Intensive Medical Therapy for High-risk Intracranial or Extracranial Atherosclerosis

Acute Stroke Clinical Trial

— INSPIRES  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03635749
• Other study ID #: 2017YFC1307905
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: September 17, 2018
• Est. completion date: October 30, 2023

Study information

• Verified date: July 2023
• Source: Beijing Tiantan Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 6100
• Est. completion date: October 30, 2023
• Est. primary completion date: January 15, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 35 Years to 80 Years

Eligibility

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.)

Related Conditions & MeSH terms

• Acute Stroke
• Atherosclerosis
• Ischemic Attack, Transient
• Stroke
• Transient Ischemic Attack

Intervention

Drug:
• Intensive antiplatelet
Day 1:clopidogrel 300mg/day+ aspirin100-300mg/ day Day2 - 21: clopidogrel 75mg/day+ aspirin 100mg/day Day22 - 90: clopidogrel 75mg/day+aspirin placebo
• Standard antiplatelet
Day 1: Aspirin 100-300mg/day + clopidogrel placebo Day 2 - 90: Aspirin 100mg/day+ clopidogrel placebo
• Immediate high-intensity statin
Day 1 - 21:Atorvastatin calcium 80mg/day Day 22 - 90:Atorvastatin calcium 40mg/day
• Delayed high-intensity statin
Day 1 - 3:Atorvastatin calcium placebo Day 4 - 21:Atorvastatin calcium 40mg/day + Atorvastatin calcium placebo Day 22 - 90:Atorvastatin calcium 40mg/day

