献类型：
--
作者：
Davis AG;Wasserman S;Maxebengula M;Stek C;Bremer M;Daroowala R;Aziz S;Goliath R;Stegmann S;Koekemoer S;Jackson A;Lai Sai L;Kadernani Y;Sihoyiya T;Liang CJ;Dodd L;Denti P;Crede T;Naude J;Szymanski P;Vallie Y;Banderker I;Moosa S;Raubenheimer P;Lai RPJ;Joska J;Nightingale S;Dreyer A;Wahl G;Offiah C;Vorster I;Candy S;Robertson F;Meintjes E;Maartens G;Black J;Meintjes G;Wilkinson RJ
背景：结核性脑膜炎（TBM）是最致命的结核病形式，在合并感染HIV-1的患者中死亡率约为50%。目前的抗生素方案是基于那些已知对肺结核有效的方案，而没有考虑到药物穿透中枢神经系统（CNS）的能力不同。宿主免疫应答驱动TBM中的病理，但有效的宿主定向疗法是稀缺的。有足够的数据表明，更高剂量的利福平（RIF）、额外的利奈唑胺（LZD）和阿司匹林（阿萨）对TBM有益，但需要对这些干预措施在HIV相关TBM背景下的安全性进行严格研究。我们假设，在治疗的前56天，在标准治疗的基础上联合使用增加剂量的RIF、LZD和阿萨在HIV-1感染的TBM患者中是安全和耐受的。 研究方法：在一项开放标签随机平行研究中，最多100名受试者将接受以下任一种治疗：（一）护理标准（n=40，对照组），ii）标准治疗加增加剂量的RIF（35 mg/kg）和LZD（1200 mg OD持续28天，600 mg OD持续28天）（n=30，实验组1），或iii）按照实验组1加额外阿萨1000 mg OD（n=30，实验组2）。56天后，参与者将继续按照国家指南进行标准治疗。主要终点是第56天时死亡和征集性治疗相关不良事件的发生率。在计划的药代动力学（PK）子研究中，我们旨在评估口服与IV利福平的PK/药效学（PD），描述LZD和RIF PK和脑脊液浓度，探索PK/PD关系，并研究LZD和RIF之间的药物相互作用。本研究的安全性和药代动力学数据将为计划的TBM强化治疗III期研究提供信息。 Clinicaltrials.gov注册：NCT 03927313（25/04/2019）
Background: Tuberculous meningitis (TBM) is the most lethal form of tuberculosis with a mortality of ~50% in those co-infected with HIV-1. Current antibiotic regimens are based on those known to be effective in pulmonary TB and do not account for the differing ability of the drugs to penetrate the central nervous system (CNS). The host immune response drives pathology in TBM, yet effective host-directed therapies are scarce. There is sufficient data to suggest that higher doses of rifampicin (RIF), additional linezolid (LZD) and adjunctive aspirin (ASA) will be beneficial in TBM yet rigorous investigation of the safety of these interventions in the context of HIV associated TBM is required. We hypothesise that increased dose RIF, LZD and ASA used in combination and in addition to standard of care for the first 56 days of treatment with be safe and tolerated in HIV-1 infected people with TBM. Methods: In an open-label randomised parallel study, up to 100 participants will receive either; i) standard of care (n=40, control arm), ii) standard of care plus increased dose RIF (35mg/kg) and LZD (1200mg OD for 28 days, 600mg OD for 28 days) (n=30, experimental arm 1), or iii) as per experimental arm 1 plus additional ASA 1000mg OD (n=30, experimental arm 2). After 56 days participants will continue standard treatment as per national guidelines. The primary endpoint is death and the occurrence of solicited treatment-related adverse events at 56 days. In a planned pharmacokinetic (PK) sub-study we aim to assess PK/pharmacodynamic (PD) of oral vs IV rifampicin, describe LZD and RIF PK and cerebrospinal fluid concentrations, explore PK/PD relationships, and investigate drug-drug interactions between LZD and RIF. Safety and pharmacokinetic data from this study will inform a planned phase III study of intensified therapy in TBM. Clinicaltrials.gov registration: NCT03927313 (25/04/2019)