A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults
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...
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| Published in | eLife Vol. 7 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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England
eLife Sciences Publications Ltd
27.02.2018
eLife Sciences Publications, Ltd |
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| 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 (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. |
|---|---|
| AbstractList | 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. 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. 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 heterogeneity = 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 2 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. The deadliest form of tuberculosis is tuberculosis meningitis (TBM), which causes inflammation in the brain. Even with the best treatment available, about half of patients with TBM become disabled or die, often because they have a stroke. Strokes are caused by blood clots or other blockages in blood vessels in the brain. Aspirin is known to prevent blood clots and helps reduce inflammation. Some scientists wonder if it might help patients with TBM by preventing blockages in blood vessels. Now, Nguyen et al. show that adding aspirin to existing TBM treatments may reduce strokes in some patients. In the experiments, 120 patients with TBM were randomly assigned to receive a low dose of aspirin (81 mg/day), a high dose of aspirin (1000mg/day), or an identical tablet that contained no medication. All the patients also took the anti-tuberculosis drugs and steroids usually used to treat the condition. Both doses of aspirin appeared to be safe. Patients who received aspirin were less likely to have a stroke or die in the first two months of treatment than patients who received the fake pill. But the difference was so small it could have been caused by chance. In the 92 patients with clear evidence of tuberculosis bacteria in their brains, the benefit of aspirin was larger and unlikely to be due to chance. The benefit was greatest for those who received the higher dose of aspirin, only 10.7% of these patients died or had a stroke, compared with 14.8% of those who received a low dose of aspirin, or 34% of those who received the fake pill. Next, Nguyen et al. looked at brain fluid taken from the TBM patients before and after they received the aspirin or fake medication. The experiments showed that patients treated with high dose aspirin had much lower levels of a clot-promoting substance called thromboxane A2 and more anti-inflammatory molecules. Larger studies are needed in children and adults to confirm that aspirin helps prevent strokes or death in patients with TBM. Studies are also needed on patients who have both TBM and HIV infections. But if more studies show aspirin is safe and effective, adding this medication to TBM treatment may be an inexpensive way to prevent death or disability. 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.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. |
| Author | Day, Jeremy N Dalli, Jesmond Wolbers, Marcel Thuong, Nguyen T T Nghia, Ho D T Dobbs, Nicholas Ly, Lucy Hang, Nguyen T Chau, Nguyen V V Mai, Nguyen T H Colas, Romain A Thao, Le T P Merson, Laura Geskus, Ronald Phu, Nguyen Hoan Thu, Do D A Kestelyn, Evelyne Heemskerk, A Dorothee Hanh, Nguyen H H Summers, David Thwaites, Guy E |
| Author_xml | – sequence: 1 givenname: Nguyen T H surname: Mai fullname: Mai, Nguyen T H organization: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam – sequence: 2 givenname: Nicholas surname: Dobbs fullname: Dobbs, Nicholas organization: Western General Hospital, Edinburgh, United Kingdom – sequence: 3 givenname: Nguyen Hoan surname: Phu fullname: Phu, Nguyen Hoan organization: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam – sequence: 4 givenname: Romain A surname: Colas fullname: Colas, Romain A organization: Lipid Mediator Unit, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom – sequence: 5 givenname: Le T P surname: Thao fullname: Thao, Le T P organization: Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam – sequence: 6 givenname: Nguyen T T surname: Thuong fullname: Thuong, Nguyen T T organization: Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam – sequence: 7 givenname: Ho D T surname: Nghia fullname: Nghia, Ho D T organization: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam – sequence: 8 givenname: Nguyen H H surname: Hanh fullname: Hanh, Nguyen H H organization: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam – sequence: 9 givenname: Nguyen T surname: Hang fullname: Hang, Nguyen T organization: Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam – sequence: 10 givenname: A Dorothee surname: Heemskerk fullname: Heemskerk, A Dorothee organization: Department of Medical Microbiology and Infection Control, VU