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

Abstract

<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>

Tuberculous Meningitis in Children: Reducing the Burden of Death and Disability

“…Despite the advent of anti-TB chemotherapy and corticosteroids most deaths (95%) from TBM will still occur by 6 months [69]. An observational report in 1961 on long-term outcomes in children with TBM, was the first to highlight persistent neurodevelopmental sequelae years following completion of TB treatment [90].…”

“…A recent model-based meta-analysis using emerging data from adult trials showed a strong positive correlation between rifampicin concentrations and survival, with doses of at least 30 mg/kg predicted to improve survival substantially compared to 10 mg/kg [68]. A dose of 35 mg/kg daily is being tested in a definitive Phase 3 trial [69] but higher mg/kg doses than that will be needed to achieve adult-equivalent exposures in children [70]. In children, a small trial suggested that a dose increase to 30 mg/kg improved neurocognitive function compared to standard dosing [71].…”

Decreased mortality seen in rifampicin/multidrug-resistant tuberculous meningitis treated with linezolid in Shenzhen, China

“…Some of these patients’ regimen were supplemented with another drug such as levofloxacin or moxifloxacin. Some research showed that high dose of RIF (20–35 mg/kg administered orally, and standard dose of INH) was able to improve treatment outcomes due to a higher RIF concentration in plasma and CSF, especially when RIF was administered intravenously [ 20 , 21 ]. Other research did not reach the same conclusion above, though [ 18 ].…”

Diagnostic and Prognostic Value of Cerebrospinal Fluid Lactate and Glucose in HIV-Associated Tuberculosis Meningitis

“…We retrospectively reviewed data from patients who presented with symptoms of a central nervous system (CNS) infection to Kiruddu National Referral Hospital and Mbarara Regional Referral Hospital, Uganda, between April 2017 and March 2022. Patients underwent lumbar puncture as part of the screening process for three clinical trials ( 34 – 36 ) and an observational cohort focused on meningitis diagnostics ( 9 ). Following informed consent, a diagnostic lumbar puncture was performed with CSF collection.…”