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

Study Overview
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Brief Summary
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The primary objective of this trial is to assess the effects of ticagrelor plus aspirin versus clopidogrel plus aspirin on reducing the 3-month risk of any stroke (both ischemic and hemorrhagic, primary outcome) when initiated within 24 hours of symptom onset in CYP2Y19 LOF alleles carriers with TIA or minor stroke.

Detailed Description
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According to the Global Burden of Disease(GBD) Study 2016, China bears the greatest lifetime risk of stroke from 25-year-age onward. Minor ischemic events, including minor stroke and TIA, were major parts of stroke manifestations. Events (CHANCE) has shown that 21-day dual antiplatelet therapy (clopidogrel and aspirin) compared to aspirin alone which initiated within 24 hours after symptoms onset would reduce 32% risk of stroke recurrence within 90 day, but not in carriers of CYP2C19 loss-of-function (LOF) alleles. The primary purpose of this study is to compare ticagrelor plus aspirin with clopidogrel plus aspirin on reducing the 3-month risk of any stroke (both ischemic and hemorrhagic, primary outcome) when initiated within 24 hours of symptom onset in CYP2Y19 LOF alleles carriers with TIA or minor stroke. Both intent analysis (ITT) and compliance program set (PPS) were used for analysis. We will use Kaplan-Meier estimates of the cumulative risk of stroke (ischemic or hemorrhagic) event during maximum 90-day follow-up, with hazards ratios and 95% CI calculated using Cox proportional hazards methods and the log-rank test to evaluate the treatment effect. All statistics will be 2-sided with P<0.05 considered significant, accounting for interim analyses. All patients who received study drugs and with at least one safety follow-up record will be included in the safety population. The data for safety evaluation included adverse reactions observed during the trial and changes in laboratory data before and after treatment.

Official Title
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Clopidogrel With Aspirin in High-risk Patients With Acute Non-disabling Cerebrovascular Events II

Conditions
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Stroke, Transient Ischemic Attack

Intervention / Treatment
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* Drug: Ticagrelor and Aspirin
* Drug: Clopidogrel and Aspirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria 40 years or older than 40 years； Acute cerebral ischemic event due to： Acute non-disabling ischemic stroke (NIHSS≤3 at the time of randomization)or， TIA with moderate-to-high risk of stroke (ABCD2 score ≥ 4 at the time of randomization)； Can be treated with study drug within 24 hours of symptoms onset*(*Symptom onset is defined by the last seen normal principle)； CYP2C19 loss-of-function allele carriers； Informed consent signed. Exclusion Criteria 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. Iatrogenic causes (angioplasty or surgery) of minor stroke or TIA. Preceding moderate or severe dependency (modified Rankin scale [mRS] score 3-5). Contraindication to clopidogrel, ticagrelor or aspirin Known allergy Severe renal (creatinine exceeding 1.5 times of the upper limit of normal range) or hepatic (ALT or AST > twice the upper limit of normal range) insufficiency Severe cardiac failure (NYHA level: III to IV) History of hemostatic disorder or systemic bleeding History of thrombocytopenia or neutropenia History of drug-induced hematologic disorder or hepatic dysfunction Low white blood cell (<2×109/L) or platelet count (<100×109/L) Hematocrit (HCT) <30% Clear indication for anticoagulation (presumed cardiac source of embolus, e.g., atrial fibrillation, prosthetic cardiac valves known or suspected endocarditis) History of intracranial hemorrhage or amyloid angiopathy History of aneurysm (including intracranial aneurysm and peripheral aneurysm) History of asthma or COPD (chronic obstructive pulmonary disease) High-risk for bradyarrhythmia (first-degree or second-degree AV block caused by sinus node disease, and brady-arrhythmic syncope without pacemaker) History of hyperuricemia nephropathy Anticipated requirement for long-term (>7 days) non-steroidal anti-inflammatory drugs (NSAIDs) Planned or likely revascularization (any angioplasty or vascular surgery) within the next 3 months Scheduled for surgery or interventional treatment requiring study drug cessation Severe non-cardiovascular comorbidity with life expectancy < 3 months Inability to understand and/or follow research procedures due to mental, cognitive, or emotional disorders Dual antiplatelet treatment (or more than two antiplatelet agents) in 72 hours before randomization Current treatment (last dose given within 10 days before randomization) with heparin therapy or oral anti coagulation Intravenous thrombolytic therapy (such as intravenous rtPA) or mechanical thrombectomy within 24 hours prior to randomization Gastrointestinal bleed within 3 months or major surgery within 30 days Diagnosis or suspicious diagnosis of acute coronary syndrome Participation in another clinical study with an experimental product during the last 30 days Currently receiving an experimental drug or device Pregnant, currently trying to become pregnant, or of child-bearing potential and not using birth control

