Clopidogrel in High-risk Patients With Acute Non-disabling Cerebrovascular Events

Study Overview
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Brief Summary
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The purpose of this study is to assess the effects of a 3-month regimen of clopidogrel initiated with a loading dose (LD) of 300 mg followed by 75 mg/day during the first 21days versus a 3-month regimen of ASA 75 mg/day alone on reducing the 3-month risk of any stroke (both ischemic and hemorrhagic, primary outcome) when initiated within 24 hours of symptom onset in high-risk patients with TIA or minor stroke.

Detailed Description
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Inclusion criteria: Adult subjects (male or female ≥ 40 years) Acute non-disabling ischemic stroke (NIHSS≤3 at the time of randomization) that can be treated with study drug within 24 hours of symptoms onset. Symptom onset is defined by the last see normal principle. TIA (Neurological deficit attributed to focal brain ischemia, with resolution of the deficit within 24 hours of symptom onset), that can be treated with study drug within 24 hours of symptoms onset and with moderate-to-high risk of stroke recurrence (ABCD2 score ≥ 4 at the time of randomization). Symptom onset is defined by the last see normal principle. Informed consent signed Primary Efficacy Endpoint: Percentage of patients with the 3-month new vascular events, defined as any event of the following:Any stroke (ischemic or hemorrhage).

Official Title
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Randomized,Double-blind Trial Comparing the Effects of a 3-month Clopidogrel Regimen,Combined With ASA During the First 21days,Versus ASA Alone for the Acute Treatment of TIA or Minor Stroke

Conditions
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Stroke, Transient Ischemic Attack

Intervention / Treatment
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* Drug: Clopidogrel
* Drug: Placebo of clopidogrel and Asprin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Adult subjects (male or female≥40 years) Acute non-disabling ischemic stroke (NIHSS≤3 at the time of randomization) that can be treated with study drug within 24 hours of symptoms onset. Symptom onset is defined by the last see normal principle TIA (Neurological deficit attributed to focal brain ischemia, with resolution of the deficit within 24 hours of symptom onset), that can be treated with study drug within 24 hours of symptoms onset and with moderate-to-high risk of stroke recurrence (ABCD2 score≥4 at the time of randomization).Symptom onset is defined by the last see normal principle Informed consent signed Exclusion Criteria: Diagnosis of hemorrhage or other pathology, such as vascular malformation, tumor, abscess or other major non-ischemic brain disease (e.g., multiple sclerosis) on baseline head CT or MRI Isolated or pure sensory symptoms (e.g., numbness), isolated visual changes, or isolated dizziness/vertigo without evidence of acute infarction on baseline head CT or MRI Modified Rankin Scale Score>2 at randomization (pre-morbid historical assessment) NIH Stroke Score≥4 at randomization Clear indication for anticoagulation(presumed cardiac source of embolus, e.g., atrial fibrillation, prosthetic cardiac valves known or suspected endocarditis) Contraindication to clopidogrel or ASA Known allergy Severe renal or hepatic insufficiency Severe cardiac failure, asthma Hemostatic disorder or systemic bleeding History of hemostatic disorder or systemic bleeding History of thrombocytopenia or neutropenia History of drug-induced hematologic or hepatic abnormalities Low white blood cell (<2 x109/l) or platelet count (<100 x109/l) Use of thrombolysis within 24 hours prior to randomization History of intracranial hemorrhage Anticipated requirement for long-term non-study antiplatelet drugs, or NSAIDs affecting platelet function Current treatment (last dose given within 10 days before randomization) with heparin therapy or oral anti coagulation Gastrointestinal bleed or major surgery within 3 months Planned or likely revascularization (any angioplasty or vascular surgery) within the next 3 months (if clinically indicated, vascular imaging should be performed prior to randomization whenever possible) Scheduled for surgery or interventional treatment requiring study drug cessation Qualifying TIA or minor stroke induced by angiography or surgery Severe non-cardiovascular comorbidity with life expectancy < 3 months Women of childbearing age not practicing reliable contraception who do not have a documented negative pregnancy test Currently receiving an investigational drug or device

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Combination Clopidogrel and asprin<br> | Drug: Clopidogrel<br>* The first group will receive a 300mg loading dose (LD) of clopidogrel on the day of randomization, followed by 75 mg clopidogrel/day from Day 2 to 3 months. ASA will be given in a total dose ranging between 75 mg and 300 mg (open label) on the first day, followed by blinded 75 mg once /day from Day 2 to Day 21st. Between Day 21st and 3-month visits, ASA 75 mg will be replaced by a placebo of ASA 75 mg.<br>* Other names: Plavix;|
| Placebo Comparator: Asprin and placebo<br> | Drug: Placebo of clopidogrel and Asprin<br>* The second group will receive open label ASA in a total dose ranging between 75 mg and 300 mg on the first day, followed by blinded 75 mg once /day from Day 2 to 3 months. A placebo for clopidogrel will be given from the day of randomization until the 3-month visit.<br>* Other names: Acetylsalicylic acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with the 3-month new vascular events, defined as any event of the following: Any stroke (ischemic or hemorrhage) |  | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with the 3-month new clinical vascular events (ischemic stroke/ hemorrhagic stroke/ TIA/ MI/ vascular death) as a cluster and evaluated individually. |  | 3 months | 
| Modified Rankin Scale score changes (continuous) and dichotomized at percentage with score 0-2 vs. 3-6 at 3 month follow-up |  | 3 months | 
| Further efficacy exploratory analysis:Impairment (changes in NIHSS scores at 3 month follow-up). |  | 3 months | 
| Further efficacy exploratory analysis:Quality of Life (EuroQol EQ-5D scale) |  | 3 months | 
| Efficacy endpoint will also be analyzed stratified by etiological subtypes, by time randomization (< 12 hours vs. ≥ 12 hours), by qualifying event (TIA vs. minor stroke), and by age |  | 3 months | 
| Severe bleeding incidence (GUSTO definition), including fatal bleeding and symptomatic intracranial hemorrhage. |  | 3 months | 
| Incidence symptomatic and asymptomatic intracranial hemorrhagic events at 3 months |  | 3 months | 
| Intracranial hemorrhage |  | 3 months | 
| Total mortality |  | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stroke, transient ischemic attack, acute treatment, acute non-disabling cerebrovascular event, clopidogrel, clopidogrel combined with ASA, recurrence of stroke and other vascular events