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Extra Alirocumab in Addition to Statin Therapy in Asymptomatic Intracranial Atherosclerotic Stenosis (EAST-aICAS) (EAST-aICAS)

Primary Purpose

Intracranial Atherosclerosis, Atherosclerotic Plaque, Stenosis

Status
Not yet recruiting
Phase
Phase 3
Locations
China
Study Type
Interventional
Intervention
Alirocumab
Atorvastatin
Sponsored by
The First Affiliated Hospital with Nanjing Medical University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Intracranial Atherosclerosis focused on measuring Alirocumab, asymptomatic, intracranial atherosclerotic stenosis

Eligibility Criteria

30 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Age ≥ 30 years and ≤ 75 years. There is a 50 to 99% stenosis of a major intracranial artery (internal carotid artery [ICA], vertebral artery [VA], basilar artery [BA] and the M1 segment of middle cerebral artery [MCA]). The diagnostic evaluation for ICAS at each site is confirmed by the local investigator, using high resolution MR. There is no TIA or Acute ischemic stroke attributale to this ICAS artery, prior to randomization. To increase the likelihood that the asymptomatic intracranial stenosis is atherosclerotic, patients aged 30-49 years are required to meet at least one additional criteria (i-vi) below: i. insulin dependent diabetes for at least 15 years. ii. at least 2 of the following atherosclerotic risk factors: hypertension (Blood pressure [BP] ≥ 140/90 or on antihypertensive therapy); dyslipidemia (LDL ≥ 130 mg /dl or high density lipoprotein (HDL) < 40 mg/dl or fasting triglycerides ≥150 mg/dl or on lipid lowering therapy); smoking; non-insulin dependent diabetes or insulin dependent diabetes of less than 15 years duration; family history of any of the following: myocardial infarction, coronary artery bypass, coronary angioplasty or stenting, stroke, carotid endarterectomy or stenting, peripheral vascular surgery in parent or sibling who was < 55 years of age for men or < 65 for women at the time of the event. iii. history of any of the following: myocardial infarction, coronary artery bypass, coronary angioplasty or stenting, carotid endarterectomy or stenting, or peripheral vascular surgery for atherosclerotic disease. iv. any stenosis of an extracranial carotid or vertebral artery, another intracranial artery, subclavian artery, coronary artery, iliac or femoral artery, other lower or upper extremity artery, mesenteric artery, or renal artery that was documented by non-invasive vascular imaging or catheter angiography and is considered atherosclerotic. v. aortic arch atheroma documented by non-invasive vascular imaging or catheter angiography. vi. any aortic aneurysm documented by non-invasive vascular imaging or catheter angiography that is considered atherosclerotic. Patient agrees with follow-up visits and is available by phone. Patient understands the purpose and requirements of the study, can make him/herself understood, and has signed informed consent. Exclusion Criteria: Previous treatment of target intracranial lesion with a stent, angioplasty, or other mechanical devices (e.g. mechanical thrombectomy, coil embolization). Plan to perform angioplasty, stenting, coiling, thrombectomy, endarterectomy or aneurysmal coil embolization for target vessels/plaques. In case that patients who receive surgeries during follow-up, they will still be followed up for 1 year. Intracranial tumor (except meningioma) or any intracranial vascular malformation. History of any intracranial hemorrhage (parenchymal, subarachnoid, subdural, epidural). Intracranial arterial stenosis due to arterial dissection; MoyaMoya disease; any known vasculitic disease; viral vasculopathy; neurosyphilis; any other intracranial infection; any intracranial stenosis associated with cerebral spinal fluid pleocytosis; radiation induced vasculopathy; fibromuscular dysplasia; sickle cell disease; neurofibromatosis; benign angiopathy of central nervous system; postpartum angiopathy; suspected vasospastic process; reversible cerebral vasoconstriction syndrome (RCVS); suspected recanalized embolus. Presence of any of the following unequivocal cardiac sources of embolism: chronic or paroxysmal atrial fibrillation, mitral stenosis, mechanical valve, endocarditis, intracardiac clot or vegetation, myocardial infarction within three months, dilated cardiomyopathy, left atrial spontaneous echo contrast, ejection fraction less than 30%. Use of cholesteryl ester transfer protein (CETP) inhibition treatment, mipomersen, or lomitapide within 12 months prior to randomization. Fenofibrate therapy must be stable for at least 6 weeks prior to final screening at a dose that is appropriate for the duration of the study in the judgment of the investigator. Other fibrate therapy (and derivatives) are prohibited. Prior use of PCSK9 inhibition treatment before this recruitment. Known allergy or contraindication to aspirin, clopidogrel, alirocumab or atorvastatin. Active peptic ulcer disease, major systemic hemorrhage within 30 days, active bleeding diathesis, platelets < 100,000, hematocrit < 30, international normalized ratio (INR) > 1.5, clotting factor abnormality that increases the risk of bleeding, current alcohol or substance abuse, uncontrolled severe hypertension (systolic pressure > 180 mm Hg or diastolic pressure > 115 mm Hg), severe liver impairment (aspartate transaminase [AST] or alanine transaminase [ALT] > 3 x normal, cirrhosis), creatine kinase > 5 times the upper limit of normal (ULN) at final screening, severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 20mL/min/1.73 square meter at final screening. Major surgery (including open femoral, aortic, cardiac or carotid surgery) within previous 30 days or planned in the 1 year after enrollment. Dementia or psychiatric problem that prevents the patient from relevant evaluation or follow-up reliably. Co-morbid conditions that may limit survival to less than 1 year. Currently breastfeeding, pregnancy, planning to become pregnant and unwilling to use contraception for the duration of this study Enrollment in another study that would conflict with the current study.

