- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01661322
Triple Antiplatelets for Reducing Dependency After Ischaemic Stroke (TARDIS)
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
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.
Study Overview
Status
Conditions
Intervention / 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
- 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.
- 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
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
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Nottingham, United Kingdom
- Nottingham University Hospitals NHS Trust
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
Adults at high risk of recurrent ischaemic stroke:
- Age ≥ 50 years
- Within 48 hours of ictus (24-48 hours if thrombolysed)
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.
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
- 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:
- Age < 50
- Isolated sensory symptoms or vertigo/dizziness or facial weakness
- Isolated hemianopia without positive neuroimaging evidence
- Intracranial haemorrhage
- Baseline neuroimaging showing parenchymal haemorrhagic transformation (PH I/II) of infarct, subarachnoid haemorrhage or other non ischaemic cause for symptoms
- Presumed cardioembolic stroke (e.g. history or current AF, myocardial infarction within 3 months)
- Participants with contraindications to, or intolerance of, aspirin, clopidogrel or dipyridamole.
- 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)
- Participant has taken clopidogrel or dipyridamole after the index event but prior to randomisation (aspirin is allowed between ictus onset and randomisation)
- 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
- Definite need for glycoprotein IIb-IIIa inhibitors
- Received thrombolysis within the last 24 hours
- No enteral access
- Pre-morbid dependency (mRS > 2).
- Severe high BP (BP > 185/110 mmHg).
- Haemoglobin less than 10g/dL
- Platelet count more than 600 x 109 /L or less than 100 x 109 /L
- White cell count more than 30 x 109 /L or less than 3.5 x 109 /L
- Major bleeding within 1 year (e.g. peptic ulcer, intracerebral haemorrhage).
- Planned surgery during 3 month follow-up (e.g. carotid endarterectomy)
- Concomitant STEMI or NSTEMI.
- Stroke secondary to a procedure (e.g. carotid or coronary intervention)
- Coma (GCS < 8)
- Non-stroke life expectancy < 6 months
- Dementia
- 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)
- 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.
- Females of childbearing potential, pregnancy or breastfeeding
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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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.
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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:
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No Intervention: Guideline antiplatelet therapy
This may be one or two antiplatelet drugs, as per standard treatment.
Clopidogrel or aspirin and dipyridamole.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
The primary outcome is ordinal stroke severity at 90 days
Time Frame: 90 days
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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
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90 days
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Death
Time Frame: 90 days
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90 days
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Safety
Time Frame: 90 days
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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. |
90 days
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Serious adverse events
Time Frame: 90 Days
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90 Days
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Platelet function.
Time Frame: 90 Days
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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. |
90 Days
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Philip Bath, University of Nottingham
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Cardiovascular Diseases
- Vascular Diseases
- Cerebrovascular Disorders
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Stroke
- Ischemic Stroke
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Peripheral Nervous System Agents
- Enzyme Inhibitors
- Analgesics
- Sensory System Agents
- Anti-Inflammatory Agents, Non-Steroidal
- Analgesics, Non-Narcotic
- Anti-Inflammatory Agents
- Antirheumatic Agents
- Fibrinolytic Agents
- Fibrin Modulating Agents
- Platelet Aggregation Inhibitors
- Cyclooxygenase Inhibitors
- Antipyretics
- Purinergic P2Y Receptor Antagonists
- Purinergic P2 Receptor Antagonists
- Purinergic Antagonists
- Purinergic Agents
- Aspirin
- Clopidogrel
Other Study ID Numbers
- 08093
- 2007-006749-42 (EudraCT Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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