Clinical trial NCT03635749: Intensive Medical Therapy for High-risk Intracranial or Extracranial Atherosclerosis
Official title: Intensive Statin and Antiplatelet Therapy for High-risk Intracranial or Extracranial Atherosclerosis (INSPIRES)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Acute Stroke
Transient Ischemic Attack
Keywords: 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
Lead sponsor: Beijing Tiantan Hospital
Sponsor class: OTHER
Collaborators: name: Ministry of Science and Technology of the People´s Republic of China
First posted: 2018-08-17
Enrollment: 6100
Sex: ALL
Minimum age (years): 35
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: The subjects are randomly assigned to the following four groups:

1. Intensive antiplatelet therapy + immediate high-intensity statin therapy (80mg atorvastatin)
2. Intensive antiplatelet therapy + delayed high-intensity statin therapy (40mg atorvastatin)
3. Standard antiplatelet therapy + immediate high-intensity statin therapy (80mg atorvastatin)
4. Standard antiplatelet therapy + delayed high-intensity statin therapy (40mg atorvastatin)
Primary purpose: TREATMENT

Brief summary: 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: 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:

1. Intensive antiplatelet therapy + immediate high-intensity statin therapy (80mg atorvastatin)
2. Intensive antiplatelet therapy + delayed high-intensity statin therapy (40mg atorvastatin)
3. Standard antiplatelet therapy + immediate high-intensity statin therapy (80mg atorvastatin)
4. 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.

Eligibility criteria: Inclusion Criteria:

1. Age :35-80 years old , male or female;
2. 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:

1. Acute single cerebral infarction with criminal intracranial and extracranial atherosclerotic stenosis (stenosis rate ≥50%)
2. 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:

1. Medium and high risk TIA with criminal intracranial and extracranial atherosclerotic stenosis (stenosis rate ≥50%)
2. Acute single cerebral infarction with criminal intracranial and extracranial atherosclerotic stenosis (stenosis rate ≥50%)
3. 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:

1. Specific cardiogenic ischemic cerebrovascular diseases(eg. combined with atrial fibrillation, heart valve prosthesis, atrial myxoma, endocarditis, etc.)
2. Other ischemic cerebrovascular diseases with specific causes (eg. aortic dissection, vasculitis, vascular malformation, etc.)
3. Non-cerebral vascular disease (eg. intracranial tumors, multiple sclerosis)
4. Cerebral infarction of large area (infarct size greater than half the single lobe area)
5. CT indicating hemorrhagic transformation of cerebral infarction before randomization
6. 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
7. MRS \> 2 before the onset
8. Use of intravenous or arterial thrombolysis intravascular therapy or bridge therapy after onset
9. 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.
10. Creatine Kinase(CK) more than 5 times of the upper limit of normal value after onset
11. 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.
12. 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)
13. 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)
14. Use of Intensive statin therapy within 14 days before randomization（atorvastatin ≥40mg/d or rosuvastatin ≥ 20mg/d）.
15. Pre-existing intracranial hemorrhage（eg. ICH, SAH）
16. Gastrointestinal bleeding or major surgery occurred within 90 days before randomization.
17. Pre-existing extracranial angioplasty or vascular surgery
18. Anticipated requirement for long-term non-study antiplatelet drugs, or non-steroid anti-inflammatory drugs.
19. Experimental drugs need to stop due to angioplasty or vascular surgery, which was planned or likely to perform within 90 days after randomization
20. Patients with severe disease expected to live for less than 90 days
21. Pregnant or childbearing-age women who have no effective contraceptives or positive pregnancy test records
22. Patients who are undergoing experimental drugs or device tests
23. 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.）

