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

• ClinicalTrials.gov Identifier: NCT02237365
• Recruitment Status: Completed
• First Posted: September 11, 2014
• Last Update Posted: March 7, 2017
• Sponsor: Oxford University Clinical Research Unit, Vietnam
• Collaborator: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
• Information provided by (Responsible Party): Oxford University Clinical Research Unit, Vietnam

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Tuberculous Meningitis	Drug: 81mg aspirin; Drug: 1000mg aspirin; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: October 17, 2014
• Actual Primary Completion Date: June 24, 2016
• Actual Study Completion Date: December 22, 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Number of episodes of either cerebral bleeding or clinically significant upper-gastro-intestinal bleeding (composite endpoint) [ Time Frame: 60 days ]

   Primary Safety Endpoint: Number of episodes of:

   1. Cerebral bleeding confirmed by brain imaging and/or
   2. 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
2. Number of episodes of MRI-proven brain infarction or death (composite endpoint) [ Time Frame: 60 days ]

   Primary Efficacy Endpoint: Number of episodes of

   1. MRI-proven brain infarction and/or
   2. Death

Secondary Outcome Measures :

1. Time to death [ Time Frame: 240 days ]
2. Number of grade 3&4 and serious adverse events [ Time Frame: 60 days ]
   Graded according to Common Terminology Criteria for Adverse Events (CTCAE) definitions
3. Duration of hospital stay [ Time Frame: 240 days ]
   Number of days admitted to hospital during the study period
4. Neurological disability score [ Time Frame: 60 days ]
   Assessed by the modified Rankin score and Glasgow outcome score
5. Neurological disability score [ Time Frame: 240 days ]
   Assessed by the modified Rankin score and Glasgow outcome score
6. Resolution of cerebrospinal fluid (CSF) inflammation [ Time Frame: 30 days ]
   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)
7. Antimicrobial activity of peripheral blood monocyte/macrophages [ Time Frame: 240 days ]
   Difference between measured antimicrobial activity at baseline and 240 days
8. Proportion of patients with MRI-proven brain infarction [ Time Frame: 240 days ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

Vietnam

Hospital for Tropical Diseases

Ho Chi Minh City, Vietnam

Sponsors and Collaborators

Oxford University Clinical Research Unit, Vietnam

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

More Information

Additional Information:

Oxford University Clinical Research Unit, Viet Nam 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Oxford University Clinical Research Unit, Vietnam
• ClinicalTrials.gov Identifier: NCT02237365
• Other Study ID Numbers: 23TB
• First Posted: September 11, 2014
• Last Update Posted: March 7, 2017
• Last Verified: March 2017

Keywords provided by Oxford University Clinical Research Unit, Vietnam:

neurological disability; tuberculous meningitis (TBM); safety; aspirin; efficacy

Additional relevant MeSH terms:

Tuberculosis; Tuberculosis, Meningeal; Meningitis; Central Nervous System Diseases; Nervous System Diseases; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Meningitis, Bacterial; Central Nervous System Bacterial Infections; Tuberculosis, Central Nervous System; Central Nervous System Infections; Aspirin; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Enzyme Inhibitors