A Pilot Study of Adjunctive Aspirin for the Treatment of HIV Negative Adults With Tuberculous Meningitis

Study Overview
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Brief Summary
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Tuberculous meningitis is a severe brain infection which often causes disability and death even when treated with the best available treatment. Aspirin is a type of anti-inflammation drug which can reduce the inflammatory response in brains of patients with tuberculous meningitis, and therefore may decrease some of the most severe outcomes. This study compares the use of aspirin (at 2 different doses) versus placebo as an additional therapy to the standard treatment to see if aspirin is safe and helpful in reducing disability and death from tuberculous meningitis. Patients will be treated with aspirin or placebo for 60 days and followed up while on standard treatment for 8 months.

Detailed Description
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The study is a parallel group, double blind, randomised, placebo controlled trial of 60 days treatment with placebo vs. 81mg daily dose vs. 1000mg daily dose aspirin for the treatment of HIV-uninfected adults with tuberculous meningitis. All patients will receive standard anti-tuberculous chemotherapy and adjunctive dexamethasone, according to Viet Nam National Tuberculosis Programme guidelines. Participants will be stratified by Medical Research Council UK disease severity grade, and randomized at enrollment to one of three study arms (1:1:1 ratio). Patients will be admitted to hospital for at least the first 14 days of study treatment enabling real-time active surveillance of any adverse events after which they will be discharged according to clinical care with continued monitoring. A schedule of clinical and laboratory monitoring including lumbar puncture, pharmacokinetic assessment of peripheral blood monocyte/macrophage antimicrobial activity, clinical assessments, brain magnetic resonance imaging (MRI) and neurological assessment will manage patient safety and capture study outcomes.

Official Title
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A Pilot Phase II Randomized Controlled Double Blind Trial of 81mg Aspirin Daily vs. 1000 mg Aspirin Daily vs. Placebo as Adjunctive Therapy in HIV Negative Adults With Tuberculous Meningitis

Conditions
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Tuberculous Meningitis

Intervention / Treatment
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* Drug: 81mg aspirin
* Drug: 1000mg aspirin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged 18 years or above. Suspected TBM and anti-tuberculosis chemotherapy either planned or started Less than 3 days of anti-tuberculosis chemotherapy taken for the current infection Patient or representative (if the patient is unable) is willing and able to give informed consent for participation in the study. Exclusion Criteria: HIV infection (negative rapid test or Elisa test is required) Unlikely, for any reason, to be able to have an MRI brain scan within 5 days (120 hours) of randomisation Known or suspected infection with multi-drug resistant tuberculosis (resistant to at least isoniazid and rifampicin) Unable to take isoniazid, rifampicin, or pyrazinamide at recommended doses for any reason History of diagnosed peptic ulceration or gastro-intestinal bleeding Active gastro-intestinal bleeding is suspected Taken >1 dose of aspirin (at any dose) or any other non-steroidal anti-inflammatory drugs for any reason within 2 weeks of screening Aspirin considered mandatory for any reason by the attending physician Aspirin considered to be contraindicated for any reason by the attending physician Pregnancy or breast feeding (negative urine pregnancy test for all females of child-bearing age) Dexamethasone considered to be contraindicated for any reason by the attending physician Any other significant disease or disorder which, in the opinion of the investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 81mg aspirin<br>Aspirin 81mg daily for 60 days | Drug: 81mg aspirin<br>* 1 tablet of 81mg aspirin and 2 tablets of placebo (visually matched to 500mg aspirin) daily for 60 days<br>|
| Experimental: 1000mg aspirin<br>Aspirin 1000mg daily for 60 days | Drug: 1000mg aspirin<br>* 1 tablet of 81mg placebo (visually matched to 81mg aspirin) and 2 tablets of 500mg aspirin daily for 60 days<br>|
| Placebo Comparator: Placebo<br>Visually matched placebo daily for 60 days | Drug: Placebo<br>* 1 tablet of 81mg placebo (visually matched to 81mg aspirin) and 2 tablets of 500mg placebo (visually matched to 500mg aspirin) daily for 60 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of episodes of either cerebral bleeding or clinically significant upper-gastro-intestinal bleeding (composite endpoint) | Primary Safety Endpoint: Number of episodes of: Cerebral bleeding confirmed by brain imaging and/or Clinically significant upper-gastro-intestinal bleeding, defined as: a) Vomiting fresh or changed blood of any volume; b) Melena; c) Unexplained drop in haemoglobin concentration of >2g/L or; d) Greater than 5mls of fresh or changed blood aspirated from nasogastric tube | 60 days | 
| Number of episodes of MRI-proven brain infarction or death (composite endpoint) | Primary Efficacy Endpoint: Number of episodes of MRI-proven brain infarction and/or Death | 60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to death |  | 240 days | 
| Number of grade 3&4 and serious adverse events | Graded according to Common Terminology Criteria for Adverse Events (CTCAE) definitions | 60 days | 
| Duration of hospital stay | Number of days admitted to hospital during the study period | 240 days | 
| Neurological disability score | Assessed by the modified Rankin score and Glasgow outcome score | 60 days | 
| Neurological disability score | Assessed by the modified Rankin score and Glasgow outcome score | 240 days | 
| Resolution of cerebrospinal fluid (CSF) inflammation | Evaluated by measurement of CSF leucocytes, protein, glucose, cytokines (TNF-α, IL-1β, IL-8, IL-10, IFNγ) and eicosanoids (15-epi-Lipoxin, Lipoxin A4, LTB4, PGE2, TBXB2, PGD2) | 30 days | 
| Antimicrobial activity of peripheral blood monocyte/macrophages | Difference between measured antimicrobial activity at baseline and 240 days | 240 days | 
| Proportion of patients with MRI-proven brain infarction |  | 240 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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safety, neurological disability, tuberculous meningitis (TBM), aspirin, efficacy