medical centre, VU University Amsterdam, Amsterdam, Netherlands – sequence: 11 givenname: Jeremy N surname: Day fullname: Day, Jeremy N organization: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom – sequence: 12 givenname: Lucy surname: Ly fullname: Ly, Lucy organization: Lipid Mediator Unit, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom – sequence: 13 givenname: Do D A surname: Thu fullname: Thu, Do D A organization: Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam – sequence: 14 givenname: Laura orcidid: 0000-0002-4168-1960 surname: Merson fullname: Merson, Laura organization: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom – sequence: 15 givenname: Evelyne surname: Kestelyn fullname: Kestelyn, Evelyne organization: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom – sequence: 16 givenname: Marcel surname: Wolbers fullname: Wolbers, Marcel organization: Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam – sequence: 17 givenname: Ronald surname: Geskus fullname: Geskus, Ronald organization: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom – sequence: 18 givenname: David surname: Summers fullname: Summers, David organization: Western General Hospital, Edinburgh, United Kingdom – sequence: 19 givenname: Nguyen V V surname: Chau fullname: Chau, Nguyen V V organization: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam – sequence: 20 givenname: Jesmond surname: Dalli fullname: Dalli, Jesmond organization: Lipid Mediator Unit, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom – sequence: 21 givenname: Guy E orcidid: 0000-0002-2858-2087 surname: Thwaites fullname: Thwaites, Guy E organization: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29482717$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | 2018, Mai et al. 2018, Mai et al. This work is licensed under the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/3.0/ ) (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2018, Mai et al 2018 Mai et al |
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| DOI | 10.7554/eLife.33478 |
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| Keywords | clinical trial Mycobacterium tuberculosis infectious disease tuberculous meningitis infarction microbiology aspirin human |
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| References | 29560861 - Elife. 2018 Mar 21;7:e35906. doi: 10.7554/eLife.35906 36943904 - Elife. 2023 Mar 21;12:e87888. doi: 10.7554/eLife.87888 Hektoen (bib10) 1896; 1 Colas (bib6) 2014; 307 R Core Team (bib18) 2017 Botting (bib3) 2010; 62 Thwaites (bib25) 2004; 351 Byrne (bib4) 2007; 59 Ardito (bib2) 2001; 39 Walker (bib29) 2017; 31 Firth (bib8) 1993; 80 Spite (bib23) 2010; 107 Lammie (bib12) 2009; 59 Poltera (bib16) 1977; 77 Thuong (bib24) 2017; 215 Vane (bib27) 1971; 231 Agresti (bib1) 2002 Raju (bib19) 2011; 124 Schoeman (bib22) 2011; 26 Richman (bib20) 2017; 101 Vilaplana (bib28) 2013; 208 Heemskerk (bib9) 2016; 374 Wallis (bib30) 2016; 16 Misra (bib14) 2010; 293 Misra (bib15) 2011; 303 Prasad (bib17) 2016; 4 Kroesen (bib11) 2017; 8 Cilliers (bib5) 2015 Marais (bib13) 2010; 10 Doniach (bib7) 1949; 61 Ruslami (bib21) 2013; 13 Thwaites (bib26) 2013; 26 |
| References_xml | – volume: 10 start-page: 803 year: 2010 ident: bib13 article-title: Tuberculous meningitis: a uniform case definition for use in clinical research publication-title: The Lancet Infectious Diseases doi: 10.1016/S1473-3099(10)70138-9 contributor: fullname: Marais – volume: 215 start-page: 1020 year: 2017 ident: bib24 article-title: Leukotriene A4 hydrolase genotype and HIV infection influence intracerebral inflammation and survival from tuberculous meningitis publication-title: The Journal of Infectious Diseases doi: 10.1093/infdis/jix050 contributor: fullname: Thuong – volume: 61 start-page: 253 year: 1949 ident: bib7 article-title: Changes in the meningeal vessels in acute and chronic (streptomycin-treated) tuberculous meningitis publication-title: The Journal of Pathology and Bacteriology doi: 10.1002/path.1700610213 contributor: fullname: Doniach – volume: 351 start-page: 1741 year: 2004 ident: bib25 article-title: Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults publication-title: New England Journal of Medicine doi: 10.1056/NEJMoa040573 contributor: fullname: Thwaites – volume-title: R Foundation for Statistical Computing year: 2017 ident: bib18 article-title: R: A language and environment for statistical computing contributor: fullname: R Core Team – volume: 62 start-page: 518 year: 2010 ident: bib3 article-title: Vane's discovery of the mechanism of action of aspirin changed our understanding of its clinical pharmacology publication-title: Pharmacological Reports doi: 10.1016/S1734-1140(10)70308-X contributor: fullname: Botting – volume: 1 start-page: 112 year: 1896 ident: bib10 article-title: The vascular changes of tuberculous meningitis, especially the tuberculous endarterities publication-title: The Journal of Experimental Medicine doi: 10.1084/jem.1.1.112 contributor: