The Effect of InTensive Statin in Ischemic Stroke With inTracranial Atherosclerotic Plaques

Study Overview
=================
Brief Summary
-----------------
Intracranial atherosclerotic disease is the most common cause of ischemic stroke that is directly attributed to the progression or rupture of intracranial high-risk plaque in Asia. Many studies mainly from Euro-American population with a focus on extracranial carotid plaque have fully demonstrated the advantages of intensive statin therapy on stabilizing or reversing plaque burden, reversing plaque composition presenting that lipid-rich necrotic core (LRNC) is gradually replaced by fibrous tissue, and even reversing pattern of arterial remodeling to reduce the occurrence of cerebrovascular events. Yet, direct evidence of the effect of intensive statin therapy on intracranial atherosclerotic plaques is lacking and the effect of statin intensity and duration on intracranial plaque burden and composition is still unclear. High resolution magnetic resonance imaging (HRMRI) is a new and non-invasive technique that enable to assess the morphologic characteristics of vascular wall and plaque composition of intracranial artery. Based on above discussion, the investigators conduct this study to further determine the effect of intensive statin in ischemic stroke with intracranial atherosclerotic plaques.

Official Title
-----------------
The Effect of InTensive Statin in Ischemic Stroke With inTracranial Atherosclerotic Plaques: a Prospective, Random, Single-center Study Based on High Resolution Magnetic Resonance Imaging

Conditions
-----------------
Stroke, Ischemic, Atherosclerosis, Cerebral

Intervention / Treatment
-----------------
* Drug: Atorvastatin Calcium
* Drug: Atorvastatin Calcium
* Drug: Probucol
* Drug: PCSK9 inhibitor


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient age between 18-80 years Time of onset: within 1 week NIHSS score ≤12 Acute ischemic stroke confirmed by head CT or MRI Premorbid mRS ≤1 The degree of stenosis of carotid artery, vertebral artery and intracranial portion of internal carotid artery on the lesion side <50% The culprit plaque or possible culprit plaque with plaque burden of 40% or more found by HRMRI in the proximal part of the middle cerebral artery M1 segment or basilar artery of ipsilateral lesion Signed informed consent Exclusion Criteria: Intracranial hemorrhage found by head CT Stroke attributable to cardioembolic origin (atrial fibrillation, valvular heart disease, aortic arch atherosclerosis) Severe hepatic or renal dysfunction Pregnant females Abnormal elevation of creatine phosphokinase Expected stent angioplasty Blood sugar is out of control Receiving statins within 1 month before onset Obstinate hypertension with more than 140/90 mmHg after medication Not willing and able to comply with scheduled visits, lifestyle guidelines, treatment plan, laboratory tests, and other study procedures Unsuitable for this clinical studies assessed by researcher

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Routine-dose statin group<br>Routine-dose statin group will be gaven the treatment of atorvastatin 20mg Qd for 12 months | Drug: Atorvastatin Calcium<br>* 20mg Qd for 12 months<br>|
| Experimental: high-dose statin or PCSK9 inhibitor group<br>high-dose statin group will be gaven the treatment of atorvastatin 40-80mg Qd till 6 months at the moment the subjects will be followed up to determine plaques status by HRMRI examination, among which the subjects presenting culprit plaque progression with the significant increasing of plaque burden including intraplaque hemorrhage will be again randomized into two groups at a ratio of 1:1 as followed: atorvastatin-probucol group will be administrated atorvastatin 40-80mg Qd plus probucol 0.5g Bid till 12 months, the other group will maintain the original scheme till 12 months. PCSK9 inhibitor group will receive the subcutaneous injection of Evolocumab (140mg, 2 / month) for one year. | Drug: Atorvastatin Calcium<br>* 40-80mg Qd for 6 months<br>Drug: Probucol<br>* 0.5g Bid for 6 months<br>Drug: PCSK9 inhibitor<br>* Evolocumab 140mg subcutaneously injected, twice each month<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in remodeling index after the statin treatment | remodeling index: crimed vessel area/normal vessel area on high-resolution MRI | baseline, 6 months, 12 months after treatment | 
| Changes in plaque burden after the statin treatment | plaque burden: crimed vessel wall area/crimed vessel area on high-resolution MRI | baseline, 6 months, 12 months after treatment | 
| Changes plaque composition in after the statin treatment | plaque composition: lipid core and fiber tissue of plaque on high-resolution MRI | baseline, 6 months, 12 months after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| level of serum bio-markers compared with baseline | Serum level of LDL、hs-CRP、sLOX1 and oxLDL | 6 months | 
| level of serum bio-markers compared with baseline | Serum level of LDL、hs-CRP、sLOX1 and oxLDL | 12 months | 
| mRS (0-2) | proportion of mRS (0-2) | 6 months | 
| mRS (0-2) | proportion of mRS (0-2) | 12 months | 
| vascular events | incidence of Transient ischemic attack, stroke or other vascular events | 6 months | 
| vascular events | incidence of Transient ischemic attack, stroke or other vascular events | 12 months | 
| abnormal test data | incidence of abnormal liver function or muscle enzyme levels | 12 months | 
| any adverse event | incidence of adverse event | 12 months | 
| death of any causes | proportion of death | 12months |