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

NCT06080256 | Unknown Phase 3 DMC

• 1 other identifier: EAST-aICAS
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

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.

Conditions

Intracranial Atherosclerosis; Atherosclerotic Plaque; Stenosis

Keywords

Alirocumab; asymptomatic; intracranial atherosclerotic stenosis

Outcome Measures

Primary Outcomes (7)

• 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%

  This will be assessed at 6 months after recruitment.

• 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

  This will be assessed at 6 months after recruitment.

• 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%

  This will be assessed at 6 months after recruitment.

• 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;

  This will be assessed at 6 months after recruitment.

• 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

  This will be assessed at 6 months after recruitment.

• 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.

  This will be assessed at 6 months after recruitment.

• 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.

  This will be assessed at 6 months after recruitment.

Secondary Outcomes (2)

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

  This will be assessed during 6 months of follow-up.

• Changes in LDL-cholesterol levels

  This will be assessed during 6 months of follow-up.

Study Arms (2)

Alirocumab added to statin therapy

EXPERIMENTAL

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

Drug: Alirocumab; Drug: Atorvastatin

Statin therapy

ACTIVE COMPARATOR

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

Drug: Atorvastatin

Interventions

Alirocumab DRUG

alirocumab (75 mg every 2 weeks)

Alirocumab added to statin therapy

Atorvastatin DRUG

Atorvastatin 20-40mg

Alirocumab added to statin therapy; Statin therapy

Eligibility Criteria

• Age: 30 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 attributed to this ICAS artery; OR, there was an episode of TIA or acute ischemic stroke attributed to this ICAS artery, but this episode occured ≥12 months before 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.

You may not qualify if:

• TIA or acute ischemic stroke attributed to this ICAS artery during the past 12 months before the randomization;
• 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 6 months.
• 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 6 months 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 6 months.
• Currently breastfeeding, pregnancy, planning to become pregnant and unwilling to use contraception for the duration of this study

Sponsors & Collaborators

• The First Affiliated Hospital with Nanjing Medical University: lead

Study Sites (1)

the First affiliated hospital of Nanjing Medical University

Nanjing, Jiangsu, 210001, China

Location

Related Publications (4)

• 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.

  PMID: 24135208 BACKGROUND

• 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.

  PMID: 30403574 BACKGROUND

• 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.

  PMID: 35368058 BACKGROUND

• Chen X, Dai J, Nie P, Gu P, Wang M, Zhang K, Wang Z. Design of the "EAST" strategy in patients with asymptomatic intracranial atherosclerotic stenosis. Clin Neurol Neurosurg. 2024 Oct;245:108507. doi: 10.1016/j.clineuro.2024.108507. Epub 2024 Aug 15.

  PMID: 39182330 DERIVED

MeSH Terms

Conditions

Intracranial Arteriosclerosis; Plaque, Atherosclerotic; Constriction, Pathologic

Interventions

alirocumab; Atorvastatin

Condition Hierarchy (Ancestors)

Intracranial Arterial Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids

Study Officials

• Kezhong Zhang, MD

  The First Affiliated Hospital with Nanjing Medical University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Zhaolu Wang, MD

CONTACT

18100613663; wangzhaolu123@163.com

Xinyu Chen, MD

CONTACT

19975038610; njmuchenxinyu@163.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: investigator-initiated, open-label, blinded endpoint assessment, controlled, randomized pilot trial
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: 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.

Study Record Dates

• First Submitted: September 22, 2023
• First Posted: October 12, 2023
• Study Start: December 30, 2023
• Primary Completion: December 31, 2024
• Study Completion: December 31, 2024
• Last Updated: December 21, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, CSR
• Time Frame: the data will be available when summary data are published.

Locations

CN (1)