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

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

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.


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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


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




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 ]


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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02237365


Locations
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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
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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

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Oxford University Clinical Research Unit, Vietnam
ClinicalTrials.gov Identifier: NCT02237365     History of Changes
Other Study ID Numbers: 23TB
First Posted: September 11, 2014    Key Record Dates
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:
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Meningitis
Tuberculosis
Tuberculosis, Meningeal
Central Nervous System Diseases
Nervous System Diseases
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial 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
Antipyretics