PCSK9 Inhibitor With Statin Therapy for Asymptomatic Intracranial Atherosclerosis (PISTIAS-2)

PCSK9 Inhibitor With Statin Therapy for Asymptomatic Intracranial Atherosclerosis (PISTIAS-2): A Multicenter, Open-label, Blinded-endpoint, Randomized Controlled Trial

This is a prospective, multicenter, open-label, blinded-endpoint, randomized controlled trial designed to evaluate the efficacy and safety of PCSK9 inhibitor combined with statin therapy compared to statin monotherapy in reversing asymptomatic intracranial atherosclerosis, assessed using high-resolution magnetic resonance imaging of the intracranial vessel walls.

Study Overview

• Status: Recruiting
• Conditions: Intracranial Atherosclerosis; Intracranial Artery Stenosis; Atherosclerotic Plaque
• Intervention / Treatment: Drug: Recaticimab and Statin; Drug: Statin

Detailed Description

Intracranial atherosclerotic stenosis (ICAS) is a leading cause of ischemic stroke worldwide, accounting for approximately 10-20% of all ischemic strokes in Europe and the United States, and up to 50% in Asian populations. While evidence-based management strategies for symptomatic ICAS have been progressively established over the past decades, asymptomatic ICAS - representing an earlier-stage, broader, high-risk population - has long been under-recognized and under-studied. Asymptomatic ICAS (stenosis > 50%) has a reported prevalence of approximately 6%-13%, and is associated with a substantially increased risk of future cerebrovascular events. Moreover, accumulating evidence has demonstrated that asymptomatic ICAS is independently associated with cognitive decline and incident dementia, likely due to chronic downstream hypo-perfusion and cumulative ischemic injury. Therefore, the development of systematic, evidence-based, and precision prevention strategies for asymptomatic ICAS is essential for reducing the overall disease burden attributable to ICAS-related cerebrovascular and neurodegenerative disorders.

It is well established that dysregulation of lipid metabolism is a fundamental pathophysiological mechanism driving the initiation and progression of ICAS, and low-density lipoprotein cholesterol (LDL-C) has been consistently identified as the primary therapeutic target for atherosclerotic cardiovascular disease and for the prevention of ischemic stroke. Existing evidence has demonstrated that reductions in lipid levels and the regression of atherosclerotic plaques are closely associated with a decreased risk of cardiovascular events. Statin therapy remains the cornerstone of lipid-lowering treatment, capable of stabilizing atherosclerotic plaques and improving clinical outcomes. However, limitations of statins such as the plateau effect of LDL-C reduction, intolerance, and poor adherence in certain patients necessitate alternative or adjunctive lipid-lowering strategies. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, human monoclonal antibodies targeting PCSK9, have shown excellent efficacy in achieving intensive LDL-C reduction and have been extensively validated for safety in large clinical trials. Recently published studies have highlighted the potential of PCSK9 inhibitors in plaque regression and stabilization beyond coronary and carotid arteries. The SLICE-CEA CardioLink-8 trial demonstrated that adding evolocumab to moderate- or high-intensity statin therapy for 6 months significantly reduced the lipid-rich necrotic core in asymptomatic high-risk carotid plaques. Similarly, the ARCHITECT study revealed that alirocumab in combination with high-intensity statin therapy led to significant regression of coronary plaque burden and enhanced plaque stability in asymptomatic patients over a 78-week period. Several observational studies have indicated that intensive lipid-lowering therapy may reverse asymptomatic ICAS. However, to date, no clinical trials have specifically evaluated the efficacy and safety of PCSK9 inhibitors in addition to statin therapy in patients with asymptomatic ICAS. This represents a critical evidence gap, as these patients constitute a broader, earlier, and high-risk population for cerebrovascular events.

The PISTIAS-2 is an investigator-initiated, multicentre, prospective, open-label, blinded end-point, randomized controlled trial designed to evaluate the efficacy and safety of PCSK9 inhibitor combined with statin therapy compared to statin monotherapy in patients with asymptomatic ICAS. Patients aged 18 to 60 years with asymptomatic ICAS, defined as 50% to 99% stenosis in at least one major intracranial artery without a prior history of ischemic stroke or transient ischemic attack, will be enrolled for 24-week treatment. Eligible participants will be centrally randomized into two groups: (1) Experimental group [PCSK9 inhibitor combined with statin therapy]: Recaticimab 450 mg every 12 weeks combined with rosuvastatin 10 mg q.n. or atorvastatin 20 mg q.n. (2) Control group [Statin alone]: Rosuvastatin 10 mg q.n. or atorvastatin 20 mg q.n. Considering inter-individual variability in lipid-lowering response, ezetimibe 10 mg once daily is permitted at the discretion of the study physician based on the predefined criteria: (1) patients already receiving statin therapy prior to enrollment whose LDL-C remains above 2.6 mmol/L, and (2) statin-naïve patients whose LDL-C exceeds 2.6 mmol/L at the 12-week lipid profile reassessment. In this trial, we employed a novel PCSK9 inhibitor, Recaticimab, a humanized IgG1 monoclonal antibody engineered with a strategic YTE mutation in its Fc region, which enhances its affinity for the neonatal Fc receptor (FcRn). This modification reduces FcRn-mediated antibody catabolism, thereby extending the half-life of Recaticimab and enabling a prolonged dosing interval of up to 12 weeks.