fullname: Hektoen – volume: 59 start-page: 156 year: 2009 ident: bib12 article-title: Tuberculous cerebrovascular disease: a review publication-title: Journal of Infection doi: 10.1016/j.jinf.2009.07.012 contributor: fullname: Lammie – volume: 80 start-page: 27 year: 1993 ident: bib8 article-title: Bias reduction of maximum likelihood estimates publication-title: Biometrika doi: 10.1093/biomet/80.1.27 contributor: fullname: Firth – volume: 59 start-page: 313 year: 2007 ident: bib4 article-title: Aspirin and ibuprofen enhance pyrazinamide treatment of murine tuberculosis publication-title: Journal of Antimicrobial Chemotherapy doi: 10.1093/jac/dkl486 contributor: fullname: Byrne – volume: 77 start-page: 12 year: 1977 ident: bib16 article-title: Thrombogenic intracranial vasculitis in tuberculous meningitis. A 20 year "post mortem" survey publication-title: Acta neurologica Belgica contributor: fullname: Poltera – volume: 16 start-page: e34 year: 2016 ident: bib30 article-title: Tuberculosis--advances in development of new drugs, treatment regimens, host-directed therapies, and biomarkers publication-title: The Lancet Infectious Diseases doi: 10.1016/S1473-3099(16)00070-0 contributor: fullname: Wallis – volume: 26 start-page: 956 year: 2011 ident: bib22 article-title: The role of aspirin in childhood tuberculous meningitis publication-title: Journal of Child Neurology doi: 10.1177/0883073811398132 contributor: fullname: Schoeman – volume: 374 start-page: 124 year: 2016 ident: bib9 article-title: Intensified antituberculosis therapy in adults with tuberculous meningitis publication-title: New England Journal of Medicine doi: 10.1056/NEJMoa1507062 contributor: fullname: Heemskerk – volume: 8 year: 2017 ident: bib11 article-title: Non-Steroidal Anti-inflammatory Drugs As Host-Directed Therapy for Tuberculosis: A Systematic Review publication-title: Frontiers in Immunology doi: 10.3389/fimmu.2017.00772 contributor: fullname: Kroesen – volume: 13 start-page: 27 year: 2013 ident: bib21 article-title: Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial publication-title: The Lancet Infectious Diseases doi: 10.1016/S1473-3099(12)70264-5 contributor: fullname: Ruslami – volume: 231 start-page: 232 year: 1971 ident: bib27 article-title: Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs publication-title: Nature New Biology doi: 10.1038/newbio231232a0 contributor: fullname: Vane – volume-title: Categorical Data Analysis year: 2002 ident: bib1 doi: 10.1002/0471249688 contributor: fullname: Agresti – volume: 31 start-page: 3636 year: 2017 ident: bib29 article-title: 13-Series resolvins mediate the leukocyte-platelet actions of atorvastatin and pravastatin in inflammatory arthritis publication-title: The FASEB Journal doi: 10.1096/fj.201700268 contributor: fullname: Walker – volume: 4 start-page: CD002244 year: 2016 ident: bib17 article-title: Corticosteroids for managing tuberculous meningitis publication-title: Cochrane Database of Systematic Reviews doi: 10.1002/14651858.CD002244.pub4 contributor: fullname: Prasad – volume: 303 start-page: 22 year: 2011 ident: bib15 article-title: Stroke in tuberculous meningitis publication-title: Journal of the Neurological Sciences doi: 10.1016/j.jns.2010.12.015 contributor: fullname: Misra – year: 2015 ident: bib5 article-title: Anti-inflammatory treatment for carditis in acute rheumatic fever publication-title: Cochrane Database of Systematic Reviews doi: 10.1002/14651858.CD003176.pub3 contributor: fullname: Cilliers – volume: 293 start-page: 12 year: 2010 ident: bib14 article-title: Role of aspirin in tuberculous meningitis: a randomized open label placebo controlled trial publication-title: Journal of the Neurological Sciences doi: 10.1016/j.jns.2010.03.025 contributor: fullname: Misra – volume: 107 start-page: 1170 year: 2010 ident: bib23 article-title: Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins publication-title: Circulation Research doi: 10.1161/CIRCRESAHA.110.223883 contributor: fullname: Spite – volume: 307 start-page: C39 year: 2014 ident: bib6 article-title: Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue publication-title: American Journal of Physiology-Cell Physiology doi: 10.1152/ajpcell.00024.2014 contributor: fullname: Colas – volume: 208 start-page: 199 year: 2013 ident: bib28 article-title: Ibuprofen therapy resulted in significantly decreased tissue bacillary loads and increased survival in a new murine experimental model of active tuberculosis publication-title: The Journal of Infectious Diseases doi: 10.1093/infdis/jit152 contributor: fullname: 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of Medicine doi: 10.1016/j.amjmed.2011.01.018 contributor: fullname: Raju |
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| SubjectTerms | 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 |
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| Title | A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults |
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