1.STUDY OBJECTIVES

Tuberculosis meningitis (TBM) is an illness with high risk of death and severe brain effects. Even among treated patients, outcomes are poor. Mortality or the risk of death ranges from 25% to 50% in adults without HIV, and exceeds 50% in individuals living with HIV co-infection, with most deaths occurring within the first month of presentation. Among patients who survive TBM, the majority suffer from serious brain disability, resulting in lost productivity and decreased quality of life. The WHO recommended regimen for TBM consists of the same drugs and dosing as those used to treat pulmonary TB, only for a prolonged course of 9 to 12 months instead of 6 months. Studies have showed that risk of relapse was low and virtually identical in TBM patients who received 6 months versus longer than 6 months of therapy. Thus, there is no evidence base to support prolonging TBM treatment beyond 6 months. This study will look at whether taking a 6-month regimen of high dose rifampicin, high dose isoniazid, linezolid, and pyrazinamide is as good as taking the standard 9-month regimen for a combination of combination of rifampicin, isoniazid, pyrazinamide, and ethambutol. The safety, tolerability, and effectiveness of the 6-month regimen will be compared to standard combination TB therapy. This study will also measure the level of these drugs in blood and CSF. Participants with definite, probable, or possible TBM will be randomized to one of the two study arms, either 6-month regimen of high-dose RIF, high-dose INH, LZD, and PZA or 9-months regimen of standard of care, Rifampicin, Isoniazid, Ethambutol and Pyrazinamide. Test results for cryptococcal antigen, gram stain, and bacterial culture on CSF as standard of care for TBM or suspected TBM participants must be obtained. Participants living with and without HIV co-infection, with definite, probable, or possible TBM, aged ≥15 years will be enrolled. The Kericho site will enroll up to 30 participants. The participants will be followed up for up to 72 weeks after enrollment. The study will provide information on enhanced treatment regimen for TBM.  

Tuberculosis meningitis (TBM) is a devastating illness, killing and disabling more patients than any other form of TB. TBM is characterized by a progressive granulomatous inflammation of the meninges, often at the base of the brain, resulting in hydrocephalus, brain infarction, and death, if left untreated. Even among treated patients, outcomes are poor. Mortality ranges from 25 to 50% in adults without HIV, and exceeds 50% in individuals living with HIV co-infection, with most deaths occurring within the first month of presentation. Among patients who survive TBM, the majority suffer from serious neurologic disability, resulting in lost productivity and decreased quality of life. Despite these bleak outcomes, a paucity of data exists on the optimal approach to TBM treatment. The WHO recommended regimen for TBM consists of the same drugs and dosing as those used to treat pulmonary TB, only for a prolonged course of 9 to 12 months instead of 6 months. A Cochrane review in 2016 showed that risk of relapse was low and virtually identical (0.8%) in TBM patients who received 6 months versus longer than 6 months of therapy. Thus, there is no evidence base to support prolonging TBM treatment beyond 6 months. The overall goal of the proposed trial is to assess the PK, safety, and longitudinal treatment outcomes of an optimized 6-month regimen of high-dose Rifampicin (RIF), high-dose Isoniazid (INH), Linezolid (LZD), and Pyrazinamide (PZA) to the WHO 9-month SOC regimen for the treatment of TBM

Participants with definite, probable, or possible TBM will be randomized to one of the two study arms below and randomization will be stratified by HIV status and stage of disease as defined by the British Medical Research Council (BMRC) TBM grade. Test results for cryptococcal antigen, gram stain, and bacterial culture on CSF as SOC for TBM or suspected TBM participants must be obtained. Participants will be randomized to receive 6-month regimen of high-dose RIF, high-dose INH, LZD, and PZA or 9 months regimen of standard of care, Rifampicin, Isoniazid, Ethambutol and Pyrazinamide. Participants living with and without HIV co-infection, with definite, probable, or possible TBM, aged ≥15 years will be enrolled. The Kericho site will enroll up to 30 participants. The participants will be followed up for up to 72weeks after enrollment. The study will provide information on enhanced treatment strategies for TBM.