Intensive Medical Therapy for High-risk Intracranial or Extracranial Atherosclerosis

Study Overview
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Brief Summary
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Large-artery stenosis plays an important role in the occurrence of ischemic stroke. The primary purpose of this study is to evaluate the efficacy and safety of intensive antiplatelet therapy versus standard antiplatelet therapy and immediate high-intensity statin therapy (80mg atorvastatin) versus delayed high-intensity statin therapy (40mg atorvastatin) and intensive antiplatelet combined with immediate high-intensity statin therapy (80mg atorvastatin) versus standard antiplatelet combined with delayed high-intensity statin therapy (40mg atorvastatin) in reducing the risk of stroke at 90 days in patients with acute and high-risk symptomatic extracranial or intracranial arterial stenosis.

Detailed Description
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Large-artery atherosclerotic stenosis is the main cause of ischemic stroke, especially in Asian population. However, targeted treatment evidence for large-artery atherosclerotic stenosis is limited according to the current guidelines. And also, randomized trial for statin therapy in patients with acute large arterial stenosis at early stage is still limited. The primary purpose of this study is to evaluate the efficacy and safety of intensive antiplatelet therapy versus standard antiplatelet therapy in reducing the risk of stroke at 90 days in patients with acute and high-risk symptomatic extracranial or intracranial arterial stenosis; the efficacy and safety of immediate high-intensity statin therapy (80mg atorvastatin) versus delayed high-intensity statin therapy (40mg atorvastatin) in reducing the risk of stroke at 90 days in patients with acute and high-risk symptomatic extracranial or intracranial arterial stenosis; and the efficacy and safety of intensive antiplatelet combined with immediate high-intensity statin therapy (80mg atorvastatin) versus standard antiplatelet combined with delayed high-intensity statin therapy (40mg atorvastatin) in reducing the risk of stroke at 90 days in patients with acute and high-risk symptomatic extracranial or intracranial arterial stenosis. This trial is a randomized, double-blind, placebo-controlled, multicenter, 2×2 factorial designed clinical trial. 6100 patients in 250 centers in China will be enrolled with one of the following situations (1) Mild ischemic stroke (NIHSS 4 5) within 24 hours of onset meets any of the following imaging conditions: a) Acute single cerebral infarction with criminal intracranial and extracranial atherosclerotic stenosis (stenosis rate ≥50%),b) Acute multiple cerebral infarction (considered to be caused by large artery atherosclerosis, including non-stenotic vulnerable plaque);Or (2) Moderate-to-high-risk TIA (ABCD2≥4) or mild ischemic stroke (NIHSS≤5) within 24 to 72 hours of onset meets any of the following imaging conditions: a) Medium and high risk TIA with criminal intracranial and extracranial atherosclerotic stenosis (stenosis rate ≥50%),b) Acute single cerebral infarction with criminal intracranial and extracranial atherosclerotic stenosis (stenosis rate ≥50%),c) Acute multiple cerebral infarction (considered to be caused by large artery atherosclerosis, including non-stenotic vulnerable plaque) . Patients will be randomly assigned into 4 groups according to the ratio of 1:1:1:1: Intensive antiplatelet therapy + immediate high-intensity statin therapy (80mg atorvastatin) Intensive antiplatelet therapy + delayed high-intensity statin therapy (40mg atorvastatin) Standard antiplatelet therapy + immediate high-intensity statin therapy (80mg atorvastatin) Standard antiplatelet therapy + delayed high-intensity statin therapy (40mg atorvastatin) Face to face interviews will be made at baseline, 7, 14 (or hospital discharge), 90 ± 7 days and 12th month ± 14 days after randomization. Survival curves will be estimated for the primary outcome using the Kaplan-Meier procedure and compared using a Cox regression model Wald test, stratified by the opposite arm of the factorial design. Safety outcomes will be calculated using the Kaplan-Meier curve to simulate the 3-month cumulative risk, and the Cox proportional hazards model to calculate the HR and 95% confidence interval. Primary outcome is defined as stroke (including hemorrhagic and ischemic stroke). Secondary outcomes include composite vascular events (stroke, myocardial infarction, and cardiovascular death); ischemic stroke; transient ischemic attack; myocardial infarction; vascular death; all-cause death; poor functional outcome (mRS 2-6); and quality of life (EQ-5D scale). Safety outcomes, relating to antiplatelet therapy (i.e. bleeding, intracranial hemorrhage, and adverse events) and statin therapy (i.e. hepatotoxicity, muscle toxicity and adverse events) will be investigated.