Sites / Locations

  • the First affiliated hospital of Nanjing Medical University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Alirocumab added to statin therapy

Statin therapy

Arm Description

Alirocumab (75 mg every 2 weeks for 6 months) added to statin (Atorvastatin 20-40mg). Anti-platelet aggregation and risk factor management.

Atorvastatin 20-40mg. Anti-platelet aggregation and risk factor management in both arms.

Outcomes

Primary Outcome Measures

Plaque burden (PB)
lumen area (LA) is manually contoured on T1-weighted SPACE at the most stenotic site (LAplaque). PB is calculated as (1 - LAplaque/OWAplauqe) × 100%
Degree of stenosis caused by the plaque
degree of stenosis = (1 - Dplaque/Dreference) × 100%, where Dplaque indicated the diameter of the culprit artery at the most stenotic site, and Dreference was the diameter of the normal artery proximal to the plaque
Plaque enhancement
grading of plaque enhancement: grade 0 indicated enhancement is similar to or less than that of normal-appearing intracranial arterial walls in the same individual; grade 1, enhancement is greater than that of grade 0 but less than that of the pituitary infundibulum; and grade 2, enhancement is similar to or greater than that of the infundibulum. plaque enhancement ratio (ER): circular region of interest (ROI) was drawn within the plaque on pre-contrast and post-contrast T1-weighted SPACE images, respectively. The mean signal intensity (SI) of plaques were obtained. ER = (SIpost - SIpre)/SIpre ×100%
Remodeling index (RI) of the plaque
the outer wall area (OWA) is manually contoured on T1-weighted SPACE at the most stenotic site (OWAplaque) and the reference site (OWAreference). RI is calculated as OWAplaque/OWAreference × 100%. Arterial remodeling is categorized as positive if RI > 1.05, intermediate if 0.95 ≤ RI ≤ 1.05, and negative if RI < 0.95;
Presence of T1 hyperintensity in the plaque
the brightest spot of the plaque with SI >150% of that of the reference vessel wall on pre-contrast T1 image
Plaque distribution: whether it is a concentric plaque or not
a concentric plaque is defined if the wall involvement was more than 75%, and the minimum wall thickness is higher than 50% of the maximum wall thickness.
Hemodynamic characteristics: Hypoperfusion volume
dynamic susceptibility contrast-perfusion weighted imaging (DSC-PWI) performed and computed using the singular value decomposition deconvolution method using a commercial software NeuBrainCARE (v1.1.10). Hypoperfusion volume on the ipsilateral side of stroke were automatically calculated by use of time to maximum (Tmax) with time thresholds of > 4 seconds and > 6 seconds, respectively.

Secondary Outcome Measures

Any stroke (ischemic or hemorrhagic) or death during 6 months of follow-up in an intention-to treat analysis.
Changes in LDL-cholesterol levels

Full Information

First Posted
September 22, 2023
Last Updated
October 10, 2023
Sponsor
The First Affiliated Hospital with Nanjing Medical University
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1. Study Identification