Ages Eligible for Study
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Minimum Age: 40 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 |
| --- | --- |
| Experimental: Ticagrelor plus Aspirin Group<br>Ticagrelor of loading dosing of 180mg followed by 90mg bid for 3 months plus aspirin of loading dose of 75-300mg followed by 75mg daily for 21 days | Drug: Ticagrelor and Aspirin<br>* Day of randomization: Day1:Ticagrelor 180mg; placebo of clopidogrel 300mg; aspirin 75-300mg (open label) Day2-21st: Ticagrelor 90mg bid/day; placebo of clopidogrel 75mg; aspirin 75mg (open label) Day 22nd-3 months:Ticagrelor 90mg bid/day; placebo of clopidogrel 75mg<br>|
| Active Comparator: Clopidogrel plus Aspirin Group<br>Clopidogrel of loading dosing of 300mg followed by 75mg daily for 3 months plus aspirin loading dose of 75-300mg followed by 75mg daily for 21 days | Drug: Clopidogrel and Aspirin<br>* Day of randomization: Day 1: Clopidogrel 300mg; placebo of ticagrelor 180mg; aspirin 75-300mg (open label) Day2-21st: Clopidogrel 75mg/day; placebo of ticagrelor 90mg bid/day; aspirin 75mg (open label) Day 22nd-3 months:Clopidogrel 75mg; placebo of ticagrelor 90mg bid/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Any new stroke events (ischemic stroke or hemorrhagic stroke) within 3 months | The aim is to assess the effects of ticagrelor plus aspirin versus clopidogrel plus aspirin on reducing the 3-month risk of any stroke (both ischemic and hemorrhagic, primary outcome) when initiated within 24 hours of symptom onset in CYP2Y19 LOF alleles carriers with TIA or minor stroke. | 3 months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Any new stroke events within 30 days and 1 year | Percentage of patients with the 30 days and 1 year new stroke events (ischemic stroke/ hemorrhagic stroke) as a cluster and evaluated individually. | 30 days and 1 year after randomization | 
| New clinical vascular events including stroke, TIA, myocardial infarction, and vascular deaths within 3 months and 1 year | Percentage of patients with the 3 months and 1 year new clinical vascular events (ischemic stroke/ hemorrhagic stroke/ TIA/ myocardial infarction/vascular death) | 3 months and 1 year after randomization | 
| New ischemic stroke within 3 months and 1 year | Percentage of patients with the 3 months and 1 year new ischemic stroke will be evaluated. | 3 months and 1 year after randomization | 
| Disabling stroke (Modified Rankin Scale score, mRS>1) at 3 months and 1 year | Modified Rankin Scale, a commonly used scale for measuring the degree of dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. 0 - No symptoms.1 - No significant disability. Able to carry out all usual activities, despite some symptoms.2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.3 - Moderate disability. Requires some help, but able to walk unassisted.4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.6 - Dead. The mRS scores between 3 to 6 points are considered to be poor functional outcome. (dead). | 3 months and 1 year after randomization | 
| Incidence and severity of recurrent stroke and TIA during follow-up to 3 months and 1-year | (Severity is measured using a six-level ordered categorical scale that incorporates the mRS: fatal stroke/severe non-fatal stroke [mRS 4 or 5]/moderate stroke [mRS 2 or 3]/mild stroke [mRS 0 or 1]/TIA/no stroke-TIA). | 3 months and 1 year after randomization | 
| Neurological impairment at 3 months (NIHSS increased≥4 from baseline) | The National Institutes of Health Stroke Scale (NIHSS) score classifies neurologic deficit from 0 (no deficit) to 42 (most severe). | 3 months after randomization | 
| Quality of Life (EuroQol EQ-5D scale) at 3 months and at 1 year | Further efficacy exploratory analysis:Quality of Life (EuroQol EQ-5D scale). We will use the EQ-5D-5L scale to evaluate the quality of life. EQ-5D-5L is a standardized instrument for measuring generic health status. It has been widely used in population health surveys, clinical studies, economic evaluation and in routine outcome measurement in the delivery of operational healthcare. The EQ-5D-5L has five domain scales (mobility, self-care, usual activities, pain and discomfort, and anxiety and depression) and five levels for each domain. | 3 months and 1 year after randomization | 
| Stratified analysis | The influence on treatment effect of age, gender, Body Mass Index (BMI), index event type (TIA vs. minor stroke), time from index event to randomization, etiology subtype, diabetes mellitus, hypertension, type of LOF allele, previous ischemic stroke or TIA, prior antiplatelet therapy, prior statin therapy, prior smoking status, and symptomatic intracranial and extracranial artery stenosis will be evaluated in subgroup analyses. | 3 months and 1 year after randomization | 

 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, ticagrelor, clopidogrel combined with ASA, ticagrelor combined with ASA, recurrence of stroke and other vascular events, CYP2C19 loss-of-function allele(s) carrier