Official Title
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Intensive Statin and Antiplatelet Therapy for High-risk Intracranial or Extracranial Atherosclerosis (INSPIRES)

Conditions
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Acute Stroke, Transient Ischemic Attack

Intervention / Treatment
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* Drug: Intensive antiplatelet
* Drug: Standard antiplatelet
* Drug: Immediate high-intensity statin
* Drug: Delayed high-intensity statin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age :35-80 years old , male or female; Any of the following three two situations: (1) Mild ischemic stroke (NIHSS 4 to 5 points) within 24 hours of onset meets any of the following imaging conditions: Acute single cerebral infarction with criminal intracranial and extracranial atherosclerotic stenosis (stenosis rate ≥50%) Acute multiple cerebral infarction (considered to be caused by large artery atherosclerosis, including non-stenotic vulnerable plaque) Or (2) Moderate-to-high-risk TIA (ABCD2≥4 points) or mild ischemic stroke (NIHSS≤5 points) within 24 to 72 hours of onset meets any of the following imaging conditions: Medium and high risk TIA with criminal intracranial and extracranial atherosclerotic stenosis (stenosis rate ≥50%) Acute single cerebral infarction with criminal intracranial and extracranial atherosclerotic stenosis (stenosis rate ≥50%) Acute multiple cerebral infarction (considered to be caused by large artery atherosclerosis, including non-stenotic vulnerable plaque) The rate of intracranial artery stenosis is assessed by MRA, CTA, or DSA according to WASID standards; the rate of extracranial artery stenosis is assessed by carotid ultrasound, CEMRA, CTA or DSA, according to NASCET standards; 3. Signed informed consent Exclusion Criteria: Specific cardiogenic ischemic cerebrovascular diseases(eg. combined with atrial fibrillation, heart valve prosthesis, atrial myxoma, endocarditis, etc.) Other ischemic cerebrovascular diseases with specific causes (eg. aortic dissection, vasculitis, vascular malformation, etc.) Non-cerebral vascular disease (eg. intracranial tumors, multiple sclerosis) Cerebral infarction of large area (infarct size greater than half the single lobe area) CT indicating hemorrhagic transformation of cerebral infarction before randomization Patients with pre-existing contraindications of using clopidogrel, aspirin or statin drugs: Known history of allergy ; Severe heart failure and asthma ; Coagulant disorders and systemic bleeding ; Pre-existing drug - induced blood system disease or abnormal liver function ; Leukopenia (< 2×109/l) or thrombocytopenia (<100×109/l) ; active liver disease ; pregnancy or lactation period ; Severe heart failure：New York Heart Association (NYHA) Functional Classification III and IV MRS > 2 before the onset Use of intravenous or arterial thrombolysis intravascular therapy or bridge therapy after onset Use of defibrinating therapy like snake venom, defibrase, lumbrokinase, etc. or use of anticoagulant therapy like argatroban, or use of antiplatelet therapy except clopidogrel and aspirin, such as tirofiban, ticagrelor, ozagrel, and so on after onset. Creatine Kinase(CK) more than 5 times of the upper limit of normal value after onset Use of drugs affecting the metabolism of statins such as immune-suppressive drugs, antifungal agents, or fibrates drugs and so on, within 14 days before randomization. Severe hepatic or renal insufficiency (Note: Severe hepatic insufficiency refers to the ALT value > 2 times the upper limit of normal value or AST times > 2 times the upper limit of normal value; Severe hepatic insufficiency is refers to creatinine values > 1.5 times he upper limit of normal value or GFR < 40 ml/min/1.73 m2) Usage of dual antiplatelet therapy with aspirin plus clopidogrel within 14 days before randomization. (patients who received dual antiplatelet therapy (aspirin combined with clopidogrel) but did not use clopidogrel