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Triple Antiplatelets for Reducing Dependency After Ischaemic Stroke (TARDIS)

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by University of Nottingham
Sponsor:
Information provided by (Responsible Party):
University of Nottingham
ClinicalTrials.gov Identifier:
NCT01661322
First received: July 23, 2012
Last updated: June 16, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Stroke
Drug: Aspirin, Dipyradimole, Clopidogrel
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by University of Nottingham:

Primary Outcome Measures:
  • The primary outcome is ordinal stroke severity at 90 days [ Time Frame: 90 days ] [ Designated as safety issue: Yes ]
    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


Secondary Outcome Measures:
  • Safety [ Time Frame: 90 days ] [ Designated as safety issue: Yes ]

    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.


  • Serious adverse events [ Time Frame: 90 Days ] [ Designated as safety issue: Yes ]
  • Death [ Time Frame: 90 days ] [ Designated as safety issue: Yes ]
  • Platelet function. [ Time Frame: 90 Days ] [ Designated as safety issue: Yes ]

    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.



Estimated Enrollment: 4100
Study Start Date: April 2009
Estimated Study Completion Date: September 2017
Estimated Primary Completion Date: September 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Intensive antiplatelet therapy
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.
Drug: Aspirin, Dipyradimole, Clopidogrel
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.
Other Names:
  • Aspirin
  • Dipyradimole
  • Clopidogrel
No Intervention: Guideline antiplatelet therapy
Two antiplatelet drugs, as per standard treatment

Detailed Description:

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

  Eligibility

Ages Eligible for Study:   50 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Adults at high risk of recurrent ischaemic stroke:

  1. Age ≥ 50 years
  2. Within 48 hours of ictus (24-48 hours if thrombolysed)
  3. TIA with limb weakness and/or dysphasia lasting between 10 minutes and < 24 hours with no residual symptoms and presenting with any of the following

    • ABCD2 score > 4, or
    • Crescendo TIA or
    • Already on dual antiplatelet therapy

    Note: Neuroimaging is not necessary for transient ischaemic attack. Crescendo TIA is > 1 TIA in one week and the onset time of last TIA is taken as time of ictus.

  4. Ischaemic non cardioembolic stroke presenting with any of the following

    • Ongoing limb weakness and/or dysphasia of more than one hour duration
    • Resolved limb weakness of more than one hour duration with ongoing facial weakness
    • Ongoing isolated hemianopia of more than 1 hour duration with positive neuroimaging evidence to support the index event (e.g. ischaemic stroke in occipital lobe)
    • Resolved limb weakness and/or dysphasia between 24-48 hours after index event onset

    Note: Neuroimaging is essential for ischaemic stroke to exclude intracranial haemorrhage and/or non stroke diagnosis

  5. Informed consent from participant. If the participant is unable to give meaningful consent e.g. due to dysphasia, confusion, or reduced conscious level, proxy consent may be obtained from a relative, carer or legal representative.

Exclusion Criteria:

  1. Age < 50
  2. Isolated sensory symptoms or vertigo/dizziness or facial weakness
  3. Isolated hemianopia without positive neuroimaging evidence
  4. Intracranial haemorrhage
  5. Baseline neuroimaging showing parenchymal haemorrhagic transformation (PH I/II) of infarct, subarachnoid haemorrhage or other non ischaemic cause for symptoms
  6. Presumed cardioembolic stroke (e.g. history or current AF, myocardial infarction within 3 months)
  7. Participants with contraindications to, or intolerance of, aspirin, clopidogrel or dipyridamole.
  8. Participants with definite need for treatment with aspirin, clopidogrel or dipyridamole individually or in combination (e.g. aspirin and clopidogrel for recent MI/acute coronary syndrome)
  9. Participant has taken clopidogrel or dipyridamole after the index event but prior to randomisation (aspirin is allowed between ictus onset and randomisation)
  10. Definite need for full dose oral (e.g. warfarin, dabigatran) or medium to high dose parenteral (e.g. heparin) anti-coagulation. NB Low dose heparin for DVT prophylaxis is allowed
  11. Definite need for glycoprotein IIb-IIIa inhibitors
  12. Received thrombolysis within the last 24 hours
  13. No enteral access
  14. Pre-morbid dependency (mRS > 2).
  15. Severe high BP (BP > 185/110 mmHg).
  16. Haemoglobin less than 10g/dL
  17. Platelet count more than 600 x 109 /L or less than 100 x 109 /L
  18. White cell count more than 30 x 109 /L or less than 3.5 x 109 /L
  19. Major bleeding within 1 year (e.g. peptic ulcer, intracerebral haemorrhage).
  20. Planned surgery during 3 month follow-up (e.g. carotid endarterectomy)
  21. Concomitant STEMI or NSTEMI.
  22. Stroke secondary to a procedure (e.g. carotid or coronary intervention)
  23. Coma (GCS < 8)
  24. Non-stroke life expectancy < 6 months
  25. Dementia
  26. Participation in another drug or devices trial concurrently or within 30 days. (participants may take part in observational studies or non-drug or devices trials)
  27. Geographical or other factors that may interfere with follow-up e.g. no fixed address or telephone contact number, not registered with a GP, or overseas visitor.
  28. Females of childbearing potential, pregnancy or breastfeeding
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01661322

Contacts
Contact: Sally Utton, BA Hons +44 115 823 0287 sally.utton@nottingham.ac.uk
Contact: Philip Bath, MBBS +44 115 823 1767 philip.bath@nottingham.ac.uk

Locations
United Kingdom
Nottingham University Hospitals NHS Trust Recruiting
Nottingham, United Kingdom
Contact: Sally Utton, BA Hons    +44 115 823 0287    sally.utton@nottingham.ac.uk   
Principal Investigator: Philip Bath, MBBS         
Sponsors and Collaborators
University of Nottingham
Investigators
Principal Investigator: Philip Bath University of Nottingham
  More Information

Additional Information:
No publications provided

Responsible Party: University of Nottingham
ClinicalTrials.gov Identifier: NCT01661322     History of Changes
Other Study ID Numbers: 08093, 2007-006749-42
Study First Received: July 23, 2012
Last Updated: June 16, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by University of Nottingham:
Acute ischaemic stroke
TIA

Additional relevant MeSH terms:
Platelet Aggregation Inhibitors
Cerebral Infarction
Stroke
Brain Diseases
Brain Infarction
Brain Ischemia
Cardiovascular Diseases
Central Nervous System Diseases
Cerebrovascular Disorders
Nervous System Diseases
Vascular Diseases
Aspirin
Clopidogrel
Analgesics
Analgesics, Non-Narcotic
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Antipyretics
Antirheumatic Agents
Cardiovascular Agents
Central Nervous System Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Fibrin Modulating Agents
Fibrinolytic Agents
Hematologic Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Peripheral Nervous System Agents
Pharmacologic Actions

ClinicalTrials.gov processed this record on November 23, 2014