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

  1. Nguyen TH Mai
  2. Nicholas Dobbs
  3. Nguyen Hoan Phu
  4. Romain A Colas
  5. Le TP Thao
  6. Nguyen TT Thuong
  7. Ho DT Nghia
  8. Nguyen HH Hanh
  9. Nguyen T Hang
  10. A Dorothee Heemskerk
  11. Jeremy N Day
  12. Lucy Ly
  13. Do DA Thu
  14. Laura Merson
  15. Evelyne Kestelyn
  16. Marcel Wolbers
  17. Ronald Geskus
  18. David Summers
  19. Nguyen VV Chau
  20. Jesmond Dalli
  21. Guy E Thwaites  Is a corresponding author
  1. Oxford University Clinical Research Unit, Viet Nam
  2. Western General Hospital, United Kingdom
  3. William Harvey Research Institute, United Kingdom
  4. University of Oxford, United Kingdom

Abstract

Background 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. Methods We conducted a randomised controlled trial in HIV-uninfected adults with TBM of daily aspirin 81mg or 1000mg, 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&4 and serious adverse events; and cerebrospinal fluid (CSF) inflammatory lipid mediator profiles. Findings 41 participants were randomised to placebo, 39 to aspirin 81mg/day, and 40 to aspirin 1000mg/day between October 2014 and May 2016. TBM was proven microbiologically in 92/120(76.7%) and baseline brain imaging revealed {greater than or equal to}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 81mg and 1000mg aspirin respectively (P=0.59). The primary efficacy outcome occurred in 11/38(28.9%) given placebo, 8/36(22.2%) given aspirin 81mg, and 6/38(15.8%) given 1000mg 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 1000mg; P=0.06). CSF analysis demonstrated aspirin dose-dependent inhibition of thromboxane A2 and upregulation of pro-resolving CSF protectins. Interpretation The addition of aspirin to dexamethasone may improve outcomes from TBM and warrants investigation in a large phase 3 trial. Clinical trial registration: NCT02237365.

Article and author information

Author details

  1. Nguyen TH Mai

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  2. Nicholas Dobbs

    Western General Hospital, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Nguyen Hoan Phu

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  4. Romain A Colas

    Lipid Mediator Unit, William Harvey Research Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Le TP Thao

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  6. Nguyen TT Thuong

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  7. Ho DT Nghia

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  8. Nguyen HH Hanh

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  9. Nguyen T Hang

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  10. A Dorothee Heemskerk

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  11. Jeremy N Day

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  12. Lucy Ly

    Lipid Mediator Unit, William Harvey Research Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Do DA Thu

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  14. Laura Merson

    Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4168-1960
  15. Evelyne Kestelyn

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  16. Marcel Wolbers

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  17. Ronald Geskus

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  18. David Summers

    Western General Hospital, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  19. Nguyen VV Chau

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  20. Jesmond Dalli

    Lipid Mediator Unit, William Harvey Research Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  21. Guy E Thwaites

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    For correspondence
    gthwaites@oucru.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2858-2087

Funding

Wellcome (089276/E/09/Z)

  • Guy E Thwaites

H2020 European Research Council (677542)

  • Jesmond Dalli

St Bartholomews Charity (MGU0343)

  • Jesmond Dalli

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Madhukar Pai, McGill University, Canada

Ethics

Human subjects: Written informed consent to participate in the study was obtained from all participants or from their relatives if the participant could not provide consent due to incapacity.The trial was approved by the Oxford Tropical Research Ethics Committee and the Institutional Review Board of the Hospital for Tropical Diseases and the Ethical Committee of the Ministry of Health, Vietnam.

Version history

  1. Received: November 10, 2017
  2. Accepted: February 12, 2018
  3. Accepted Manuscript published: February 27, 2018 (version 1)
  4. Version of Record published: March 21, 2018 (version 2)
  5. Version of Record updated: March 21, 2023 (version 3)

Copyright

© 2018, Mai et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Nguyen TH Mai
  2. Nicholas Dobbs
  3. Nguyen Hoan Phu
  4. Romain A Colas
  5. Le TP Thao
  6. Nguyen TT Thuong
  7. Ho DT Nghia
  8. Nguyen HH Hanh
  9. Nguyen T Hang
  10. A Dorothee Heemskerk
  11. Jeremy N Day
  12. Lucy Ly
  13. Do DA Thu
  14. Laura Merson
  15. Evelyne Kestelyn
  16. Marcel Wolbers
  17. Ronald Geskus
  18. David Summers
  19. Nguyen VV Chau
  20. Jesmond Dalli
  21. Guy E Thwaites
(2018)
A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults
eLife 7:e33478.
https://doi.org/10.7554/eLife.33478

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