INSPIRES: Intensive Medical Therapy for High-risk Intracranial or Extracranial Atherosclerosis

Sponsor

Beijing Tiantan Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT03635749

Collaborator

Ministry of Science and Technology of the People's Republic of China (Other)

6,100

Enrollment

113

Locations

Arms

56.4

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Stroke Transient Ischemic Attack	Drug: Intensive antiplatelet Drug: Standard antiplatelet Drug: Immediate high-intensity statin Drug: Delayed high-intensity statin	Phase 3

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:

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

6100 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Intervention 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)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 (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 Atherosclerosis (INSPIRES)

Actual Study Start Date :

Sep 17, 2018

Anticipated Primary Completion Date :

Aug 30, 2022

Anticipated Study Completion Date :

May 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	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 Other Names: Dual antiplatelet Drug: Immediate high-intensity statin Day 1 - 21：Atorvastatin calcium 80mg/day Day 22 - 90：Atorvastatin calcium 40mg/day Other Names: Immediate Atorvastatin
Other: 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.	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 Other Names: Dual antiplatelet Drug: 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 Other Names: Delayed Atorvastatin
Other: Aspirin+immediate high-intensity statin This group will receive active aspirin and clopidogrel placebo; active atorvastatin calcium with high dosage in the early phase.	Drug: Standard antiplatelet Day 1: Aspirin 100-300mg/day + clopidogrel placebo Day 2 - 90: Aspirin 100mg/day+ clopidogrel placebo Other Names: Aspirin Drug: Immediate high-intensity statin Day 1 - 21：Atorvastatin calcium 80mg/day Day 22 - 90：Atorvastatin calcium 40mg/day Other Names: Immediate Atorvastatin
Placebo Comparator: 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.	Drug: Standard antiplatelet Day 1: Aspirin 100-300mg/day + clopidogrel placebo Day 2 - 90: Aspirin 100mg/day+ clopidogrel placebo Other Names: Aspirin Drug: 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 Other Names: Delayed Atorvastatin

Outcome Measures

Primary Outcome Measures

Stroke [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

Secondary Outcome Measures

Composite vascular events [90 days]
stroke (including hemorrhagic and ischemic stroke), myocardial infarction, and cardiovascular death.
Ischemic stroke [90 days]
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.
Transient ischemic attack [90 days]
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)
Myocardial infarction [90 days]
Acute myocardial infarction is diagnosed by the third edition of the international general diagnostic criteria (Glob Heart. 2012 Dec;7(4):275-95)
Vascular death [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. 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.
All-cause death [90 days]
All-cause death
Poor functional outcome [90 days]
The modified Rankin Scale (mRS)= 2-6
Quality of life (EQ-5D scale) [90 days]
EQ-5D scale index score ≤0.5
Change of atherosclerotic plaque using high-resolution magnetic resonance imaging (HR-MRI) [90 days]
Change of atherosclerotic plaque using high-resolution magnetic resonance 。 Patients in HR-MRI subgroup only

Eligibility Criteria

Criteria

Ages Eligible for Study:

