Intensive Medical Therapy for High-risk Intracranial or Extracranial Arterial Stenosis (INSPIRES)
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| ClinicalTrials.gov Identifier: NCT03635749 |
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Recruitment Status :
Not yet recruiting
First Posted : August 17, 2018
Last Update Posted : August 17, 2018
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Acute Stroke Transient Ischemic Attack | Drug: Dual antiplatelet Drug: Aspirin Drug: Early intensive statin Drug: Delayed intensive statin | Phase 3 |
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 early intensive statin therapy (80mg atorvastatin) versus delayed intensive 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 early intensive statin therapy (80mg atorvastatin) versus standard antiplatelet combined with delayed intensive 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 150 centers in China will be enrolled with one of the following situations 1.High risk TIA (ABCD2 ≥ 4) with stenosis of offending intracranial or extracranial artery ≥50%; 2.Acute ischemic stroke (NIHSS≤5) with stenosis of offending intracranial or extracranial artery ≥50%; 3.Acute ischemic stroke (NIHSS≤5) with multiple infractions. Patients will be randomly assigned into 4 groups according to the ratio of 1:1:1:1:
- Intensive antiplatelet therapy + early intensive statin therapy (80mg atorvastatin)
- Intensive antiplatelet therapy + delayed intensive statin therapy (40mg atorvastatin)
- Standard antiplatelet therapy + early intensive statin therapy (80mg atorvastatin)
- Standard antiplatelet therapy + delayed intensive 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.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 6100 participants |
| Allocation: | Randomized |
| Intervention Model: | Factorial Assignment |
| Intervention Model Description: | The subjects are randomly assigned to the following four groups:
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| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Masking Description: | 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. |
| Primary Purpose: | Treatment |
| Official Title: | Intensive Statin and Antiplatelet Therapy for High-risk Intracranial or Extracranial Arterial Stenosis (INSPIRES) |
| Estimated Study Start Date : | August 30, 2018 |
| Estimated Primary Completion Date : | November 30, 2021 |
| Estimated Study Completion Date : | December 30, 2023 |
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: DAPT + early intensive statin
This group will receive active clopidogrel and active aspirin (Dual antiplatelet therapy, DAPT); active atorvastatin calcium with high dosage in the early phase.
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Drug: Dual antiplatelet
Day 1：clopidogrel 300mg/day+ aspirin100-300mg/ day Day2 - 21: clopidogrel 75mg/day+ aspirin 100mg/day Day22 - 90: clopidogrel 75mg/day+aspirin placebo Other Name: Intensive antiplatelet Drug: Early intensive statin Day 1 - 21：Atorvastatin calcium 80mg/day Day 22 - 90：Atorvastatin calcium 40mg/day Other Name: Atorvastatin |
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DAPT + delayed intensive 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.
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Drug: Dual antiplatelet
Day 1：clopidogrel 300mg/day+ aspirin100-300mg/ day Day2 - 21: clopidogrel 75mg/day+ aspirin 100mg/day Day22 - 90: clopidogrel 75mg/day+aspirin placebo Other Name: Intensive antiplatelet Drug: Delayed intensive statin Day 1 - 3：Atorvastatin calcium placebo Day 4 - 21：Atorvastatin calcium 40mg/day + Atorvastatin calcium placebo Day 22 - 90：Atorvastatin calcium 40mg/day Other Name: Atorvastatin |
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Aspirin+early intensive statin
This group will receive active aspirin and clopidogrel placebo; active atorvastatin calcium with high dosage in the early phase.
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Drug: Aspirin
Day 1: Aspirin 100-300mg/day + clopidogrel placebo Day 2 - 90: Aspirin 100mg/day+ clopidogrel placebo Other Name: Standard antiplatelet Drug: Early intensive statin Day 1 - 21：Atorvastatin calcium 80mg/day Day 22 - 90：Atorvastatin calcium 40mg/day Other Name: Atorvastatin |
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Placebo Comparator: Aspirin+delayed intensive statin
This group will receive active aspirin and clopidogrel placebo; atorvastatin calcium placebo and active atorvastatin calcium with moderate dosage in the early phase.
