<ns4:p><ns4:bold>Background: </ns4:bold>Tuberculous meningitis (TBM), the most severe form of tuberculosis (TB), results in death or neurological disability in &gt;50%, despite World Health Organisation recommended therapy. Current TBM regimen dosages are based on data from pulmonary TB alone. Evidence from recent phase II pharmacokinetic studies suggests that high dose rifampicin (R) administered intravenously or orally enhances central nervous system penetration and may reduce TBM associated mortality. We hypothesize that, among persons with TBM, high dose oral rifampicin (35 mg/kg) for 8 weeks will improve survival compared to standard of care (10 mg/kg), without excess adverse events.</ns4:p><ns4:p> <ns4:bold>Protocol: </ns4:bold>We will perform a parallel group, randomised, placebo-controlled, double blind, phase III multicentre clinical trial comparing high dose oral rifampicin to standard of care. The trial will be conducted across five clinical sites in Uganda, South Africa and Indonesia. Participants are HIV-positive or negative adults with clinically suspected TBM, who will be randomised (1:1) to one of two arms: 35 mg/kg oral rifampicin daily for 8 weeks (in combination with standard dose isoniazid [H], pyrazinamide [Z] and ethambutol [E]) or standard of care (oral HRZE, containing 10 mg/kg/day rifampicin). The primary end-point is 6-month survival. Secondary end points are: i) 12-month survival ii) functional and neurocognitive outcomes and iii) safety and tolerability. Tertiary outcomes are: i) pharmacokinetic outcomes and ii) cost-effectiveness of the intervention. We will enrol 500 participants over 2.5 years, with follow-up continuing until 12 months post-enrolment.</ns4:p><ns4:p> <ns4:bold>Discussion:</ns4:bold> Our best TBM treatment still results in unacceptably high mortality and morbidity. Strong evidence supports the increased cerebrospinal fluid penetration of high dose rifampicin, however conclusive evidence regarding survival benefit is lacking. This study will answer the important question of whether high dose oral rifampicin conveys a survival benefit in TBM in HIV-positive and -negative individuals from Africa and Asia.</ns4:p><ns4:p> <ns4:bold>Trial registration: </ns4:bold><ns4:ext-link xmlns:ns3="http://www.w3.org/1999/xlink" ext-link-type="uri" ns3:href="http://www.isrctn.com/ISRCTN15668391">ISRCTN15668391</ns4:ext-link> (17/06/2019)</ns4:p>