Unique Protocol Identification Number
NCT06080256
Brief Title
Extra Alirocumab in Addition to Statin Therapy in Asymptomatic Intracranial Atherosclerotic Stenosis (EAST-aICAS)
Acronym
EAST-aICAS
Official Title
Extra Alirocumab in Addition to Statin Therapy in Asymptomatic Intracranial Atherosclerotic Stenosis (EAST-aICAS)----a Pilot Study
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
October 30, 2023 (Anticipated)
Primary Completion Date
June 30, 2024 (Anticipated)
Study Completion Date
July 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
The First Affiliated Hospital with Nanjing Medical University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The primary goal of the trial is to investigate whether the lipid lowering strategy using Alirocumab plus statin could cause more changes from baseline in intracranial atherosclerotic plaque and hemodynamic features during 6 months of follow-up, in patients with asymptomatic intracranial artery stenosis.
Detailed Description
Intracranial atherosclerosis stenosis (ICAS) is one of the most common causes of stroke worldwide and is particularly prevalent in Asian. It accounts for up to 30-50% of strokes amongst Asian patient cohorts, in contrast to 5-10% of strokes amongst western patient cohorts. The SAMMPRIS established aggressive medical management (Intensive lipid lowering with statin to reach a low-density lipoprotein (LDL)-cholesterol lower than 1.8mmol/L, et al) as a superior choice for symptomatic ICAS compared to the percutaneous transluminal angioplasty and stenting. However, around 15% still had recurrent stroke or death during a median follow-up of 32.4 months in SAMMPRIS study in the aggressive medical management group. On the other hand, in view of the ready availability of MRA or CTA , asymptomatic ICAS (ICAS without causing TIA or stroke) can be found at heath checkup. It would be of great significance to take measures to prevent TIA/stroke in those asymptomatic ICAS. Alirocumab, a member of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, is a fully human monoclonal antibody that reduces LDL cholesterol levels by approximately 60%. The ODYSSEY OUTCOMES study showed that Alirocumab reduced the risk of cardiovascular events (e.g. cardiovascular death, myocardial infarction and stroke), in patients with atherosclerotic cardiovascular disease. This pilot study will recruit 80 patients with asymptomatic intracranial artery stenosis, and directly compare Alirocumab on top of statin with statin therapy in changes of intracranial atherosclerotic plaque and hemodynamic features during 6 months of follow-up.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Intracranial Atherosclerosis, Atherosclerotic Plaque, Stenosis
Keywords
Alirocumab, asymptomatic, intracranial atherosclerotic stenosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Patients meeting the enrollment criteria will be randomly assigned to one of the two treatment groups (1:1) and will be followed up for 6 months.
Masking
InvestigatorOutcomes Assessor
Masking Description
investigator-initiated, open-label, blinded endpoint assessment, controlled, randomized pilot trial
Allocation
Randomized
Enrollment
80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Alirocumab added to statin therapy
Arm Type
Experimental
Arm Description
Alirocumab (75 mg every 2 weeks for 6 months) added to statin (Atorvastatin 20-40mg). Anti-platelet aggregation and risk factor management.
Arm Title
Statin therapy
Arm Type
Active Comparator
Arm Description
Atorvastatin 20-40mg. Anti-platelet aggregation and risk factor management in both arms.
Intervention Type
Drug
Intervention Name(s)
Alirocumab
Intervention Description
alirocumab (75 mg every 2 weeks)
Intervention Type
Drug
Intervention Name(s)
Atorvastatin
Intervention Description
Atorvastatin 20-40mg
Primary Outcome Measure Information:
Title
Plaque burden (PB)
Description
lumen area (LA) is manually contoured on T1-weighted SPACE at the most stenotic site (LAplaque). PB is calculated as (1 - LAplaque/OWAplauqe) × 100%
Time Frame
This will be assessed at 6 months after recruitment.
Title
Degree of stenosis caused by the plaque
Description
degree of stenosis = (1 - Dplaque/Dreference) × 100%, where Dplaque indicated the diameter of the culprit artery at the most stenotic site, and Dreference was the diameter of the normal artery proximal to the plaque
Time Frame
This will be assessed at 6 months after recruitment.
Title
Plaque enhancement
Description
grading of plaque enhancement: grade 0 indicated enhancement is similar to or less than that of normal-appearing intracranial arterial walls in the same individual; grade 1, enhancement is greater than that of grade 0 but less than that of the pituitary infundibulum; and grade 2, enhancement is similar to or greater than that of the infundibulum. plaque enhancement ratio (ER): circular region of interest (ROI) was drawn within the plaque on pre-contrast and post-contrast T1-weighted SPACE images, respectively. The mean signal intensity (SI) of plaques were obtained. ER = (SIpost - SIpre)/SIpre ×100%
Time Frame
This will be assessed at 6 months after recruitment.
Title
Remodeling index (RI) of the plaque
Description
the outer wall area (OWA) is manually contoured on T1-weighted SPACE at the most stenotic site (OWAplaque) and the reference site (OWAreference). RI is calculated as OWAplaque/OWAreference × 100%. Arterial remodeling is categorized as positive if RI > 1.05, intermediate if 0.95 ≤ RI ≤ 1.05, and negative if RI < 0.95;
Time Frame
This will be assessed at 6 months after recruitment.
Title
Presence of T1 hyperintensity in the plaque
Description
the brightest spot of the plaque with SI >150% of that of the reference vessel wall on pre-contrast T1 image
Time Frame
This will be assessed at 6 months after recruitment.
Title
Plaque distribution: whether it is a concentric plaque or not
Description
a concentric plaque is defined if the wall involvement was more than 75%, and the minimum wall thickness is higher than 50% of the maximum wall thickness.
Time Frame
This will be assessed at 6 months after recruitment.
Title
Hemodynamic characteristics: Hypoperfusion volume
Description
dynamic susceptibility contrast-perfusion weighted imaging (DSC-PWI) performed and computed using the singular value decomposition deconvolution method using a commercial software NeuBrainCARE (v1.1.10). Hypoperfusion volume on the ipsilateral side of stroke were automatically calculated by use of time to maximum (Tmax) with time thresholds of > 4 seconds and > 6 seconds, respectively.
Time Frame
This will be assessed at 6 months after recruitment.