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Drug: Aspirin
Day 1: Aspirin 100-300mg/day + clopidogrel placebo Day 2 - 90: Aspirin 100mg/day+ clopidogrel placebo Other Name: Standard antiplatelet Drug: Delayed intensive statin Day 1 - 3：Atorvastatin calcium placebo Day 4 - 21：Atorvastatin calcium 40mg/day + Atorvastatin calcium placebo Day 22 - 90：Atorvastatin calcium 40mg/day Other Name: Atorvastatin |
- Stroke [ Time Frame: 90 days ]including hemorrhagic and ischemic stroke
- Composite vascular events [ Time Frame: 90 days ]stroke (including hemorrhagic and ischemic stroke), myocardial infarction, and cardiovascular death.
- Ischemic stroke [ Time Frame: 90 days ]Symptomatic ischemic stroke
- Transient ischemic attack [ Time Frame: 90 days ]Transient ischemic attack
- Myocardial infarction [ Time Frame: 90 days ]Myocardial infarction
- Vascular death [ Time Frame: 90 days ]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.
- All-cause death [ Time Frame: 90 days ]All-cause death
- Poor functional outcome [ Time Frame: 90 days ]The modified Rankin Scale (mRS)= 2-6
- Quality of life (EQ-5D scale) [ Time Frame: 90 days ]Quality of life (EQ-5D scale)
- Change of atherosclerotic plaque using high-resolution magnetic resonance imaging (HR-MRI) [ Time Frame: 90 days ]Change of atherosclerotic plaque using high-resolution magnetic resonance 。 Patients in HR-MRI subgroup only
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| Ages Eligible for Study: | 35 Years to 80 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Age :35-80 years old , male or female;
- Less than 72 hours from the onset;
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Any of the following three situations:
- Medium-high risk TIA (ABCD2 ≥ 4) with criminal extracranial or intracranial arteries (stenosis ≥50%)
- Acute single cerebral infarction (NIHSS≤5) with criminal extracranial or intracranial arteries (stenosis ≥50%).
- Acute multiple cerebral infarction (NIHSS≤5) with criminal extracranial or intracranial arteries. (stenosis degree unlimited)
- 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
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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
- Intravenous or arterial thrombolysis or intravascular therapy after onset
- Accepting defibrinogen therapy including defibrase and lumbrokinase after onset
- Creatine Kinase(CK) more than 5 times of the upper limit of normal value after onset
- Drugs affecting the metabolism of statins such as immune-suppressive drugs, antifungal agents, or fibrates drugs and so on, which were used 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 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)
- Intensive statin therapy have been conducted after onset and before randomization.（atorvastatin ≥40mg or rosuvastatin ≥ 20mg）.
- 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
- Long term use of non-research-oriented antiplatelet agents or Nonsteroidal Antiinflammatory 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.）
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03635749
| Contact: Yilong Wang, MD, PhD | 0086-010-67092222 | yilong528@gmail.com |
Show 226 Study Locations
| Principal Investigator: | Yilong Wang, MD, PhD | Beijing Tiantan Hospital |
| Responsible Party: | Yilong Wang, Director of Department of Science & Research Administration of Beijing Tiantan Hospital, Ministry of Science and Technology of the People´s Republic of China |
| ClinicalTrials.gov Identifier: | NCT03635749 History of Changes |
| Other Study ID Numbers: |
2017YFC1307905 |
| First Posted: | August 17, 2018 Key Record Dates |
| Last Update Posted: | August 17, 2018 |
| Last Verified: | August 2018 |
| Studies a U.S. FDA-regulated Drug Product: | No |
| Studies a U.S. FDA-regulated Device Product: | No |
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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 |
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Stroke Ischemic Attack, Transient Constriction, Pathologic Cerebrovascular Disorders Brain Diseases Central Nervous System Diseases Nervous System Diseases Vascular Diseases Cardiovascular Diseases Pathological Conditions, Anatomical Brain Ischemia Aspirin Calcium, Dietary Clopidogrel Atorvastatin |
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