<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02237365</url>
  </required_header>
  <id_info>
    <org_study_id>23TB</org_study_id>
    <nct_id>NCT02237365</nct_id>
  </id_info>
  <brief_title>A Pilot Study of Adjunctive Aspirin for the Treatment of HIV Negative Adults With Tuberculous Meningitis</brief_title>
  <acronym>AspirinTBM</acronym>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Oxford University Clinical Research Unit, Vietnam</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Oxford University Clinical Research Unit, Vietnam</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Tuberculous meningitis is a severe brain infection which often causes disability and death&#xD;
      even when treated with the best available treatment. Aspirin is a type of anti-inflammation&#xD;
      drug which can reduce the inflammatory response in brains of patients with tuberculous&#xD;
      meningitis, and therefore may decrease some of the most severe outcomes. This study compares&#xD;
      the use of aspirin (at 2 different doses) versus placebo as an additional therapy to the&#xD;
      standard treatment to see if aspirin is safe and helpful in reducing disability and death&#xD;
      from tuberculous meningitis. Patients will be treated with aspirin or placebo for 60 days and&#xD;
      followed up while on standard treatment for 8 months.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study is a parallel group, double blind, randomised, placebo controlled trial of 60 days&#xD;
      treatment with placebo vs. 81mg daily dose vs. 1000mg daily dose aspirin for the treatment of&#xD;
      HIV-uninfected adults with tuberculous meningitis.&#xD;
&#xD;
      All patients will receive standard anti-tuberculous chemotherapy and adjunctive&#xD;
      dexamethasone, according to Viet Nam National Tuberculosis Programme guidelines. Participants&#xD;
      will be stratified by Medical Research Council UK disease severity grade, and randomized at&#xD;
      enrollment to one of three study arms (1:1:1 ratio). Patients will be admitted to hospital&#xD;
      for at least the first 14 days of study treatment enabling real-time active surveillance of&#xD;
      any adverse events after which they will be discharged according to clinical care with&#xD;
      continued monitoring.&#xD;
&#xD;
      A schedule of clinical and laboratory monitoring including lumbar puncture, pharmacokinetic&#xD;
      assessment of peripheral blood monocyte/macrophage antimicrobial activity, clinical&#xD;
      assessments, brain magnetic resonance imaging (MRI) and neurological assessment will manage&#xD;
      patient safety and capture study outcomes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 17, 2014</start_date>
  <completion_date type="Actual">December 22, 2016</completion_date>
  <primary_completion_date type="Actual">June 24, 2016</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of episodes of either cerebral bleeding or clinically significant upper-gastro-intestinal bleeding (composite endpoint)</measure>
    <time_frame>60 days</time_frame>
    <description>Primary Safety Endpoint: Number of episodes of:&#xD;
Cerebral bleeding confirmed by brain imaging and/or&#xD;
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 &gt;2g/L or; d) Greater than 5mls of fresh or changed blood aspirated from nasogastric tube</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of episodes of MRI-proven brain infarction or death (composite endpoint)</measure>
    <time_frame>60 days</time_frame>
    <description>Primary Efficacy Endpoint: Number of episodes of&#xD;
MRI-proven brain infarction and/or&#xD;
Death</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to death</measure>
    <time_frame>240 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of grade 3&amp;4 and serious adverse events</measure>
    <time_frame>60 days</time_frame>
    <description>Graded according to Common Terminology Criteria for Adverse Events (CTCAE) definitions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of hospital stay</measure>
    <time_frame>240 days</time_frame>
    <description>Number of days admitted to hospital during the study period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurological disability score</measure>
    <time_frame>60 days</time_frame>
    <description>Assessed by the modified Rankin score and Glasgow outcome score</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurological disability score</measure>
    <time_frame>240 days</time_frame>
    <description>Assessed by the modified Rankin score and Glasgow outcome score</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Resolution of cerebrospinal fluid (CSF) inflammation</measure>
    <time_frame>30 days</time_frame>
    <description>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)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Antimicrobial activity of peripheral blood monocyte/macrophages</measure>
    <time_frame>240 days</time_frame>
    <description>Difference between measured antimicrobial activity at baseline and 240 days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with MRI-proven brain infarction</measure>
    <time_frame>240 days</time_frame>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">120</enrollment>
  <condition>Tuberculous Meningitis</condition>
  <arm_group>
    <arm_group_label>81mg aspirin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Aspirin 81mg daily for 60 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>1000mg aspirin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Aspirin 1000mg daily for 60 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Visually matched placebo daily for 60 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>81mg aspirin</intervention_name>
    <description>1 tablet of 81mg aspirin and 2 tablets of placebo (visually matched to 500mg aspirin) daily for 60 days</description>
    <arm_group_label>81mg aspirin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>1000mg aspirin</intervention_name>
    <description>1 tablet of 81mg placebo (visually matched to 81mg aspirin) and 2 tablets of 500mg aspirin daily for 60 days</description>
    <arm_group_label>1000mg aspirin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>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</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female, aged 18 years or above.&#xD;
&#xD;
          -  Suspected TBM and anti-tuberculosis chemotherapy either planned or started&#xD;