Secondary Outcome Measure Information:
Title
Any stroke (ischemic or hemorrhagic) or death during 6 months of follow-up in an intention-to treat analysis.
Time Frame
This will be assessed during 6 months of follow-up.
Title
Changes in LDL-cholesterol levels
Time Frame
This will be assessed during 6 months of follow-up.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
30 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age ≥ 30 years and ≤ 75 years. There is a 50 to 99% stenosis of a major intracranial artery (internal carotid artery [ICA], vertebral artery [VA], basilar artery [BA] and the M1 segment of middle cerebral artery [MCA]). The diagnostic evaluation for ICAS at each site is confirmed by the local investigator, using high resolution MR. There is no TIA or Acute ischemic stroke attributale to this ICAS artery, prior to randomization. To increase the likelihood that the asymptomatic intracranial stenosis is atherosclerotic, patients aged 30-49 years are required to meet at least one additional criteria (i-vi) below: i. insulin dependent diabetes for at least 15 years. ii. at least 2 of the following atherosclerotic risk factors: hypertension (Blood pressure [BP] ≥ 140/90 or on antihypertensive therapy); dyslipidemia (LDL ≥ 130 mg /dl or high density lipoprotein (HDL) < 40 mg/dl or fasting triglycerides ≥150 mg/dl or on lipid lowering therapy); smoking; non-insulin dependent diabetes or insulin dependent diabetes of less than 15 years duration; family history of any of the following: myocardial infarction, coronary artery bypass, coronary angioplasty or stenting, stroke, carotid endarterectomy or stenting, peripheral vascular surgery in parent or sibling who was < 55 years of age for men or < 65 for women at the time of the event. iii. history of any of the following: myocardial infarction, coronary artery bypass, coronary angioplasty or stenting, carotid endarterectomy or stenting, or peripheral vascular surgery for atherosclerotic disease. iv. any stenosis of an extracranial carotid or vertebral artery, another intracranial artery, subclavian artery, coronary artery, iliac or femoral artery, other lower or upper extremity artery, mesenteric artery, or renal artery that was documented by non-invasive vascular imaging or catheter angiography and is considered atherosclerotic. v. aortic arch atheroma documented by non-invasive vascular imaging or catheter angiography. vi. any aortic aneurysm documented by non-invasive vascular imaging or catheter angiography that is considered atherosclerotic. Patient agrees with follow-up visits and is available by phone. Patient understands the purpose and requirements of the study, can make him/herself understood, and has signed informed consent. Exclusion Criteria: Previous treatment of target intracranial lesion with a stent, angioplasty, or other mechanical devices (e.g. mechanical thrombectomy, coil embolization). Plan to perform angioplasty, stenting, coiling, thrombectomy, endarterectomy or aneurysmal coil embolization for target vessels/plaques. In case that patients who receive surgeries during follow-up, they will still be followed up for 1 year. Intracranial tumor (except meningioma) or any intracranial vascular malformation. History of any intracranial hemorrhage (parenchymal, subarachnoid, subdural, epidural). Intracranial arterial stenosis due to arterial dissection; MoyaMoya disease; any known vasculitic disease; viral vasculopathy; neurosyphilis; any other intracranial infection; any intracranial stenosis associated with cerebral spinal fluid pleocytosis; radiation induced vasculopathy; fibromuscular dysplasia; sickle cell disease; neurofibromatosis; benign angiopathy of central nervous system; postpartum angiopathy; suspected vasospastic process; reversible cerebral vasoconstriction syndrome (RCVS); suspected recanalized embolus. Presence of any of the following unequivocal cardiac sources of embolism: chronic or paroxysmal atrial fibrillation, mitral stenosis, mechanical valve, endocarditis, intracardiac clot or vegetation, myocardial infarction within three months, dilated cardiomyopathy, left atrial spontaneous echo contrast, ejection fraction less than 30%. Use of cholesteryl ester transfer protein (CETP) inhibition treatment, mipomersen, or lomitapide within 12 months prior to randomization. Fenofibrate therapy must be stable for at least 6 weeks prior to final screening at a dose that is appropriate for the duration of the study in the judgment of the investigator. Other fibrate therapy (and derivatives) are prohibited. Prior use of PCSK9 inhibition treatment before this recruitment. Known allergy or contraindication to aspirin, clopidogrel, alirocumab or atorvastatin. Active peptic ulcer disease, major systemic hemorrhage within 30 days, active bleeding diathesis, platelets < 100,000, hematocrit < 30, international normalized ratio (INR) > 1.5, clotting factor abnormality that increases the risk of bleeding, current alcohol or substance abuse, uncontrolled severe hypertension (systolic pressure > 180 mm Hg or diastolic pressure > 115 mm Hg), severe liver impairment (aspartate transaminase [AST] or alanine transaminase [ALT] > 3 x normal, cirrhosis), creatine kinase > 5 times the upper limit of normal (ULN) at final screening, severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 20mL/min/1.73 square meter at final screening. Major surgery (including open femoral, aortic, cardiac or carotid surgery) within previous 30 days or planned in the 1 year after enrollment. Dementia or psychiatric problem that prevents the patient from relevant evaluation or follow-up reliably. Co-morbid conditions that may limit survival to less than 1 year. Currently breastfeeding, pregnancy, planning to become pregnant and unwilling to use contraception for the duration of this study Enrollment in another study that would conflict with the current study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Zhaolu Wang, MD
Phone
18100613663
Email
wangzhaolu123@163.com
First Name & Middle Initial & Last Name or Official Title & Degree
Xinyu Chen, MD
Phone
19975038610
Email
njmuchenxinyu@163.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kezhong Zhang, MD
Organizational Affiliation
The First Affiliated Hospital with Nanjing Medical University
Official's Role
Principal Investigator
Facility Information:
Facility Name
the First affiliated hospital of Nanjing Medical University
City
Nanjing
State/Province
Jiangsu
ZIP/Postal Code
210001
Country
China
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Zhaolu Wang, MD, PhD
Phone
18100613663
Email
wangzhaolu123@163.com

