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.

Proresolving mediator profiles in cerebrospinal fluid are linked with disease severity and outcome in adults with tuberculous meningitis

“…In order to determine whether there was a relationship between CSF lipid mediator concentrations and disease severity in TBM, we investigated baseline lipid mediator profiles of patients recruited to the aspirin TBM study (NCT02237365) (14). Here, CSF was collected from enrolled patients with known or suspected TBM just prior to the start of treatment in a randomized comparison of aspirin vs. placebo as an adjunct to dexamethasone administration for the first 60 d of TBM treatment (14). Disease severity was assessed using the MRC grade (22), which uses Glasgow coma score and focal neurologic deficits to categorize disease severity as mild (grade 1), moderate (grade 2), or severe (grade 3).…”

“…We recently reported that treatment with aspirin, dexamethasone, and antituberculosis drugs was associated with reduction in new brain infarcts and deaths within 60 d in patients with microbiologically confirmed TBM (14). Therefore, we investigated the impact of aspirin cotreatment with dexamethasone and antituberculosis drugs on CSF lipid mediator pathways in this patient subpopulation (see Supplemental Table S7 for demographics and baseline characteristics).…”

Pro-Resolving Mediator Profiles And 5-Lipoxygenase Activity In Cerebrospinal Fluid Correlate with Disease Severity and Outcome in Adults with Tuberculous Meningitis

“…In order to determine whether there was a relationship between CSF lipid mediator concentrations and disease severity in TBM we investigated lipid mediator profiles of patients recruited to the Aspirin TBM study (NCT02237365). Here CSF was collected from enrolled patients with known or suspected TBM just prior to the start of treatment in a randomised comparison of aspirin versus placebo as an adjunct to dexamethasone administration for the first 60 days of TBM treatment (14). Disease severity was assessed using the Medical Research Council grade (15) that uses Glasgow coma score and focal neurological deficits to categorise disease severity as mild (grade 1), moderate (grade 2), or severe (grade 3; See Supplemental Table 1 for patient information).…”

“…We recently tested the hypothesis that the addition of aspirin to standard TBM treatment (anti-tuberculosis drugs and corticosteroids) may further improve outcomes by inhibiting thromboxane A 2 (TxA 2 ) and preventing brain infarcts (a common life-threatening complication of TBM), and by enhancing the resolution of intra-cerebral inflammation through the increased expression of SPMs (14). The trial found that in patients with microbiologically confirmed TBM, aspirin was associated with reduced brain infarcts and/or death in the first 60 days of treatment.…”

Mesenchymal stem cells (MSCs) offer a drug tolerant and immune- privileged niche to Mycobacterium tuberculosis

“…PGE2 is also known to inhibit anti-bacterial effector functions of phagocytes including phagocytosis, NO production, lysosomal killing and antigen presentation 69 . Incidentally aspirin is currently in clinical trial as adjunct therapy against tuberculosis meningitis in adults 71 . COX2 inhibitors specially non-steroid anti-inflammatory drugs (NSAIDs) like aspirin, ibuprofen, rofecoxib, celecoxib etc.…”