<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/NCT01661322</url>
  </required_header>
  <id_info>
    <org_study_id>08093</org_study_id>
    <secondary_id>2007-006749-42</secondary_id>
    <nct_id>NCT01661322</nct_id>
  </id_info>
  <brief_title>Triple Antiplatelets for Reducing Dependency After Ischaemic Stroke</brief_title>
  <acronym>TARDIS</acronym>
  <official_title>Safety and Efficacy of Intensive Versus Guideline Antiplatelet Therapy in High Risk Patients With Recent Ischaemic Stroke or Transient Ischaemic Attack: a Randomised Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Nottingham</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Nottingham</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The risk of recurrence is greatest immediately after stroke or Transient Ischaemic Attack&#xD;
      (TIA). Existing prevention strategies (antithrombotic, lipid/blood pressure lowering,&#xD;
      endarterectomy) reduce, not abolish, further events. Dual antiplatelet therapy - aspirin &amp;&#xD;
      clopidogrel (AC) for IHD, aspirin &amp; dipyridamole (AD) for stroke, is superior to aspirin&#xD;
      monotherapy. The investigators hypothesise that triple antiplatelet therapy (ACD) will be&#xD;
      superior to AD in patients at high-risk of recurrence, providing bleeding does not become&#xD;
      excessive.&#xD;
&#xD;
      Design: TARDIS is a multicentre, parallel-group, prospective, randomised, open-label,&#xD;
      blinded-endpoint, controlled trial. In the start-up phase, the investigators will assess over&#xD;
      3 years the safety, tolerability and feasibility of intensive therapy (ACD) versus guideline&#xD;
      therapy (AD) given for 1 month in 750 patients with acute stroke/TIA. The main phase will&#xD;
      then assess the safety and efficacy of ACD in up to 3500 patients. The primary outcome is&#xD;
      ordinal stroke (fatal/severe non-fatal/mild/TIA/none) at 90 days. Secondary outcomes include&#xD;
      death, MI, vascular events, function, bleeding, serious adverse events; sub-studies will&#xD;
      assess cerebral emboli and platelet function.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      2.1 Purpose To perform a randomised trial assessing the efficacy, safety and tolerability of&#xD;
      intensive antiplatelet therapy (Asp+Dip+Clop) versus guideline antiplatelet therapy (Asp+Dip&#xD;
      or Clop) in patients with recent ischaemic stroke or TIA and who are at high risk of&#xD;
      recurrence.&#xD;
&#xD;
      2.2 Primary Objective To assess ordinal stroke severity at 90 days after short-term&#xD;
      administration (1 month) of intensive antiplatelet therapy versus guideline therapy in&#xD;
      patients with very recent ischaemic stroke or TIA.&#xD;
&#xD;
      2.3 Secondary Objectives&#xD;
&#xD;
        1. To assess the safety of short-term administration (1 month) of intensive antiplatelet&#xD;
           therapy versus guideline therapy in patients with very recent ischaemic stroke or TIA.&#xD;
&#xD;
        2. To further assess, in high risk patients with stroke/TIA, whether:&#xD;
&#xD;
      ii. it is feasible to administer intensive therapy acutely and is tolerable to take for 1&#xD;
      month, iii. intensive therapy is superior in respect of surrogate markers such as platelet&#xD;
      function.&#xD;
&#xD;
      iv. intensive therapy improves functional outcome&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Trial reached a definitive answer ahead of full recruitment.&#xD;
  </why_stopped>
  <start_date>April 2009</start_date>
  <completion_date type="Actual">September 2017</completion_date>
  <primary_completion_date type="Actual">September 2017</primary_completion_date>
  <phase>Phase 3</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>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The primary outcome is ordinal stroke severity at 90 days</measure>
    <time_frame>90 days</time_frame>