with loading dose after onset were excluded) Use of Intensive statin therapy within 14 days before randomization（atorvastatin ≥40mg/d or rosuvastatin ≥ 20mg/d）. Pre-existing intracranial hemorrhage（eg. ICH, SAH） Gastrointestinal bleeding or major surgery occurred within 90 days before randomization. Pre-existing extracranial angioplasty or vascular surgery Anticipated requirement for long-term non-study antiplatelet drugs, or non-steroid anti-inflammatory drugs. Experimental drugs need to stop due to angioplasty or vascular surgery, which was planned or likely to perform within 90 days after randomization Patients with severe disease expected to live for less than 90 days Pregnant or childbearing-age women who have no effective contraceptives or positive pregnancy test records Patients who are undergoing experimental drugs or device tests Unable to finish the follow-up of 90 days due to geographical factor or other reasons（eg. dementia, alcoholism, substance abuse, severe mental disease, etc.）

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 80 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: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: The subjects are randomly assigned to the following four groups: Intensive antiplatelet therapy + immediate high-intensity statin therapy (80mg atorvastatin) Intensive antiplatelet therapy + delayed high-intensity statin therapy (40mg atorvastatin) Standard antiplatelet therapy + immediate high-intensity statin therapy (80mg atorvastatin) Standard antiplatelet therapy + delayed high-intensity statin therapy (40mg atorvastatin)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: DAPT + immediate high-intensity statin<br>This group will receive active clopidogrel and active aspirin (Dual antiplatelet therapy, DAPT); active atorvastatin calcium with high dosage in the early phase. | Drug: Intensive antiplatelet<br>* Day 1：clopidogrel 300mg/day+ aspirin100-300mg/ day Day2 - 21: clopidogrel 75mg/day+ aspirin 100mg/day Day22 - 90: clopidogrel 75mg/day+aspirin placebo<br>* Other names: Dual antiplatelet;Drug: Immediate high-intensity statin<br>* Day 1 - 21：Atorvastatin calcium 80mg/day Day 22 - 90：Atorvastatin calcium 40mg/day<br>* Other names: Immediate Atorvastatin;|
| Other: DAPT + delayed high-intensity statin<br>This group will receive active clopidogrel and active aspirin (Dual antiplatelet therapy, DAPT); atorvastatin calcium placebo and active atorvastatin calcium with moderate dosage in the ealy phase. | Drug: Intensive antiplatelet<br>* Day 1：clopidogrel 300mg/day+ aspirin100-300mg/ day Day2 - 21: clopidogrel 75mg/day+ aspirin 100mg/day Day22 - 90: clopidogrel 75mg/day+aspirin placebo<br>* Other names: Dual antiplatelet;Drug: Delayed high-intensity statin<br>* Day 1 - 3：Atorvastatin calcium placebo Day 4 - 21：Atorvastatin calcium 40mg/day + Atorvastatin calcium placebo Day 22 - 90：Atorvastatin calcium 40mg/day<br>* Other names: Delayed Atorvastatin;|
| Other: Aspirin+immediate high-intensity statin<br>This group will receive active aspirin and clopidogrel placebo; active atorvastatin calcium with high dosage in the early phase. | Drug: Standard antiplatelet<br>* Day 1: Aspirin 100-300mg/day + clopidogrel placebo Day 2 - 90: Aspirin 100mg/day+ clopidogrel placebo<br>* Other names: Aspirin;Drug: Immediate high-intensity statin<br>* Day 1 - 21：Atorvastatin calcium 80mg/day Day 22 - 90：Atorvastatin calcium 40mg/day<br>* Other names: Immediate Atorvastatin;|