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Individual participant data (IPD) will be available to other researchers under the approval of the ethical committee.
IPD Sharing Time Frame
the data will be available when summary data are published.
Citations:
PubMed Identifier
24135208
Citation
Holmstedt CA, Turan TN, Chimowitz MI. Atherosclerotic intracranial arterial stenosis: risk factors, diagnosis, and treatment. Lancet Neurol. 2013 Nov;12(11):1106-14. doi: 10.1016/S1474-4422(13)70195-9.
Results Reference
background
PubMed Identifier
30403574
Citation
Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, Edelberg JM, Goodman SG, Hanotin C, Harrington RA, Jukema JW, Lecorps G, Mahaffey KW, Moryusef A, Pordy R, Quintero K, Roe MT, Sasiela WJ, Tamby JF, Tricoci P, White HD, Zeiher AM; ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018 Nov 29;379(22):2097-2107. doi: 10.1056/NEJMoa1801174. Epub 2018 Nov 7.
Results Reference
background
PubMed Identifier
35368058
Citation
Raber L, Ueki Y, Otsuka T, Losdat S, Haner JD, Lonborg J, Fahrni G, Iglesias JF, van Geuns RJ, Ondracek AS, Radu Juul Jensen MD, Zanchin C, Stortecky S, Spirk D, Siontis GCM, Saleh L, Matter CM, Daemen J, Mach F, Heg D, Windecker S, Engstrom T, Lang IM, Koskinas KC; PACMAN-AMI collaborators. Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction: The PACMAN-AMI Randomized Clinical Trial. JAMA. 2022 May 10;327(18):1771-1781. doi: 10.1001/jama.2022.5218.
Results Reference
background

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Extra Alirocumab in Addition to Statin Therapy in Asymptomatic Intracranial Atherosclerotic Stenosis (EAST-aICAS)

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