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

Nguyen Th Mai, Nicholas Dobbs, Nguyen Hoan Phu, Romain A. Colas, Le Tp Thao, Nguyen Tt Thuong, Ho Dt Nghia, Nguyen Hh Hanh, Nguyen T. Hang, A. Dorothee Heemskerk, Jeremy N. Day, Lucy Ly, Do DA Thu, Laura Merson, Evelyne Kestelyn, Marcel Wolbers, Ronald Geskus, David Summers, Nguyen Vv Chau, Jesmond Dalli & 1 others Guy E. Thwaites

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13 Citations (Scopus)

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.

Original languageEnglish
JournaleLife
Volume7
DOIs
Publication statusPublished - 27 Feb 2018
Externally publishedYes

Keywords

  • aspirin
  • clinical trial
  • human
  • infarction
  • infectious disease
  • microbiology
  • Mycobacterium tuberculosis
  • tuberculous meningitis

Cite this

Mai, Nguyen Th ; Dobbs, Nicholas ; Phu, Nguyen Hoan ; Colas, Romain A. ; Thao, Le Tp ; Thuong, Nguyen Tt ; Nghia, Ho Dt ; Hanh, Nguyen Hh ; Hang, Nguyen T. ; Heemskerk, A. Dorothee ; Day, Jeremy N. ; Ly, Lucy ; Thu, Do DA ; Merson, Laura ; Kestelyn, Evelyne ; Wolbers, Marcel ; Geskus, Ronald ; Summers, David ; Chau, Nguyen Vv ; Dalli, Jesmond ; Thwaites, Guy E. / A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults. In: eLife. 2018 ; Vol. 7.
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title = "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 = "aspirin, clinical trial, human, infarction, infectious disease, microbiology, Mycobacterium tuberculosis, tuberculous meningitis",
author = "Mai, {Nguyen Th} and Nicholas Dobbs and Phu, {Nguyen Hoan} and Colas, {Romain A.} and Thao, {Le Tp} and Thuong, {Nguyen Tt} and Nghia, {Ho Dt} and Hanh, {Nguyen Hh} and Hang, {Nguyen T.} and Heemskerk, {A. Dorothee} and Day, {Jeremy N.} and Lucy Ly and Thu, {Do DA} and Laura Merson and Evelyne Kestelyn and Marcel Wolbers and Ronald Geskus and David Summers and Chau, {Nguyen Vv} and Jesmond Dalli and Thwaites, {Guy E.}",
year = "2018",
month = "2",
day = "27",
doi = "10.7554/eLife.33478",
language = "English",
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journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications, Ltd",

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Mai, NT, Dobbs, N, Phu, NH, Colas, RA, Thao, LT, Thuong, NT, Nghia, HD, Hanh, NH, Hang, NT, Heemskerk, AD, Day, JN, Ly, L, Thu, DDA, Merson, L, Kestelyn, E, Wolbers, M, Geskus, R, Summers, D, Chau, NV, Dalli, J & Thwaites, GE 2018, 'A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults', eLife, vol. 7. https://doi.org/10.7554/eLife.33478

A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults. / Mai, Nguyen Th; Dobbs, Nicholas; Phu, Nguyen Hoan; Colas, Romain A.; Thao, Le Tp; Thuong, Nguyen Tt; Nghia, Ho Dt; Hanh, Nguyen Hh; Hang, Nguyen T.; Heemskerk, A. Dorothee; Day, Jeremy N.; Ly, Lucy; Thu, Do DA; Merson, Laura; Kestelyn, Evelyne; Wolbers, Marcel; Geskus, Ronald; Summers, David; Chau, Nguyen Vv; Dalli, Jesmond; Thwaites, Guy E.

In: eLife, Vol. 7, 27.02.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults

AU - Mai, Nguyen Th

AU - Dobbs, Nicholas

AU - Phu, Nguyen Hoan

AU - Colas, Romain A.

AU - Thao, Le Tp

AU - Thuong, Nguyen Tt

AU - Nghia, Ho Dt

AU - Hanh, Nguyen Hh

AU - Hang, Nguyen T.

AU - Heemskerk, A. Dorothee

AU - Day, Jeremy N.

AU - Ly, Lucy

AU - Thu, Do DA

AU - Merson, Laura

AU - Kestelyn, Evelyne

AU - Wolbers, Marcel

AU - Geskus, Ronald

AU - Summers, David

AU - Chau, Nguyen Vv

AU - Dalli, Jesmond

AU - Thwaites, Guy E.

PY - 2018/2/27

Y1 - 2018/2/27

N2 - 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.

AB - 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.

KW - aspirin

KW - clinical trial

KW - human

KW - infarction

KW - infectious disease

KW - microbiology

KW - Mycobacterium tuberculosis

KW - tuberculous meningitis

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JF - eLife

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