| Placebo Comparator: Aspirin+delayed high-intensity statin<br>This group will receive active aspirin and clopidogrel placebo; atorvastatin calcium placebo and active atorvastatin calcium with moderate dosage in the early phase. | Drug: Standard antiplatelet<br>* Day 1: Aspirin 100-300mg/day + clopidogrel placebo Day 2 - 90: Aspirin 100mg/day+ clopidogrel placebo<br>* Other names: Aspirin;Drug: Delayed high-intensity statin<br>* Day 1 - 3：Atorvastatin calcium placebo Day 4 - 21：Atorvastatin calcium 40mg/day + Atorvastatin calcium placebo Day 22 - 90：Atorvastatin calcium 40mg/day<br>* Other names: Delayed Atorvastatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stroke | Symptoms and signs of acute neurological deficits caused by sudden focal or whole brain, spinal cord or retinal vascular damage, which are related to cerebral circulatory disorders, including hemorrhagic and ischemic stroke | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite vascular events | stroke (including hemorrhagic and ischemic stroke), myocardial infarction, and cardiovascular death. | 90 days | 
| Ischemic stroke | An acute focal infarction of the brain or retina. Criteria:(1) acute onset of a new focal neurological deficit with clinical or imaging evidence of infarction lasting more than 24 hours and not attributable to a non-ischemic etiology (not associated with brain infection, trauma, tumor, seizure, severe metabolic disease, or degenerative neurological disease); or (2) acute onset of a new focal neurological deficit and not attributable to a non-ischemic etiology lasting less than 24 hours, but accompanied by neuroimaging evidence of new brain infarction; or, (3) rapid worsening of an existing focal neurological deficit (an increase in NIHSS of ≥4 on the basis of a primary ischemic stroke, excluding hemorrhagic transformation or symptomatic cranial disease after infarction) lasting more than 24 hours and not attributable to a non-ischemic etiology, and accompanied by new ischemic changes on brain MRI or CT. | 90 days | 
| Transient ischemic attack | A neurological deficit of sudden onset, resolving completely, attributed to focal brain or retinal ischemia without evidence of associated acute focal infarction of the brain. Criteria: rapid onset of a focal neurological deficit that is without evidence of acute focal infarction of the brain, and is not attributable to a non-ischemic etiology (brain infection, trauma, tumor, seizure, severe metabolic disease, or degenerative neurological disease) | 90 days | 
| Myocardial infarction | Acute myocardial infarction is diagnosed by the third edition of the international general diagnostic criteria (Glob Heart. 2012 Dec;7(4):275-95) | 90 days | 
| Vascular death | Vascular death includes stroke, sudden cardiac death, acute myocardial infarction, heart failure, pulmonary embolism, heart / cerebrovascular intervention or surgery (death unrelated to acute MI) and other cardiovascular causes of death [such as: Arrhythmia irrelevant with sudden cardiac death, aortic aneurysm rupture, or peripheral artery disease. Any death of unknown/unclear cause that occurs within 30 days after stroke, myocardial infarction, or cardio-cerebrovascular operation/surgery will be regarded as death due to stroke, myocardial infarction, or cardio-cerebrovascular operation/surgery, respectively. | 90 days | 
| All-cause death | All-cause death | 90 days | 
| Poor functional outcome | The modified Rankin Scale (mRS)= 2-6 | 90 days | 
| Quality of life (EQ-5D scale) | EQ-5D scale index score ≤0.5 | 90 days | 
| Change of atherosclerotic plaque using high-resolution magnetic resonance imaging (HR-MRI) | Change of atherosclerotic plaque using high-resolution magnetic resonance 。 Patients in HR-MRI subgroup only | 90 days | 
| Early Neurological Deficits | NIHSS score increase of no less than 2points | 7 days | 
| Ordinal stroke or TIA | The new stroke or TIA is classified on a six-level ordered category scale combined vascular events with mRS score at 90 days or at 1year, respectively: fatal stroke (stroke with subsequent death), severe stroke (stroke followed by mRS of 4-5), moderate stroke (stroke followed by mRS of 2-3), mild stroke (stroke followed by mRS of 0-1), TIA and no stroke/TIA. | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Stroke, Transient Ischemic Attack, Antiplatelet Therapy, Randomized Controlled Trial, Double Blind Study, Multicenter Study, Symptomatic Extracranial or Intracranial Arterial Stenosis, Statin Therapy, Clinical Trial