    <description>5-level ordinal stroke and TIA scale with stroke ordered by its severity using the modified Rankin Scale (mRS): fatal stroke / severe non-fatal stroke (mRS 2-5) / mild stroke (mRS 0,1) / TIA / no stroke-TIA, measured at 90 days.; this approach allows for smaller sample sizes compared to binary outcomes such as stroke/no stroke</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety</measure>
    <time_frame>90 days</time_frame>
    <description>Days 7 and 35 Full blood count by local investigator&#xD;
Days 7, 35 and 90:&#xD;
Ordinal bleeding (fatal/major/moderate/minor/none42) as adjudicated by an independent blinded panel; death; binary major bleeding (fatal, symptomatic, causing fall in haemoglobin of ≥2g/l, or leading to transfusion of ≥2 units of blood/red cells);45 binary minor bleeding (e.g. bruising) binary bleeding; all bleeding, symptomatic intracerebral haemorrhage, major extracranial bleeding, binary serious adverse events, ordinal adverse events (fatal/serious/other/none42); thrombotic thrombocytopenic purpura; granulocytopenia.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serious adverse events</measure>
    <time_frame>90 Days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Death</measure>
    <time_frame>90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Platelet function.</measure>
    <time_frame>90 Days</time_frame>
    <description>Days 7 and 35 Full blood count by local investigator&#xD;
Days 7, 35 and 90:&#xD;
Ordinal bleeding (fatal/major/moderate/minor/none42) as adjudicated by an independent blinded panel; death; binary major bleeding (fatal, symptomatic, causing fall in haemoglobin of ≥2g/l, or leading to transfusion of ≥2 units of blood/red cells);45 binary minor bleeding (e.g. bruising) binary bleeding; all bleeding, symptomatic intracerebral haemorrhage, major extracranial bleeding, binary serious adverse events, ordinal adverse events (fatal/serious/other/none42); thrombotic thrombocytopenic purpura; granulocytopenia.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">3096</enrollment>
  <condition>Stroke</condition>
  <arm_group>
    <arm_group_label>Intensive antiplatelet therapy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants in the intensive antiplatelet group will receive Aspirin+Dipyridamole+Clopidogrel triple therapy for 28-30 days (to cover the period of maximum risk of recurrence) along with standard 'best care' (including lifestyle advice, BP and lipid lowering). Clop will be given as a loading dose of 300 mg,12 then 75 mg daily, Asp as a loading dose of 300 mg,22 then 75 mg daily, and Dip modified release 200 mg twice daily 9 for 28-30 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Guideline antiplatelet therapy</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>This may be one or two antiplatelet drugs, as per standard treatment. Clopidogrel or aspirin and dipyridamole.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aspirin, Dipyradimole, Clopidogrel</intervention_name>
    <description>Participants in the intensive antiplatelet group will receive Asp+Dip+Clop triple therapy for 28-30 days (to cover the period of maximum risk of recurrence) along with standard 'best care' (including lifestyle advice, BP and lipid lowering). Clop will be given as a loading dose of 300 mg,12 then 75 mg daily, Asp as a loading dose of 300 mg,22 then 75 mg daily, and Dip modified release 200 mg twice daily 9 for 28-30 days.</description>
    <arm_group_label>Intensive antiplatelet therapy</arm_group_label>
    <other_name>Aspirin</other_name>
    <other_name>Dipyradimole</other_name>
    <other_name>Clopidogrel</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Adults at high risk of recurrent ischaemic stroke:&#xD;
&#xD;
          1. Age ≥ 50 years&#xD;
&#xD;
          2. Within 48 hours of ictus (24-48 hours if thrombolysed)&#xD;
&#xD;
          3. TIA with limb weakness and/or dysphasia lasting between 10 minutes and &lt; 24 hours with&#xD;
             no residual symptoms and presenting with any of the following&#xD;
&#xD;
               -  ABCD2 score &gt; 4, or&#xD;
&#xD;
