Extra Alirocumab in Addition to Statin Therapy in Symptomatic IntraCranial Atherosclerotic Stenosis ----a Pilot Study (EAST-sICAS)

• ClinicalTrials.gov Identifier: NCT06052020
• Recruitment Status: Recruiting
• First Posted: September 25, 2023
• Last Update Posted: September 28, 2023
• Sponsor: The First Affiliated Hospital with Nanjing Medical University
• Information provided by (Responsible Party): Kezhong Zhang, The First Affiliated Hospital with Nanjing Medical University

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 recent stroke/transient ischemic attack (TIA) caused by intracranial artery stenosis.

Condition or disease	Intervention/treatment
Stroke; Intracranial Atherosclerotic Stenosis	Drug: Alirocumab; Drug: Atorvastatin

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.

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.

The proposed pilot study will recruit 50 patients with recent stroke/transient ischemic attack (TIA) caused by intracranial artery stenosis, and directly compare the differences before and after Alirocumab on top of statin therapy in changes of intracranial atherosclerotic plaque and hemodynamic features during 6 months of follow-up.

Study Design

• Study Type: Observational
• Estimated Enrollment: 50 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Extra Alirocumab in Addition to Statin Therapy in Symptomatic IntraCranial Atherosclerotic Stenosis ----a Pilot Study
• Actual Study Start Date: September 15, 2023
• Estimated Primary Completion Date: September 15, 2024
• Estimated Study Completion Date: September 30, 2024

Groups and Cohorts

Group/Cohort	Intervention/treatment
Alirocumab added to statin therapy; Alirocumab (75 mg every 2 weeks for 6 months) added to statin (Atorvastatin 20-40mg). Anti-platelet aggregation and risk factor management.	Drug: Alirocumab; alirocumab (75 mg every 2 weeks); Drug: Atorvastatin; Atorvastatin 20-40mg

Outcome Measures

Primary Outcome Measures :

1. Plaque burden (PB) [ Time Frame: This will be assessed at 6 months after recruitment. ]
   lumen area (LA) is manually contoured on T1-weighted SPACE at the most stenotic site (LAplaque). PB is calculated as (1 - LAplaque/OWAplauqe) × 100%
2. Degree of stenosis caused by the plaque [ Time Frame: This will be assessed at 6 months after recruitment. ]
   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
3. Plaque enhancement [ Time Frame: This will be assessed at 6 months after recruitment. ]
   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%
4. Remodeling index (RI) of the plaque [ Time Frame: This will be assessed at 6 months after recruitment. ]
   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;
5. Presence of T1 hyperintensity in the plaque [ Time Frame: This will be assessed at 6 months after recruitment. ]
   the brightest spot of the plaque with SI >150% of that of the reference vessel wall on pre-contrast T1 image
6. Plaque distribution: whether it is a concentric plaque or not [ Time Frame: This will be assessed at 6 months after recruitment. ]
   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.
7. Hemodynamic characteristics: Hypoperfusion volume [ Time Frame: This will be assessed at 6 months after recruitment. ]
   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 :

1. 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. ]
2. Changes in LDL-cholesterol levels [ Time Frame: This will be assessed during 6 months year of follow-up. ]

Eligibility Criteria

• Ages Eligible for Study: 30 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Probability Sample

Study Population

TIA or Acute ischemic stroke attributed to a 50 to 99% stenosis of a major intracranial artery

Criteria

Inclusion Criteria:

1. Age ≥ 30 years and ≤ 75 years.
2. TIA or Acute ischemic stroke that occurred within 6 weeks prior to randomization.
3. Modified Rankin score of ≤ 4.
4. TIA or acute ischemic stroke attributed to 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.

5. To increase the likelihood that the symptomatic 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.

6. Patient agrees with follow-up visits and is available by phone.
7. Patient understands the purpose and requirements of the study, can make him/herself understood, and has signed informed consent.

Exclusion Criteria:

1. Previous treatment of target intracranial lesion with a stent, angioplasty, or other mechanical devices (e.g. mechanical thrombectomy, coil embolization).
2. 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.
3. Intracranial tumor (except meningioma) or any intracranial vascular malformation.
4. History of any intracranial hemorrhage (parenchymal, subarachnoid, subdural, epidural).
5. 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.
6. 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%.
7. 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.
8. Prior use of PCSK9 inhibition treatment before this recruitment.
9. Known allergy or contraindication to aspirin, clopidogrel, alirocumab or atorvastatin.
10. 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.
11. Major surgery (including open femoral, aortic, cardiac or carotid surgery) within previous 30 days or planned in the 1 year after enrollment.
12. Dementia or psychiatric problem that prevents the patient from relevant evaluation or follow-up reliably.
13. Co-morbid conditions that may limit survival to less than 1 year.
14. Currently breastfeeding, pregnancy, planning to become pregnant and unwilling to use contraception for the duration of this study
15. Enrollment in another study that would conflict with the current study.

Contacts and Locations

Contacts

Contact: Zhaolu Wang, MD; 18100613663; wangzhaolu123@163.com

Contact: Xinyu Chen; 19975038610; njmuchenxinyu@163.com

Locations

China, Jiangsu

the First affiliated hospital of Nanjing Medical University; Recruiting

Nanjing, Jiangsu, China, 210001

Contact: Zhaolu Wang, MD, PhD 18100613663 wangzhaolu123@163.com

Sponsors and Collaborators

The First Affiliated Hospital with Nanjing Medical University

Investigators

• Principal Investigator: Kezhong Zhang, MD; The First Affiliated Hospital with Nanjing Medical University

More Information

Publications:

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.

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.

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.

• Responsible Party: Kezhong Zhang, Professor, The First Affiliated Hospital with Nanjing Medical University
• ClinicalTrials.gov Identifier: NCT06052020
• Other Study ID Numbers: EAST-sICAS
• First Posted: September 25, 2023
• Last Update Posted: September 28, 2023
• Last Verified: September 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Individual participant data (IPD) will be available to other researchers under the approval of the ethical committee.
• Supporting Materials: Study Protocol; Clinical Study Report (CSR)
• Time Frame: the data will be available when summary data are published.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Kezhong Zhang, The First Affiliated Hospital with Nanjing Medical University:

Alirocumab; stroke; intracranial atherostenosis stenosis

Additional relevant MeSH terms:

Constriction, Pathologic; Pathological Conditions, Anatomical; Atorvastatin; Alirocumab; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors; PCSK9 Inhibitors; Serine Proteinase Inhibitors; Protease Inhibitors