Primary outcomes:
measure: Stroke
timeFrame: 90 days
Secondary outcomes:
measure: Composite vascular events
timeFrame: 90 days
measure: Ischemic stroke
timeFrame: 90 days
measure: Transient ischemic attack
timeFrame: 90 days
measure: Myocardial infarction
timeFrame: 90 days
measure: Vascular death
timeFrame: 90 days
measure: All-cause death
timeFrame: 90 days
measure: Poor functional outcome
timeFrame: 90 days
measure: Quality of life (EQ-5D scale)
timeFrame: 90 days
measure: Change of atherosclerotic plaque using high-resolution magnetic resonance imaging (HR-MRI)
timeFrame: 90 days
measure: Early Neurological Deficits
timeFrame: 7 days
measure: Ordinal stroke or TIA
timeFrame: 90 days
Other outcomes:
Locations:
city: Beijing
country: China
facility: Tiantan Hospital
state: Beijing
city: Anshan
country: China
facility: Anshan Central Hospital
city: Anshan
country: China
facility: General Hospital of Anshan Iron and Steel Company
city: Anyang
country: China
facility: Anyang People's Hospital
city: Baoding
country: China
facility: Baoding First Central Hospital
city: Beijing
country: China
facility: Beijing Hepingli Hospital
city: Benxi
country: China
facility: Benxi Central Hospital
city: Changsha
country: China
facility: First Hospital of Changsha
city: Changsha
country: China
facility: Second people's Hospital of Hunan Province
city: Changsha
country: China
facility: Xiangya Third Hospital of Central South University
city: Changzhi
country: China
facility: Changzhi Medical College Affiliated Heping Hospital
city: Changzhi
country: China
facility: Changzhi People's Hospital
city: Changzhi
country: China
facility: Lu'an Group General Hospital
city: Changzhou
country: China
facility: Changzhou Second People's Hospital
city: Changzhou
country: China
facility: Changzhou Wujin Hospital of Traditional Chinese Medicine
city: Chongqing
country: China
facility: Chongqing Sanxia Central Hospital
city: Chongqing
country: China
facility: Southwest Hospital affiliated to the Army Military Medical University
city: Dalian
country: China
facility: Dalian Central Hospital
city: Dalian
country: China
facility: Dalian Friendship Hospital
city: Dalian
country: China
facility: Second people's Hospital of Dalian
city: Dalian
country: China
facility: Xinhua Hospital Affiliated to Dalian University
city: Dali
country: China
facility: People's Hospital of Dali Bai Autonomous Prefecture
city: Datong
country: China
facility: Datong Third People's Hospital
city: Dazhou
country: China
facility: Dazhou Central Hospital
city: Dongguan
country: China
facility: Dongguan Hong Wah hospital
city: Dongguan
country: China
facility: Donghua Hospital
city: Dongyang
country: China
facility: Dongyang People's Hospital
city: Dongying
country: China
facility: People's Hospital of Dongying District
city: Fushun
country: China
facility: General Hospital of Fushun Mining Bureau
city: Fuxin
country: China
facility: Fuxin Mining Group General Hospital
city: Guilin
country: China
facility: Nanxi Mountain hospital in Guangxi District
city: Guiyang
country: China
facility: Guiyang Second Hospital
city: Ha'erbin
country: China
facility: General Hospital of the General Administration of agriculture and reclamation of Heilongjiang
city: Handan
country: China
facility: Handan Central Hospital
city: Handan
country: China
facility: Handan First Hospital
city: Hebei
country: China
facility: Second hospital of Hebei Medical University
city: Hengshui
country: China
facility: Hengshui Sixth People's Hospital
city: Hengyang
country: China
facility: Nanhua Hospital Affiliated to Nanhua University
city: Hohhot
country: China
facility: The Inner Mongolia Autonomous Region people's Hospital
city: Jiamusi
country: China
facility: First Affiliated Hospital of Jiamusi University
city: Jiamusi
country: China
facility: Jiamusi Central Hospital
city: Jilin
country: China
facility: Jilin Electric Power Hospital
city: Jilin
country: China
facility: Jinlin Central Hospital
city: Jilin
country: China
facility: Jinlin People's Hospital
city: Jilin
country: China
facility: Second hospital of Jilin University
city: Jinan
country: China
facility: Qianfo Hill Hospital of Shandong Province
city: Jinan
country: China
facility: Shandong Transportation Hospital
city: Jiujiang
country: China
facility: Affiliated Hospital of Jiujiang University
city: Jixi
country: China
facility: Jixi People's Hospital
city: Kai Feng
country: China
facility: Kaifeng Central Hospital
city: Liaocheng
country: China
facility: Liaocheng Brain Hospital
city: Liaocheng
country: China
facility: Liaocheng Second People's Hospital
city: Liaoyang
country: China
facility: Liaoyang Central Hospital
city: Linfen
country: China
facility: Linfen People's Hospital