               -  Crescendo TIA or&#xD;
&#xD;
               -  Already on dual antiplatelet therapy&#xD;
&#xD;
             Note: Neuroimaging is not necessary for transient ischaemic attack. Crescendo TIA is &gt;&#xD;
             1 TIA in one week and the onset time of last TIA is taken as time of ictus.&#xD;
&#xD;
          4. Ischaemic non cardioembolic stroke presenting with any of the following&#xD;
&#xD;
               -  Ongoing limb weakness and/or dysphasia of more than one hour duration&#xD;
&#xD;
               -  Resolved limb weakness of more than one hour duration with ongoing facial&#xD;
                  weakness&#xD;
&#xD;
               -  Ongoing isolated hemianopia of more than 1 hour duration with positive&#xD;
                  neuroimaging evidence to support the index event (e.g. ischaemic stroke in&#xD;
                  occipital lobe)&#xD;
&#xD;
               -  Resolved limb weakness and/or dysphasia between 24-48 hours after index event&#xD;
                  onset&#xD;
&#xD;
             Note: Neuroimaging is essential for ischaemic stroke to exclude intracranial&#xD;
             haemorrhage and/or non stroke diagnosis&#xD;
&#xD;
          5. Informed consent from participant. If the participant is unable to give meaningful&#xD;
             consent e.g. due to dysphasia, confusion, or reduced conscious level, proxy consent&#xD;
             may be obtained from a relative, carer or legal representative.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Age &lt; 50&#xD;
&#xD;
          2. Isolated sensory symptoms or vertigo/dizziness or facial weakness&#xD;
&#xD;
          3. Isolated hemianopia without positive neuroimaging evidence&#xD;
&#xD;
          4. Intracranial haemorrhage&#xD;
&#xD;
          5. Baseline neuroimaging showing parenchymal haemorrhagic transformation (PH I/II) of&#xD;
             infarct, subarachnoid haemorrhage or other non ischaemic cause for symptoms&#xD;
&#xD;
          6. Presumed cardioembolic stroke (e.g. history or current AF, myocardial infarction&#xD;
             within 3 months)&#xD;
&#xD;
          7. Participants with contraindications to, or intolerance of, aspirin, clopidogrel or&#xD;
             dipyridamole.&#xD;
&#xD;
          8. Participants with definite need for treatment with aspirin, clopidogrel or&#xD;
             dipyridamole individually or in combination (e.g. aspirin and clopidogrel for recent&#xD;
             MI/acute coronary syndrome)&#xD;
&#xD;
          9. Participant has taken clopidogrel or dipyridamole after the index event but prior to&#xD;
             randomisation (aspirin is allowed between ictus onset and randomisation)&#xD;
&#xD;
         10. Definite need for full dose oral (e.g. warfarin, dabigatran) or medium to high dose&#xD;
             parenteral (e.g. heparin) anti-coagulation. NB Low dose heparin for DVT prophylaxis is&#xD;
             allowed&#xD;
&#xD;
         11. Definite need for glycoprotein IIb-IIIa inhibitors&#xD;
&#xD;
         12. Received thrombolysis within the last 24 hours&#xD;
&#xD;
         13. No enteral access&#xD;
&#xD;
         14. Pre-morbid dependency (mRS &gt; 2).&#xD;
&#xD;
         15. Severe high BP (BP &gt; 185/110 mmHg).&#xD;
&#xD;
         16. Haemoglobin less than 10g/dL&#xD;
&#xD;
         17. Platelet count more than 600 x 109 /L or less than 100 x 109 /L&#xD;
&#xD;
         18. White cell count more than 30 x 109 /L or less than 3.5 x 109 /L&#xD;
&#xD;
         19. Major bleeding within 1 year (e.g. peptic ulcer, intracerebral haemorrhage).&#xD;
&#xD;
         20. Planned surgery during 3 month follow-up (e.g. carotid endarterectomy)&#xD;
&#xD;
         21. Concomitant STEMI or NSTEMI.&#xD;
&#xD;
         22. Stroke secondary to a procedure (e.g. carotid or coronary intervention)&#xD;
&#xD;
         23. Coma (GCS &lt; 8)&#xD;
&#xD;
         24. Non-stroke life expectancy &lt; 6 months&#xD;
&#xD;
         25. Dementia&#xD;
&#xD;
         26. Participation in another drug or devices trial concurrently or within 30 days.&#xD;