35 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.）

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tiantan Hospital	Beijing	Beijing	China	100050
2	Anshan Central Hospital	Anshan		China
3	General Hospital of Anshan Iron and Steel Company	Anshan		China
4	Anyang People's Hospital	Anyang		China
5	Baoding First Central Hospital	Baoding		China
6	Beijing Hepingli Hospital	Beijing		China
7	Benxi Central Hospital	Benxi		China
8	First Hospital of Changsha	Changsha		China
9	Second people's Hospital of Hunan Province	Changsha		China
10	Xiangya Third Hospital of Central South University	Changsha		China
11	Changzhi Medical College Affiliated Heping Hospital	Changzhi		China
12	Changzhi People's Hospital	Changzhi		China
13	Lu'an Group General Hospital	Changzhi		China
14	Changzhou Second People's Hospital	Changzhou		China
15	Changzhou Wujin Hospital of Traditional Chinese Medicine	Changzhou		China
16	Chongqing Sanxia Central Hospital	Chongqing		China
17	Southwest Hospital affiliated to the Army Military Medical University	Chongqing		China
18	Dalian Central Hospital	Dalian		China
19	Dalian Friendship Hospital	Dalian		China
20	Second people's Hospital of Dalian	Dalian		China
21	Xinhua Hospital Affiliated to Dalian University	Dalian		China
22	People's Hospital of Dali Bai Autonomous Prefecture	Dali		China
23	Datong Third People's Hospital	Datong		China
24	Dazhou Central Hospital	Dazhou		China
25	Dongguan Hong Wah hospital	Dongguan		China
26	Donghua Hospital	Dongguan		China
27	Dongyang People's Hospital	Dongyang		China
28	People's Hospital of Dongying District	Dongying		China
29	General Hospital of Fushun Mining Bureau	Fushun		China
30	Fuxin Mining Group General Hospital	Fuxin		China
31	Nanxi Mountain hospital in Guangxi District	Guilin		China
32	Guiyang Second Hospital	Guiyang		China
33	General Hospital of the General Administration of agriculture and reclamation of Heilongjiang	Ha'erbin		China
34	Handan Central Hospital	Handan		China
35	Handan First Hospital	Handan		China
36	Second hospital of Hebei Medical University	Hebei		China
37	Hengshui Sixth People's Hospital	Hengshui		China
38	Nanhua Hospital Affiliated to Nanhua University	Hengyang		China
39	The Inner Mongolia Autonomous Region people's Hospital	Hohhot		China
40	First Affiliated Hospital of Jiamusi University	Jiamusi		China
41	Jiamusi Central Hospital	Jiamusi		China
42	Jilin Electric Power Hospital	Jilin		China
43	Jinlin Central Hospital	Jilin		China
44	Jinlin People's Hospital	Jilin		China
45	Second hospital of Jilin University	Jilin		China
46	Qianfo Hill Hospital of Shandong Province	Jinan		China
47	Shandong Transportation Hospital	Jinan		China
48	Affiliated Hospital of Jiujiang University	Jiujiang		China
49	Jixi People's Hospital	Jixi		China
50	Kaifeng Central Hospital	Kai Feng		China
51	Liaocheng Brain Hospital	Liaocheng		China
52	Liaocheng Second People's Hospital	Liaocheng		China
53	Liaoyang Central Hospital	Liaoyang		China
54	Linfen People's Hospital	Linfen		China
55	Second Affiliated Hospital of Henan University of Science and Technology	Luoyang		China
56	Luzhou Hospital of traditional Chinese Medicine	Luzhou		China
57	Mishan People's Hospital	Mishan		China
58	Mudanjiang Second People's Hospital	Mudanjiang		China
59	Fourth Affiliated Hospital of Nanchang University	Nanchang		China
60	Third Affiliated Hospital of Nanchang University	Nanchang		China
61	Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine	Nanjing		China
62	Li Huili Hospital of Ningbo Medical Center	Ningbo		China
63	Ningbo Second Hospital	Ningbo		China
64	Ningde People's Hospital	Ningde		China
65	Panjin Central Hospital	Panjin		China
66	Pindingshan First People's Hospital	Pingdingshan		China
67	Qiqihar First Hospital	Qiqihar		China
68	Ruzhou First People's Hospital	Rizhao		China
69	Sanmenxia Central Hospital	Sanmenxia		China
70	Fifth People's Hospital of Shanghai City, affiliated to Fudan University	Shanghai		China
71	Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine	Shanghai		China
72	Second hospital of Shanxi Medical University	Shanxi		China
73	Shengzhou People's Hospital	Shaoxing		China
74	Heilongjiang Agriculture and Reclamation Bei'an Administration Central Hospital	Shenyang		China
75	Shenzhen Second People's Hospital	Shenzhen		China
76	Shijiazhuang Pingan Hospital	Shijiazhuang		China
77	First Hospital Affiliated to Suzhou University	Suzhou		China
78	The Second Hospital Affiliated to Suzhou University	Suzhou		China
79	Taizhou First People's Hospital	Taizhou		China
80	Affiliated Hospital of North China Polytechnic University	Tangshan		China
81	Tangshan Workers' Hospital	Tangshan		China
82	Tianjin Fourth Central Hospital	Tianjin		China
83	Tieling Central Hospital	Tieling		China
84	Gaomi People's Hospital	Weifang		China
85	People's Hospital of Wendeng District	Weihai		China
86	People's Hospital of Wuhan University	Wuhan		China
87	Wuhan Central Hospital	Wuhan		China
88	Gansu Academy of Medical Sciences, Wuwei	Wuwei		China
89	Wuxi People's Hospital	Wuxi		China
90	Wuxi Second People's Hospital	Wuxi		China
91	Xi'an 141 hospital	Xi'an		China
92	Xian First Hospital	Xi'an		China
93	Xinxiang Central Hospital	Xinxiang		China
94	Xinyang Central Hospital	Xinyang		China
95	Xuchang Central Hospital	Xuchang		China
96	General Hospital of Xuzhou Mining Group	Xuzhou		China
97	Xuzhou First People's Hospital	Xuzhou		China
98	Yantai Yuhuangding Hospital Affiliated to Qiingdao University	Yantai		China
99	Yibin First People's Hospital	Yibin		China
100	Yichang First People's Hospital	Yichang		China
101	Yingkou Central Hospital	Yingkou		China
102	Yueyang Hospital of integrated traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine	Yueyang		China
103	Dehong People's Hospital of Yunnan	Yunnan		China
104	Zaozhuang Mining Group Zaozhuang hospital	Zaozhuang		China
105	Zhangjiagang First People's Hospital	Zhangjiagang		China
106	Zhangjiagang Traditional Chinese Medicine Hospital	Zhangjiagang		China
107	Workers' Hospital of Hebei iron and Steel Group Xuanhua iron and Steel Co., Ltd.	Zhangjiakou		China
108	Central Hospital of the Yellow River	Zhengzhou		China
109	Zhengzhou First People's Hospital	Zhengzhou		China
110	Affiliated Hospital of Jiangsu University	Zhenjiang		China
111	Zhoukou Yongshan hospital	Zhoukou		China
112	Zhumadian Central Hospital	Zhumadian		China
113	Zigong First People's Hospital	Zigong		China