A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults

Abstract

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. We conducted a randomised controlled trial in HIV-uninfected adults with TBM of daily aspirin 81 mg or 1000 mg, 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 and 4 and serious adverse events; and cerebrospinal fluid (CSF) inflammatory lipid mediator profiles. 41 participants were randomised to placebo, 39 to aspirin 81 mg/day, and 40 to aspirin 1000 mg/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 81 mg and 1000 mg aspirin, respectively (p=0.59). The primary efficacy outcome occurred in 11/38 (28.9%) given placebo, 8/36 (22.2%) given aspirin 81 mg, and 6/38 (15.8%) given 1000 mg 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 1000 mg; p=0.06). CSF analysis demonstrated aspirin dose-dependent inhibition of thromboxane A2 and upregulation of pro-resolving CSF protectins. The addition of aspirin to dexamethasone may improve outcomes from TBM and warrants investigation in a large phase 3 trial.

Keywords: Mycobacterium tuberculosis; aspirin; clinical trial; human; infarction; infectious disease; microbiology; tuberculous meningitis.

Conflict of interest statement

NM, ND, NP, RC, LT, NT, HN, NH, NH, AH, JD, LL, DT, LM, EK, MW, RG, DS, NC, JD, GT No competing interests declared

© 2018, Mai et al.

Figures

Figure 1.. Participant flow through the trial.

Figure 2.. Forest plots of ITT, per-protocol and planned sub-group analysis of aspirin 81 mg versus placebo (A) and aspirin 1000 mg versus placebo (B) for the primary efficacy outcome.

Estimates for subgroups without events were obtained via Firth’s penalized likelihood. Panels show 8 month survival plots for the ITT (C) and per-protocol (D) populations.

Figure 2—figure supplement 1.. C (panel within Figure 2).

ITT population survival in each group over 8 months.

Figure 2—figure supplement 2.. D (panel within Figure 2).

Per-protocol population survival in each group over 8 months.

Figure 3.. LCMS lipid mediator profiles in the CSF of adults with TBM according to treatment with aspirin or placebo.

CSF was collected from participants at baseline and 30 days after 81 mg, 1000 mg or placebo administration. (A) Partial least squares discriminant analysis 2-dimensional score plot of the distinct LM-SPM profiles identified in day 30 CSF at the indicated intervals (top panel) and corresponding 2-dimensional loading plot. Grey ellipse in the score plots denotes estimated 95% probability regions (bottom panel). Grey circles in the loading plot represent LM with a variable in importance score ≥ 1. (B) Relative regulation of Thromboxane B2 (the stable TXA2 further metabolite), Prostaglandins (PGD2, PGE2, PGF2) and Protectins (PD1, 17R-PD1, 22-OH-PD1, 10S, 17S-diHDHA, PCTR1, PCTR2 and PCTR3) by day 30 compared to baseline values (absolute values given in supplementary file 6). Results for B are mean ± s.e.m, n = 30 for placebo, n = 26 for 81 mg and n = 26 for 1000 mg group. Comparisons between treatment groups assessed using one-way ANOVA followed by multiple comparisons test. Only p-values<0.05 given in the figure (all other comparisons non-significant).

Figure 3—figure supplement 1.. Lipid mediator profiles of CSF from participants with TBM.

Lipid mediators (LM) were extracted, identified and quantified using LM profiling. (A,B) Multiple reaction monitoring chromatograms for identified mediators. (C) tandem mass fragmentation spectra employed in the identification of PD1 and 15-epi-LXA4. Results are representative of 82 patients.