Clinical trial NCT02237365: A Pilot Study of Adjunctive Aspirin for the Treatment of HIV Negative Adults With Tuberculous Meningitis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Tuberculous Meningitis
Keywords: neurological disability
tuberculous meningitis (TBM)
safety
aspirin
efficacy
Lead sponsor: Oxford University Clinical Research Unit, Vietnam
Sponsor class: OTHER
Collaborators: name: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
First posted: 2014-09-11
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of episodes of either cerebral bleeding or clinically significant upper-gastro-intestinal bleeding (composite endpoint)
timeFrame: 60 days
measure: Number of episodes of MRI-proven brain infarction or death (composite endpoint)
timeFrame: 60 days
Secondary outcomes:
measure: Time to death
timeFrame: 240 days
measure: Number of grade 3&4 and serious adverse events
timeFrame: 60 days
measure: Duration of hospital stay
timeFrame: 240 days
measure: Neurological disability score
timeFrame: 60 days
measure: Neurological disability score
timeFrame: 240 days
measure: Resolution of cerebrospinal fluid (CSF) inflammation
timeFrame: 30 days
measure: Antimicrobial activity of peripheral blood monocyte/macrophages
timeFrame: 240 days
measure: Proportion of patients with MRI-proven brain infarction
timeFrame: 240 days
Other outcomes:
Locations:
city: Ho Chi Minh City
country: Vietnam
facility: Hospital for Tropical Diseases
Study officials:
affiliation: Oxford University of Clinical Research
name: Guy Thwaites, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
name: Nguyen H Phu, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mai NTH, Dobbs N, Phu NH, Colas RA, Thao LTP, Thuong NTT, Nghia HDT, Hanh NHH, Hang NT, Heemskerk AD, Day JN, Ly L, Thu DDA, Merson L, Kestelyn E, Wolbers M, Geskus R, Summers D, Chau NVV, Dalli J, Thwaites GE. A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults. Elife. 2018 Feb 27;7:e33478. doi: 10.7554/eLife.33478.