High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study)

Abstract

Background: Tuberculous meningitis (TBM), the most severe form of tuberculosis (TB), results in death or neurological disability in >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. Protocol: 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. Discussion: 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. Trial registration: ISRCTN15668391 (17/06/2019)

Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial

“…In adults with TBM, high-dose rifampicin appears to reduce mortality [ 14 ], though this finding is not universal [ 34 ], and benefit is likely to be dose-dependent. There are several phase 3 trials of 35 mg/kg underway in adults, which will provide a definitive answer to this question [ 35 ]. From a clinical pharmacology standpoint, it is logical to choose drugs and doses that achieve therapeutic concentrations at the site of disease, and rifampicin displays poor penetration into the brain and CSF [ 12 , 36 , 37 ].…”

Buruli-RifDACC: Evaluation of the efficacy and cost-effectiveness of high-dose versus standard-dose rifampicin on outcomes in Mycobacterium ulcerans disease, a protocol for a randomised controlled trial in Ghana

“…The 10mg/kg dose of rifampicin, which WHO recommends for BU treatment, was selected because it is the dose used in tuberculosis treatment. Multiple tuberculosis studies have demonstrated that higher-dose rifampicin is safe and well tolerated 19,20 and comparative trials of its efficacy for tuberculosis are underway 19,21,22 . Preliminary data from mouse studies for BU suggest that higher-dose rifampicin may improve outcomes and may facilitate shortening of regimens in part because it may clear viable MU more quickly 23 .…”

Neurologic Complications of Tuberculosis

“…A retrospective review of clinical trial data from Indonesia suggested a higher rifampicin dosage (either oral or IV formulations) resulted in improved survival 43 . Therefore, a randomized controlled trial of high-dose oral and IV rifampicin is being launched to investigate whether this dosage achieves a higher CSF rifampicin concentration and improves outcomes 44 . Furthermore, a 2020 trial of replacing oral isoniazid and ethambutol with IV formulations resulted in significant clinical and radiographic improvement and higher rates of sputum conversion after 2 months of treatment in people with HIV with tuberculous meningitis compared with those treated with standard oral treatment 45 .…”