A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults
- Oxford University Clinical Research Unit, Viet Nam
- Western General Hospital, United Kingdom
- William Harvey Research Institute, United Kingdom
- University of Oxford, United Kingdom
Abstract
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 {greater than or equal to}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. Clinical trial registration: NCT02237365.
Article and author information
Author details
Funding
Wellcome (089276/E/09/Z)
- Guy E Thwaites
H2020 European Research Council (677542)
- Jesmond Dalli
St Bartholomews Charity (MGU0343)
- Jesmond Dalli
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Written informed consent to participate in the study was obtained from all participants or from their relatives if the participant could not provide consent due to incapacity.The trial was approved by the Oxford Tropical Research Ethics Committee and the Institutional Review Board of the Hospital for Tropical Diseases and the Ethical Committee of the Ministry of Health, Vietnam.
Copyright
© 2018, Mai et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults
eLife 7:e33478.
https://doi.org/10.7554/eLife.33478
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