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

Tuberculous Meningitis Clinical Trial

— AspirinTBM  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02237365
• Other study ID #: 23TB
• Status: Completed
• Phase: Phase 2
• First received: September 9, 2014
• Last updated: March 5, 2017
• Start date: October 17, 2014
• Est. completion date: December 22, 2016

Study information

• Verified date: March 2017
• Source: Oxford University Clinical Research Unit, Vietnam
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 120
• Est. completion date: December 22, 2016
• Est. primary completion date: June 24, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Meningitis
• Tuberculosis
• Tuberculosis, Meningeal
• Tuberculous Meningitis

Intervention

Drug:
• 81mg aspirin
1 tablet of 81mg aspirin and 2 tablets of placebo (visually matched to 500mg aspirin) daily for 60 days
• 1000mg aspirin
1 tablet of 81mg placebo (visually matched to 81mg aspirin) and 2 tablets of 500mg aspirin daily for 60 days
• 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

Locations

Country	Name	City	State
Vietnam	Hospital for Tropical Diseases	Ho Chi Minh City

Sponsors (2)

Lead Sponsor	Collaborator
Oxford University Clinical Research Unit, Vietnam	Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam

Country where clinical trial is conducted

Vietnam, 

Outcome

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

External Links

•   Oxford University Clinical Research Unit, Viet Nam