&#xD;
          -  Less than 3 days of anti-tuberculosis chemotherapy taken for the current infection&#xD;
&#xD;
          -  Patient or representative (if the patient is unable) is willing and able to give&#xD;
             informed consent for participation in the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  HIV infection (negative rapid test or Elisa test is required)&#xD;
&#xD;
          -  Unlikely, for any reason, to be able to have an MRI brain scan within 5 days (120&#xD;
             hours) of randomisation&#xD;
&#xD;
          -  Known or suspected infection with multi-drug resistant tuberculosis (resistant to at&#xD;
             least isoniazid and rifampicin)&#xD;
&#xD;
          -  Unable to take isoniazid, rifampicin, or pyrazinamide at recommended doses for any&#xD;
             reason&#xD;
&#xD;
          -  History of diagnosed peptic ulceration or gastro-intestinal bleeding&#xD;
&#xD;
          -  Active gastro-intestinal bleeding is suspected&#xD;
&#xD;
          -  Taken &gt;1 dose of aspirin (at any dose) or any other non-steroidal anti-inflammatory&#xD;
             drugs for any reason within 2 weeks of screening&#xD;
&#xD;
          -  Aspirin considered mandatory for any reason by the attending physician&#xD;
&#xD;
          -  Aspirin considered to be contraindicated for any reason by the attending physician&#xD;
&#xD;
          -  Pregnancy or breast feeding (negative urine pregnancy test for all females of&#xD;
             child-bearing age)&#xD;
&#xD;
          -  Dexamethasone considered to be contraindicated for any reason by the attending&#xD;
             physician&#xD;
&#xD;
          -  Any other significant disease or disorder which, in the opinion of the investigator,&#xD;
             may either put the participants at risk because of participation in the study, or may&#xD;
             influence the result of the study, or the participant's ability to participate in the&#xD;
             study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Guy Thwaites, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Oxford University of Clinical Research</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Nguyen H Phu, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital for Tropical Diseases</name>
      <address>
        <city>Ho Chi Minh City</city>
        <country>Vietnam</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Vietnam</country>
  </location_countries>
  <link>
    <url>http://www.oucru.org</url>
    <description>Oxford University Clinical Research Unit, Viet Nam</description>
  </link>
  <verification_date>March 2017</verification_date>
  <study_first_submitted>September 9, 2014</study_first_submitted>
  <study_first_submitted_qc>September 9, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 11, 2014</study_first_posted>
  <last_update_submitted>March 5, 2017</last_update_submitted>
  <last_update_submitted_qc>March 5, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">March 7, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>neurological disability</keyword>
  <keyword>tuberculous meningitis (TBM)</keyword>
  <keyword>safety</keyword>
  <keyword>aspirin</keyword>
  <keyword>efficacy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
    <mesh_term>Tuberculosis, Meningeal</mesh_term>
    <mesh_term>Meningitis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aspirin</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02237365
org study id: 23TB
nct id: NCT02237365
lead sponsor: 
collaborator: 
has dmc: Yes
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Number of episodes of either cerebral bleeding or clinically significant upper-gastro-intestinal bleeding (composite endpoint)
time frame: 60 days
description: 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
measure: Number of episodes of MRI-proven brain infarction or death (composite endpoint)
time frame: 60 days
description: Primary Efficacy Endpoint: Number of episodes of
MRI-proven brain infarction and/or
Death
measure: Time to death
time frame: 240 days
measure: Number of grade 3&4 and serious adverse events
time frame: 60 days
description: Graded according to Common Terminology Criteria for Adverse Events (CTCAE) definitions
measure: Duration of hospital stay
time frame: 240 days
description: Number of days admitted to hospital during the study period
measure: Neurological disability score
time frame: 60 days
description: Assessed by the modified Rankin score and Glasgow outcome score
measure: Neurological disability score
time frame: 240 days
description: Assessed by the modified Rankin score and Glasgow outcome score
measure: Resolution of cerebrospinal fluid (CSF) inflammation
time frame: 30 days
description: 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)
measure: Antimicrobial activity of peripheral blood monocyte/macrophages
time frame: 240 days
description: Difference between measured antimicrobial activity at baseline and 240 days
measure: Proportion of patients with MRI-proven brain infarction
time frame: 240 days
arm group label: 81mg aspirin
arm group type: Experimental
description: Aspirin 81mg daily for 60 days
arm group label: 1000mg aspirin
arm group type: Experimental
description: Aspirin 1000mg daily for 60 days
arm group label: Placebo
arm group type: Placebo Comparator
description: Visually matched placebo daily for 60 days
intervention type: Drug
intervention name: 81mg aspirin
description: 1 tablet of 81mg aspirin and 2 tablets of placebo (visually matched to 500mg aspirin) daily for 60 days
arm group label: 81mg aspirin
intervention type: Drug
intervention name: 1000mg aspirin
description: 1 tablet of 81mg placebo (visually matched to 81mg aspirin) and 2 tablets of 500mg aspirin daily for 60 days
arm group label: 1000mg aspirin
intervention type: Drug
intervention name: Placebo
description: 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
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Guy Thwaites, MD, PhD
role: Principal Investigator
affiliation: Oxford University of Clinical Research
last name: Nguyen H Phu, MD, PhD
role: Principal Investigator
affiliation: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
facility: 
country: Vietnam
url: http://www.oucru.org
description: Oxford University Clinical Research Unit, Viet Nam
responsible party type: Sponsor
mesh term: Tuberculosis
mesh term: Tuberculosis, Meningeal
mesh term: Meningitis
mesh term: Aspirin