Locations

Country	Name	City	State
China	Anshan Central Hospital	Anshan
China	General Hospital of Anshan Iron and Steel Company	Anshan
China	Anyang People's Hospital	Anyang
China	Baoding First Central Hospital	Baoding
China	Beijing Hepingli Hospital	Beijing
China	Tiantan Hospital	Beijing	Beijing
China	Benxi Central Hospital	Benxi
China	First Hospital of Changsha	Changsha
China	Second people's Hospital of Hunan Province	Changsha
China	Xiangya Third Hospital of Central South University	Changsha
China	Changzhi Medical College Affiliated Heping Hospital	Changzhi
China	Changzhi People's Hospital	Changzhi
China	Lu'an Group General Hospital	Changzhi
China	Changzhou Second People's Hospital	Changzhou
China	Changzhou Wujin Hospital of Traditional Chinese Medicine	Changzhou
China	Chongqing Sanxia Central Hospital	Chongqing
China	Southwest Hospital affiliated to the Army Military Medical University	Chongqing
China	People's Hospital of Dali Bai Autonomous Prefecture	Dali
China	Dalian Central Hospital	Dalian
China	Dalian Friendship Hospital	Dalian
China	Second people's Hospital of Dalian	Dalian
China	Xinhua Hospital Affiliated to Dalian University	Dalian
China	Datong Third People's Hospital	Datong
China	Dazhou Central Hospital	Dazhou
China	Dongguan Hong Wah hospital	Dongguan
China	Donghua Hospital	Dongguan
China	Dongyang People's Hospital	Dongyang
China	People's Hospital of Dongying District	Dongying
China	General Hospital of Fushun Mining Bureau	Fushun
China	Fuxin Mining Group General Hospital	Fuxin
China	Nanxi Mountain hospital in Guangxi District	Guilin
China	Guiyang Second Hospital	Guiyang
China	General Hospital of the General Administration of agriculture and reclamation of Heilongjiang	Ha'erbin
China	Handan Central Hospital	Handan
China	Handan First Hospital	Handan
China	Second hospital of Hebei Medical University	Hebei
China	Hengshui Sixth People's Hospital	Hengshui
China	Nanhua Hospital Affiliated to Nanhua University	Hengyang
China	The Inner Mongolia Autonomous Region people's Hospital	Hohhot
China	First Affiliated Hospital of Jiamusi University	Jiamusi
China	Jiamusi Central Hospital	Jiamusi
China	Jilin Electric Power Hospital	Jilin
China	Jinlin Central Hospital	Jilin
China	Jinlin People's Hospital	Jilin
China	Second hospital of Jilin University	Jilin
China	Qianfo Hill Hospital of Shandong Province	Jinan
China	Shandong Transportation Hospital	Jinan
China	Affiliated Hospital of Jiujiang University	Jiujiang
China	Jixi People's Hospital	Jixi
China	Kaifeng Central Hospital	Kai Feng
China	Liaocheng Brain Hospital	Liaocheng
China	Liaocheng Second People's Hospital	Liaocheng
China	Liaoyang Central Hospital	Liaoyang
China	Linfen People's Hospital	Linfen
China	Second Affiliated Hospital of Henan University of Science and Technology	Luoyang
China	Luzhou Hospital of traditional Chinese Medicine	Luzhou
China	Mishan People's Hospital	Mishan
China	Mudanjiang Second People's Hospital	Mudanjiang
China	Fourth Affiliated Hospital of Nanchang University	Nanchang
China	Third Affiliated Hospital of Nanchang University	Nanchang
China	Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine	Nanjing
China	Li Huili Hospital of Ningbo Medical Center	Ningbo
China	Ningbo Second Hospital	Ningbo
China	Ningde People's Hospital	Ningde
China	Panjin Central Hospital	Panjin
China	Pindingshan First People's Hospital	Pingdingshan
China	Qiqihar First Hospital	Qiqihar
China	Ruzhou First People's Hospital	Rizhao
China	Sanmenxia Central Hospital	Sanmenxia
China	Fifth People's Hospital of Shanghai City, affiliated to Fudan University	Shanghai
China	Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine	Shanghai
China	Second hospital of Shanxi Medical University	Shanxi
China	Shengzhou People's Hospital	Shaoxing
China	Heilongjiang Agriculture and Reclamation Bei'an Administration Central Hospital	Shenyang
China	Shenzhen Second People's Hospital	Shenzhen
China	Shijiazhuang Pingan Hospital	Shijiazhuang
China	First Hospital Affiliated to Suzhou University	Suzhou
China	The Second Hospital Affiliated to Suzhou University	Suzhou
China	Taizhou First People's Hospital	Taizhou
China	Affiliated Hospital of North China Polytechnic University	Tangshan
China	Tangshan Workers' Hospital	Tangshan
China	Tianjin Fourth Central Hospital	Tianjin
China	Tieling Central Hospital	Tieling
China	Gaomi People's Hospital	Weifang
China	People's Hospital of Wendeng District	Weihai
China	People's Hospital of Wuhan University	Wuhan
China	Wuhan Central Hospital	Wuhan
China	Gansu Academy of Medical Sciences, Wuwei	Wuwei
China	Wuxi People's Hospital	Wuxi
China	Wuxi Second People's Hospital	Wuxi
China	Xi'an 141 hospital	Xi'an
China	Xian First Hospital	Xi'an
China	Xinxiang Central Hospital	Xinxiang
China	Xinyang Central Hospital	Xinyang
China	Xuchang Central Hospital	Xuchang
China	General Hospital of Xuzhou Mining Group	Xuzhou
China	Xuzhou First People's Hospital	Xuzhou
China	Yantai Yuhuangding Hospital Affiliated to Qiingdao University	Yantai
China	Yibin First People's Hospital	Yibin
China	Yichang First People's Hospital	Yichang
China	Yingkou Central Hospital	Yingkou
China	Yueyang Hospital of integrated traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine	Yueyang
China	Dehong People's Hospital of Yunnan	Yunnan
China	Zaozhuang Mining Group Zaozhuang hospital	Zaozhuang
China	Zhangjiagang First People's Hospital	Zhangjiagang
China	Zhangjiagang Traditional Chinese Medicine Hospital	Zhangjiagang
China	Workers' Hospital of Hebei iron and Steel Group Xuanhua iron and Steel Co., Ltd.	Zhangjiakou
China	Central Hospital of the Yellow River	Zhengzhou
China	Zhengzhou First People's Hospital	Zhengzhou
China	Affiliated Hospital of Jiangsu University	Zhenjiang
China	Zhoukou Yongshan hospital	Zhoukou
China	Zhumadian Central Hospital	Zhumadian
China	Zigong First People's Hospital	Zigong

Sponsors (2)

Lead Sponsor	Collaborator
Beijing Tiantan Hospital	Ministry of Science and Technology of the People's Republic of China

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Composite vascular events	stroke (including hemorrhagic and ischemic stroke), myocardial infarction, and cardiovascular death.	90 days
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	All-cause death	All-cause death	90 days
Secondary	Poor functional outcome	The modified Rankin Scale (mRS)= 2-6	90 days
Secondary	Quality of life (EQ-5D scale)	EQ-5D scale index score =0.5	90 days
Secondary	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
Secondary	Early Neurological Deficits	NIHSS score increase of no less than 2points	7 days
Secondary	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