city: Luoyang
country: China
facility: Second Affiliated Hospital of Henan University of Science and Technology
city: Luzhou
country: China
facility: Luzhou Hospital of traditional Chinese Medicine
city: Mishan
country: China
facility: Mishan People's Hospital
city: Mudanjiang
country: China
facility: Mudanjiang Second People's Hospital
city: Nanchang
country: China
facility: Fourth Affiliated Hospital of Nanchang University
city: Nanchang
country: China
facility: Third Affiliated Hospital of Nanchang University
city: Nanjing
country: China
facility: Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine
city: Ningbo
country: China
facility: Li Huili Hospital of Ningbo Medical Center
city: Ningbo
country: China
facility: Ningbo Second Hospital
city: Ningde
country: China
facility: Ningde People's Hospital
city: Panjin
country: China
facility: Panjin Central Hospital
city: Pingdingshan
country: China
facility: Pindingshan First People's Hospital
city: Qiqihar
country: China
facility: Qiqihar First Hospital
city: Rizhao
country: China
facility: Ruzhou First People's Hospital
city: Sanmenxia
country: China
facility: Sanmenxia Central Hospital
city: Shanghai
country: China
facility: Fifth People's Hospital of Shanghai City, affiliated to Fudan University
city: Shanghai
country: China
facility: Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine
city: Shanxi
country: China
facility: Second hospital of Shanxi Medical University
city: Shaoxing
country: China
facility: Shengzhou People's Hospital
city: Shenyang
country: China
facility: Heilongjiang Agriculture and Reclamation Bei'an Administration Central Hospital
city: Shenzhen
country: China
facility: Shenzhen Second People's Hospital
city: Shijiazhuang
country: China
facility: Shijiazhuang Pingan Hospital
city: Suzhou
country: China
facility: First Hospital Affiliated to Suzhou University
city: Suzhou
country: China
facility: The Second Hospital Affiliated to Suzhou University
city: Taizhou
country: China
facility: Taizhou First People's Hospital
city: Tangshan
country: China
facility: Affiliated Hospital of North China Polytechnic University
city: Tangshan
country: China
facility: Tangshan Workers' Hospital
city: Tianjin
country: China
facility: Tianjin Fourth Central Hospital
city: Tieling
country: China
facility: Tieling Central Hospital
city: Weifang
country: China
facility: Gaomi People's Hospital
city: Weihai
country: China
facility: People's Hospital of Wendeng District
city: Wuhan
country: China
facility: People's Hospital of Wuhan University
city: Wuhan
country: China
facility: Wuhan Central Hospital
city: Wuwei
country: China
facility: Gansu Academy of Medical Sciences, Wuwei
city: Wuxi
country: China
facility: Wuxi People's Hospital
city: Wuxi
country: China
facility: Wuxi Second People's Hospital
city: Xi'an
country: China
facility: Xi'an 141 hospital
city: Xi'an
country: China
facility: Xian First Hospital
city: Xinxiang
country: China
facility: Xinxiang Central Hospital
city: Xinyang
country: China
facility: Xinyang Central Hospital
city: Xuchang
country: China
facility: Xuchang Central Hospital
city: Xuzhou
country: China
facility: General Hospital of Xuzhou Mining Group
city: Xuzhou
country: China
facility: Xuzhou First People's Hospital
city: Yantai
country: China
facility: Yantai Yuhuangding Hospital Affiliated to Qiingdao University
city: Yibin
country: China
facility: Yibin First People's Hospital
city: Yichang
country: China
facility: Yichang First People's Hospital
city: Yingkou
country: China
facility: Yingkou Central Hospital
city: Yueyang
country: China
facility: Yueyang Hospital of integrated traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine
city: Yunnan
country: China
facility: Dehong People's Hospital of Yunnan
city: Zaozhuang
country: China
facility: Zaozhuang Mining Group Zaozhuang hospital
city: Zhangjiagang
country: China
facility: Zhangjiagang First People's Hospital
city: Zhangjiagang
country: China
facility: Zhangjiagang Traditional Chinese Medicine Hospital
city: Zhangjiakou
country: China
facility: Workers' Hospital of Hebei iron and Steel Group Xuanhua iron and Steel Co., Ltd.
city: Zhengzhou
country: China
facility: Central Hospital of the Yellow River
city: Zhengzhou
country: China
facility: Zhengzhou First People's Hospital
city: Zhenjiang
country: China
facility: Affiliated Hospital of Jiangsu University
city: Zhoukou
country: China
facility: Zhoukou Yongshan hospital
city: Zhumadian
country: China
facility: Zhumadian Central Hospital
city: Zigong
country: China
facility: Zigong First People's Hospital
Study officials:
affiliation: Beijing Tiantan Hospital
name: Yilong Wang, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: