Intensive Statin and Antiplatelet Therapy for High-risk Intracranial or Extracranial Atherosclerosis (INSPIRES)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 6,100
- 试验地点
- 113
- 主要终点
- Stroke
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Two nearly identical tablet forms of Clopidogrel (75mg Clopidogrel and matching placebo) with almost the same size, color and smell will be used in this research.
Two nearly identical tablet forms of Aspirin (100mg Aspirin and matching placebo) with almost the same size, color and smell will be used in this research.
Two nearly identical tablet forms of Atorvastatin (20mg Atorvastatin and matching placebo) with almost the same size, color and smell will be used in this research.
Centers are not able to apply unblinding with biological experiment in this study. Researchers shall never unblind the code unless special situations occur such as Serious Adverse Events (SAE), which is essential for treatment. Clinical outcomes of efficacy and safety are submitted to Adjudication Committee, who should be blinded to randomization, for final determination.
入排标准
- 年龄范围
- 35 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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;
- •Signed informed consent
排除标准
- •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.）
研究组 & 干预措施
DAPT + immediate high-intensity statin
This group will receive active clopidogrel and active aspirin (Dual antiplatelet therapy, DAPT); active atorvastatin calcium with high dosage in the early phase.
干预措施: Intensive antiplatelet (Drug)
DAPT + immediate high-intensity statin
This group will receive active clopidogrel and active aspirin (Dual antiplatelet therapy, DAPT); active atorvastatin calcium with high dosage in the early phase.
干预措施: Immediate high-intensity statin (Drug)
DAPT + delayed high-intensity statin
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.
干预措施: Intensive antiplatelet (Drug)
DAPT + delayed high-intensity statin
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.
干预措施: Delayed high-intensity statin (Drug)
Aspirin+immediate high-intensity statin
This group will receive active aspirin and clopidogrel placebo; active atorvastatin calcium with high dosage in the early phase.
干预措施: Standard antiplatelet (Drug)
Aspirin+immediate high-intensity statin
This group will receive active aspirin and clopidogrel placebo; active atorvastatin calcium with high dosage in the early phase.
干预措施: Immediate high-intensity statin (Drug)
Aspirin+delayed high-intensity statin
This group will receive active aspirin and clopidogrel placebo; atorvastatin calcium placebo and active atorvastatin calcium with moderate dosage in the early phase.
干预措施: Standard antiplatelet (Drug)
Aspirin+delayed high-intensity statin
This group will receive active aspirin and clopidogrel placebo; atorvastatin calcium placebo and active atorvastatin calcium with moderate dosage in the early phase.
干预措施: Delayed high-intensity statin (Drug)
结局指标
主要结局
Stroke
时间窗: 90 days
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
次要结局
- Ischemic stroke(90 days)
- Myocardial infarction(90 days)
- Quality of life (EQ-5D scale)(90 days)
- Composite vascular events(90 days)
- Ordinal stroke or TIA(90 days)
- Vascular death(90 days)
- Change of atherosclerotic plaque using high-resolution magnetic resonance imaging (HR-MRI)(90 days)
- Early Neurological Deficits(7 days)
- Transient ischemic attack(90 days)
- All-cause death(90 days)
- Poor functional outcome(90 days)
研究者
yilong Wang
Vice President of Beijing Tiantan Hospital
Beijing Tiantan Hospital