             (participants may take part in observational studies or non-drug or devices trials)&#xD;
&#xD;
         27. Geographical or other factors that may interfere with follow-up e.g. no fixed address&#xD;
             or telephone contact number, not registered with a GP, or overseas visitor.&#xD;
&#xD;
         28. Females of childbearing potential, pregnancy or breastfeeding&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Philip Bath</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Nottingham</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Nottingham University Hospitals NHS Trust</name>
      <address>
        <city>Nottingham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <link>
    <url>http://www.tardistrial.org/</url>
    <description>TARDIS Trial Website</description>
  </link>
  <verification_date>June 2018</verification_date>
  <study_first_submitted>July 23, 2012</study_first_submitted>
  <study_first_submitted_qc>August 6, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 9, 2012</study_first_posted>
  <last_update_submitted>June 8, 2018</last_update_submitted>
  <last_update_submitted_qc>June 8, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">June 11, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Acute ischaemic stroke</keyword>
  <keyword>TIA</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Stroke</mesh_term>
    <mesh_term>Ischemic Stroke</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aspirin</mesh_term>
    <mesh_term>Clopidogrel</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT01661322
org study id: 08093
secondary id: 2007-006749-42
nct id: NCT01661322
lead sponsor: 
has dmc: Yes
The risk of recurrence is greatest immediately after stroke or Transient Ischaemic Attack
      (TIA). Existing prevention strategies (antithrombotic, lipid/blood pressure lowering,
      endarterectomy) reduce, not abolish, further events. Dual antiplatelet therapy - aspirin &
      clopidogrel (AC) for IHD, aspirin & dipyridamole (AD) for stroke, is superior to aspirin
      monotherapy. The investigators hypothesise that triple antiplatelet therapy (ACD) will be
      superior to AD in patients at high-risk of recurrence, providing bleeding does not become
      excessive.

      Design: TARDIS is a multicentre, parallel-group, prospective, randomised, open-label,
      blinded-endpoint, controlled trial. In the start-up phase, the investigators will assess over
      3 years the safety, tolerability and feasibility of intensive therapy (ACD) versus guideline
      therapy (AD) given for 1 month in 750 patients with acute stroke/TIA. The main phase will
      then assess the safety and efficacy of ACD in up to 3500 patients. The primary outcome is
      ordinal stroke (fatal/severe non-fatal/mild/TIA/none) at 90 days. Secondary outcomes include
      death, MI, vascular events, function, bleeding, serious adverse events; sub-studies will
      assess cerebral emboli and platelet function.
2.1 Purpose To perform a randomised trial assessing the efficacy, safety and tolerability of
      intensive antiplatelet therapy (Asp+Dip+Clop) versus guideline antiplatelet therapy (Asp+Dip
      or Clop) in patients with recent ischaemic stroke or TIA and who are at high risk of
      recurrence.

      2.2 Primary Objective To assess ordinal stroke severity at 90 days after short-term
      administration (1 month) of intensive antiplatelet therapy versus guideline therapy in
      patients with very recent ischaemic stroke or TIA.

      2.3 Secondary Objectives

        1. To assess the safety of short-term administration (1 month) of intensive antiplatelet
           therapy versus guideline therapy in patients with very recent ischaemic stroke or TIA.

        2. To further assess, in high risk patients with stroke/TIA, whether:

      ii. it is feasible to administer intensive therapy acutely and is tolerable to take for 1
      month, iii. intensive therapy is superior in respect of surrogate markers such as platelet
      function.

