Background: Adjunctive dexamethasone reduces mortality from tuberculous meningitis (TBM) but not disability, which is associated with brain infarction. We hypothesised that aspirin prevents TBM-related brain infarction through its anti-thrombotic, anti-inflammatory, and pro-resolution properties. Methods: We conducted a randomised controlled trial in HIV-uninfected adults with TBM of daily aspirin 81mg or 1000mg, or placebo, added to the first 60 days of anti-tuberculosis drugs and dexamethasone (NCT02237365). The primary safety endpoint was gastro-intestinal or cerebral bleeding by 60 days; the primary efficacy endpoint was new brain infarction confirmed by magnetic resonance imaging or death by 60 days. Secondary endpoints included 8-month survival and neuro-disability; the number of grade 3&4 and serious adverse events; and cerebrospinal fluid (CSF) inflammatory lipid mediator profiles. Findings: 41 participants were randomised to placebo, 39 to aspirin 81mg/day, and 40 to aspirin 1000mg/day between October 2014 and May 2016. TBM was proven microbiologically in 92/120(76.7%) and baseline brain imaging revealed ≥1 infarct in 40/114(35.1%) participants. The primary safety outcome occurred in 5/36(13.9%) given placebo, and in 8/35(22.9%) and 8/40(20.0%) given 81mg and 1000mg aspirin respectively (P=0.59). The primary efficacy outcome occurred in 11/38(28.9%) given placebo, 8/36(22.2%) given aspirin 81mg, and 6/38(15.8%) given 1000mg aspirin (P=0.40). Planned subgroup analysis showed a significant interaction between aspirin treatment effect and diagnostic category (Pheterogeneity=0.01) and suggested a potential reduction in new infarcts and deaths by day 60 in the aspirin treated participants with microbiologically confirmed TBM (11/32(34.4%) events in placebo vs. 4/27(14.8%) in aspirin 81 mg vs. 3/28 (10.7%) in aspirin 1000mg; P=0.06). CSF analysis demonstrated aspirin dose-dependent inhibition of thromboxane A2 and upregulation of pro-resolving CSF protectins. Interpretation: The addition of aspirin to dexamethasone may improve outcomes from TBM and warrants investigation in a large phase 3 trial.</p
