dc.contributor.author | Mai, NT | en_US |
dc.contributor.author | Dobbs, N | en_US |
dc.contributor.author | Phu, NH | en_US |
dc.contributor.author | Colas, RA | en_US |
dc.contributor.author | Thao, LT | en_US |
dc.contributor.author | Thuong, NT | en_US |
dc.contributor.author | Nghia, HD | en_US |
dc.contributor.author | Hanh, NH | en_US |
dc.contributor.author | Hang, NT | en_US |
dc.contributor.author | Heemskerk, AD | en_US |
dc.contributor.author | Day, JN | en_US |
dc.contributor.author | Ly, L | en_US |
dc.contributor.author | Thu, DDA | en_US |
dc.contributor.author | Merson, L | en_US |
dc.contributor.author | Kestelyn, E | en_US |
dc.contributor.author | Wolbers, M | en_US |
dc.contributor.author | Geskus, R | en_US |
dc.contributor.author | Summers, D | en_US |
dc.contributor.author | Chau, NV | en_US |
dc.contributor.author | Dalli, J | en_US |
dc.contributor.author | Thwaites, GE | en_US |
dc.date.accessioned | 2018-04-30T14:45:29Z | |
dc.date.available | 2018-02-12 | en_US |
dc.date.issued | 2018-02-27 | en_US |
dc.date.submitted | 2018-03-10T09:01:06.292Z | |
dc.identifier.uri | http://qmro.qmul.ac.uk/xmlui/handle/123456789/36601 | |
dc.description.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. | en_US |
dc.description.sponsorship | H2020 European Research Council 677542,
St Bartholomews Charity MGU0343,
Wellcome Trust 110179/Z/15/Z,
Wellcome Trust 106680/Z/14/Z. | en_US |
dc.language | eng | en_US |
dc.language.iso | en | en_US |
dc.relation.ispartof | Elife | en_US |
dc.subject | Mycobacterium tuberculosis | en_US |
dc.subject | aspirin | en_US |
dc.subject | clinical trial | en_US |
dc.subject | human | en_US |
dc.subject | infarction | en_US |
dc.subject | infectious disease | en_US |
dc.subject | microbiology | en_US |
dc.subject | tuberculous meningitis | en_US |
dc.subject | Adult | en_US |
dc.subject | Antitubercular Agents | en_US |
dc.subject | Aspirin | en_US |
dc.subject | Combined Modality Therapy | en_US |
dc.subject | Double-Blind Method | en_US |
dc.subject | Drug-Related Side Effects and Adverse Reactions | en_US |
dc.subject | Female | en_US |
dc.subject | Fibrinolytic Agents | en_US |
dc.subject | HIV Infections | en_US |
dc.subject | Humans | en_US |
dc.subject | Male | en_US |
dc.subject | Mental Disorders | en_US |
dc.subject | Middle Aged | en_US |
dc.subject | Placebos | en_US |
dc.subject | Survival Analysis | en_US |
dc.subject | Treatment Outcome | en_US |
dc.subject | Tuberculosis, Meningeal | en_US |
dc.title | A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults. | en_US |
dc.type | Article | |
dc.rights.holder | (c) Mai et al. | |
dc.identifier.doi | 10.7554/eLife.33478 | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/29482717 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published online | en_US |
pubs.volume | 7 | en_US |
dcterms.dateAccepted | 2018-02-12 | en_US |
qmul.funder | Sir Henry Dale Fellowship::Wellcome Trust | en_US |
qmul.funder | Sir Henry Dale Fellowship::Wellcome Trust | en_US |
qmul.funder | Sir Henry Dale Fellowship::Wellcome Trust | en_US |