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

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

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.

Study Overview

• Status: Completed
• Conditions: Tuberculous Meningitis
• Intervention / Treatment: Drug: 81mg aspirin; Drug: 1000mg aspirin; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

• Vietnam
  • Ho Chi Minh City, Vietnam
    • Hospital for Tropical Diseases

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Oxford University Clinical Research Unit, Vietnam
• Collaborators: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
• Investigators: Principal Investigator: Guy Thwaites, MD, PhD, Oxford University of Clinical Research; Principal Investigator: Nguyen H Phu, MD, PhD, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam

Publications and helpful links

General Publications

• 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 DD, Merson L, Kestelyn E, Wolbers M, Geskus R, Summers D, Chau NV, 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.

Helpful Links

• Oxford University Clinical Research Unit, Viet Nam

Study record dates

Study Major Dates

• Study Start (Actual): October 17, 2014
• Primary Completion (Actual): June 24, 2016
• Study Completion (Actual): December 22, 2016

Study Registration Dates

• First Submitted: September 9, 2014
• First Submitted That Met QC Criteria: September 9, 2014
• First Posted (Estimate): September 11, 2014

Study Record Updates

• Last Update Posted (Actual): March 7, 2017
• Last Update Submitted That Met QC Criteria: March 5, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: safety; efficacy; aspirin; neurological disability; tuberculous meningitis (TBM)
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Infections; Central Nervous System Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Meningitis, Bacterial; Central Nervous System Bacterial Infections; Tuberculosis, Central Nervous System; Tuberculosis; Meningitis; Tuberculosis, Meningeal; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin
• Other Study ID Numbers: 23TB