      iv. intensive therapy improves functional outcome
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: The primary outcome is ordinal stroke severity at 90 days
time frame: 90 days
description: 5-level ordinal stroke and TIA scale with stroke ordered by its severity using the modified Rankin Scale (mRS): fatal stroke / severe non-fatal stroke (mRS 2-5) / mild stroke (mRS 0,1) / TIA / no stroke-TIA, measured at 90 days.; this approach allows for smaller sample sizes compared to binary outcomes such as stroke/no stroke
measure: Safety
time frame: 90 days
description: Days 7 and 35 Full blood count by local investigator
Days 7, 35 and 90:
Ordinal bleeding (fatal/major/moderate/minor/none42) as adjudicated by an independent blinded panel; death; binary major bleeding (fatal, symptomatic, causing fall in haemoglobin of ≥2g/l, or leading to transfusion of ≥2 units of blood/red cells);45 binary minor bleeding (e.g. bruising) binary bleeding; all bleeding, symptomatic intracerebral haemorrhage, major extracranial bleeding, binary serious adverse events, ordinal adverse events (fatal/serious/other/none42); thrombotic thrombocytopenic purpura; granulocytopenia.
measure: Serious adverse events
time frame: 90 Days
measure: Death
time frame: 90 days
measure: Platelet function.
time frame: 90 Days
description: Days 7 and 35 Full blood count by local investigator
Days 7, 35 and 90:
Ordinal bleeding (fatal/major/moderate/minor/none42) as adjudicated by an independent blinded panel; death; binary major bleeding (fatal, symptomatic, causing fall in haemoglobin of ≥2g/l, or leading to transfusion of ≥2 units of blood/red cells);45 binary minor bleeding (e.g. bruising) binary bleeding; all bleeding, symptomatic intracerebral haemorrhage, major extracranial bleeding, binary serious adverse events, ordinal adverse events (fatal/serious/other/none42); thrombotic thrombocytopenic purpura; granulocytopenia.
arm group label: Intensive antiplatelet therapy
arm group type: Active Comparator
description: Participants in the intensive antiplatelet group will receive Aspirin+Dipyridamole+Clopidogrel triple therapy for 28-30 days (to cover the period of maximum risk of recurrence) along with standard 'best care' (including lifestyle advice, BP and lipid lowering). Clop will be given as a loading dose of 300 mg,12 then 75 mg daily, Asp as a loading dose of 300 mg,22 then 75 mg daily, and Dip modified release 200 mg twice daily 9 for 28-30 days.
arm group label: Guideline antiplatelet therapy
arm group type: No Intervention
description: This may be one or two antiplatelet drugs, as per standard treatment. Clopidogrel or aspirin and dipyridamole.
intervention type: Drug
intervention name: Aspirin, Dipyradimole, Clopidogrel
description: Participants in the intensive antiplatelet group will receive Asp+Dip+Clop triple therapy for 28-30 days (to cover the period of maximum risk of recurrence) along with standard 'best care' (including lifestyle advice, BP and lipid lowering). Clop will be given as a loading dose of 300 mg,12 then 75 mg daily, Asp as a loading dose of 300 mg,22 then 75 mg daily, and Dip modified release 200 mg twice daily 9 for 28-30 days.
arm group label: Intensive antiplatelet therapy
other name: Aspirin
other name: Dipyradimole
other name: Clopidogrel
criteria: 
gender: All
minimum age: 50 Years
maximum age: N/A
healthy volunteers: No
last name: Philip Bath
role: Principal Investigator
affiliation: University of Nottingham
facility: 
country: United Kingdom
url: http://www.tardistrial.org/
description: TARDIS Trial Website
responsible party type: Sponsor
mesh term: Stroke
mesh term: Ischemic Stroke
mesh term: Aspirin
mesh term: Clopidogrel
sharing ipd: Undecided