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

• Published in: eLife Vol. 7
• Main Authors: Mai, Nguyen T H, Dobbs, Nicholas, Phu, Nguyen Hoan, Colas, Romain A, Thao, Le T P, Thuong, Nguyen T T, Nghia, Ho D T, Hanh, Nguyen H H, Hang, Nguyen T, Heemskerk, A Dorothee, Day, Jeremy N, Ly, Lucy, Thu, Do D A, Merson, Laura, Kestelyn, Evelyne, Wolbers, Marcel, Geskus, Ronald, Summers, David, Chau, Nguyen V V, Dalli, Jesmond, Thwaites, Guy E
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 27.02.2018; eLife Sciences Publications, Ltd
• Subjects: Adult; Antitubercular Agents - administration & dosage; Antitubercular Agents - adverse effects; Aspirin; Aspirin - administration & dosage; Aspirin - adverse effects; Cerebral infarction; Cerebrospinal fluid; Chemotherapy; clinical trial; Combined Modality Therapy - adverse effects; Combined Modality Therapy - methods; Dexamethasone; Discriminant analysis; Double-Blind Method; Double-blind studies; Drug dosages; Drug-Related Side Effects and Adverse Reactions - epidemiology; Drug-Related Side Effects and Adverse Reactions - pathology; Female; Fibrinolytic Agents - administration & dosage; Fibrinolytic Agents - adverse effects; HIV; HIV Infections - complications; Human immunodeficiency virus; Humans; infarction; Inflammation; Intestine; Lipids; Magnetic resonance imaging; Male; Meningitis; Mental Disorders - epidemiology; Mental Disorders - prevention & control; Microbiology and Infectious Disease; Middle Aged; Mortality; Mycobacterium tuberculosis; Neuroimaging; NMR; Nuclear magnetic resonance; Placebos - administration & dosage; Software; Survival Analysis; Thrombosis; Thromboxane A2; Treatment Outcome; Tuberculosis; Tuberculosis, Meningeal - drug therapy; tuberculous meningitis; Ho Chi Minh City Vietnam; United Kingdom > UK; Vietnam; clinical trial; Mycobacterium tuberculosis; infectious disease; tuberculous meningitis; infarction; microbiology; aspirin; human
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.33478

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 (P = 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 A 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.