Effectiveness and safety of shortened intensive treatment for children with tuberculous meningitis (SURE): a protocol for a phase 3 randomised controlled trial evaluating 6 months of antituberculosis therapy and 8 weeks of aspirin in Asian and African children with tuberculous meningitis

Abstract

Introduction: Childhood tuberculous meningitis (TBM) is a devastating disease. The long-standing WHO recommendation for treatment is 2 months of intensive phase with isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E), followed by 10 months of isoniazid and rifampicin. In 2022, WHO released a conditional recommendation that 6 months of intensified antituberculosis therapy (ATT) could be used as an alternative for drug-susceptible TBM. However, this has never been evaluated in a randomised clinical trial. Trials evaluating ATT shortening regimens using high-dose rifampicin and drugs with better central nervous system penetration alongside adjuvant anti-inflammatory therapy are needed to improve outcomes.

Methods and analysis: The Shortened Intensive Therapy for Children with Tuberculous Meningitis (SURE) trial is a phase 3, randomised, partially blinded, factorial trial being conducted in Asia (India and Vietnam) and Africa (Uganda, Zambia and Zimbabwe). It is coordinated by the Medical Research Council Clinical Trial Unit at University College London (MRCCTU at UCL). 400 children (aged 29 days to <18 years) with clinically diagnosed TBM will be randomised, using a factorial design, to either a 24-week intensified regimen (isoniazid (20 mg/kg), rifampicin (30 mg/kg), pyrazinamide (40 mg/kg) and levofloxacin (20 mg/kg)) or the standard 48-week ATT regimen and 8 weeks of high-dose aspirin or placebo. The primary outcome for the first randomisation is all-cause mortality, and for the second randomisation is the paediatric modified Rankin Scale (mRS), both at 48 weeks. Nested substudies include pharmacokinetics, pharmacogenetics, pathophysiology, diagnostics and prognostic biomarkers, in-depth neurodevelopmental outcomes, MRI and health economics.

Ethics and dissemination: Local ethics committees at all participating study sites and respective regulators approved the SURE protocol. Ethics approval was also obtained from UCL, UK (14935/001). Informed consent from parents/carers and assent from age-appropriate children are required for all participants. Results will be published in international peer-reviewed journals, and appropriate media will be used to summarise results for patients and their families and policymakers.

Trial registration: ISRCTN40829906 (registered 13 November 2018).

Keywords: Clinical trials; Infectious disease/HIV; Infectious diseases & infestations; Paediatric infectious disease & immunisation; Randomized Controlled Trial; Tuberculosis.

Figure 1. Trial entry, randomisation and treatment. HD, high-dose; E, ethambutol; H, isoniazid; L, levofloxacin; R, rifampicin; TB, tuberculosis and Z, pyrazinamide. ˆ Target of 400. If planned recruitment to 400 is not possible, the modified target of 300 would be acceptable to allow 80% power and 350 to allow 85% power. * reduced mg/kg dosing used for children 25 kg and over. Both randomisations use minimisation with a random element and 1:1 allocation ratio.