Background

TB meningitis (TBM) remains a challenging disease to diagnose and treat, particularly in young children. About one in five children who get TBM die of the disease, and about three in five who survive will suffer long-term disability. The global burden of TBM in children is likely to be under-recognised.

In 2022, the World Health Organization (WHO) made a conditional recommendation that an intensified 6-month TB drug regimen could be used as an alternative to the standard of 12 months. Evidence for this shortened intensified regimen comes from a systematic review and meta-analysis of observational studies showing reduced mortality in children with TBM. The 6-month TB drug regimen uses TB drugs at higher doses and with better brain penetration and is the standard treatment for drug-susceptible TBM in some countries. Halving the treatment time would potentially have large benefits for families and health systems. However, there has been no large randomised controlled trial to directly compare the six-month against the 12-month regimen.

Arterial ischaemic stroke is the main cause of irreversible neurological damage in children with TBM and is not prevented by adjunctive corticosteroids. Infarction may already exist at presentation, but many infarcts develop during treatment. Cerebral vasculitis due to hyperinflammation, in addition to hypercoagulability, are contributing factors in the pathogenesis of brain damage in childhood TBM. Aspirin may have a role in the treatment of TBM due to its anti-inflammatory and anti-thrombotic properties. Adjunctive anti-inflammatory treatment to complement the short-term survival benefits of corticosteroids has been proposed and evaluated in a small number of clinical trials. However, results have been inconclusive to date. Larger RCTs evaluating the effect of high-dose aspirin on mortality and neurodevelopmental outcomes in children with TBM are needed.

Objectives

Primary Objectives

• To determine whether the standard 12-month ATT regimen for treating paediatric TBM can be reduced to 6 months with similar efficacy and safety, with an intensified regimen of anti-TB drugs in children aged 29 days and under 18 years with TBM;
• To determine whether the standard 12-month ATT regimen for treating paediatric TBM can be reduced to 6 months with similar efficacy, with an intensified regimen of anti-TB drugs in children aged under 18 years with TBM;

AND

• To determine whether adjunctive aspirin for the first 60 days of treatment reduces TBM-related neuro-disability with minimal or no toxicity in children with TBM.

Secondary Objectives

• To determine whether the doses of anti-TB drugs, prescribed according to weight bands, result in appropriate drug exposures when compared with historical paediatric and adult PK data.
• To further understand the pathophysiology of TBM in children and the effects of intensified anti-bacterial and anti-inflammatory treatment on intra-cerebral inflammation and the macroscopic complications of TBM (infarcts, tuberculomas, hydrocephalus).

Location of activity

Study sites in Viet Nam

• Pham Ngoc Thach Hospital
• National Lung Hospital
• Children Hospital 2
• Vietnam Children’s Hospital

International study sites

• Post Graduate Institute of Education and Medical Research (PGI), Chandigarh India
• Lady Hardinge Hospital, Delhi India
• Makere University – John Hopkins University, Kampala Uganda
• University Teaching Hospital, Lusaka Zambia
• University of Zimbabwe Clinical Research centre, Harare Zimbabwe