The primary outcome is the change in intracranial plaque burden from baseline to week 24, measured by high-resolution magnetic resonance imaging (HR-MRI).The key secondary outcomes include: change in stenosis degree from baseline to week 24, time from randomization to the first-ever ischemic stroke or transient ischemic attack, and change in plasma marker glial fibrillary acidic protein(GFAP) and neurofilament light (NfL). Other secondary outcomes include: time from randomization to the occurrence of major adverse cardiovascular events, new-onset silent cerebral infarction, percentage of patients who achieved LDL-C goal at week 24, percentage change in LDL-C relative to baseline, and change in plasma marker Aβ40, Aβ42, Aβ42/Aβ40. In addition, several pre-specified exploratory outcomes have been defined for this study. Details are provided in the "Outcome Measures" section.

After the 24-week treatment period, an extended prospective follow-up (clinical or telephone follow-up) will continue for more than one year to document long-term effects.The sample size is calculated based on the primary outcome and a total of 300 participants are anticipated. An interim analysis will be conducted when 50% of the participants (i.e., 150 subjects) have completed the 24-week follow-up with HR-MRI. An independent Data Safety Monitoring Board will oversee the overall conduct of the trial.

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Weihai Xu, MD; Phone Number: 86+13651147766; Email: xuwh@pumch.cn
• Study Contact Backup: Name: Yiyang Liu, PhD; Phone Number: 86+13938912070; Email: liuyydoct@163.com

Study Locations

• China
  • Chongqing, China
    • Not yet recruiting
    • Chongqing General Hospital
    • Contact: Jingxi Ma, MD; Phone Number: 86+15765059385; Email: majingxi@ucas.ac.cn
    • Principal Investigator: Jingxi Ma, MD
  • Shanghai, China
    • Not yet recruiting
    • Huashan Hospital, Fudan University
    • Contact: Jianhui Fu, MD; Phone Number: 86+13701818645; Email: jianhuifu@126.com
    • Principal Investigator: Jianhui Fu, MD
  • Beijing
    • Beijing, Beijing, China, 100853
      • Not yet recruiting
      • Chinese PLA General Hospital
      • Contact: Shiwen Wu, MD; Phone Number: 86+13910238117; Email: wu_shiwen@outlook.com
      • Principal Investigator: Shiwen Wu, MD
    • Beijing, Beijing, China, 100730
      • Recruiting
      • Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
      • Contact: Weihai Xu, MD; Phone Number: 86+13651147766; Email: xuwh@pumch.cn
      • Principal Investigator: Weihai Xu, MD
  • Guangdong
    • Meizhou, Guangdong, China
      • Not yet recruiting
      • The Third Affiliated Hospital of Sun Yat-sen University, Yuedong Hospital
      • Contact: Ying Bian, MD; Phone Number: 86+13692279949; Email: bianying1001@126.com
      • Principal Investigator: Ying Bian, MD
  • Hebei
    • Cangzhou, Hebei, China
      • Not yet recruiting
      • Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine
      • Contact: Yonglin Shan, MD; Phone Number: 86+13832756668; Email: shanyonglin1985@sina.com
      • Principal Investigator: Yonglin Shan, MD
    • Qinhuangdao, Hebei, China
      • Not yet recruiting
      • Peking University Third Hospital Qinhuangdao Hospital
      • Contact: Yaqun Liu, MD; Phone Number: 86+18533550025; Email: bysyqhdyyyxll@163.com
      • Principal Investigator: Yaqun Liu, MD
    • Shijiazhuang, Hebei, China, 050051
      • Recruiting
      • Hebei Provincial People's Hospital
      • Contact: Hebo Wang, MD; Phone Number: 86+13582131890; Email: wanghbhope@hebmu.edu.cn
      • Principal Investigator: Hebo Wang, MD
    • Tangshan, Hebei, China, 063000
      • Not yet recruiting
      • Tangshan Worker's Hospital
      • Contact: Baoquan Lu, MD; Phone Number: 86+13930565557; Email: balcom@163.com
      • Principal Investigator: Baoquan Lu, MD
  • Heilongjiang
    • Harbin, Heilongjiang, China
      • Not yet recruiting
      • First Affiliated Hospital of Harbin Medical University
      • Contact: Hongquan Jiang, MD; Phone Number: 86+13796707995; Email: quan@hrbmu.edu.cn
      • Principal Investigator: Hongquan Jiang, MD
  • Henan
    • Zhengzhou, Henan, China
      • Not yet recruiting
      • The First Affiliated Hospital of Zhengzhou University
      • Contact: Bo Song, MD; Phone Number: 86+13603983297; Email: fccsongb@zzu.edu.cn
      • Principal Investigator: Bo Song, MD
  • Hubei
    • Shiyan, Hubei, China, 442000
      • Not yet recruiting
      • Taihe Hospital
      • Contact: Zhibing Ai, MD; Phone Number: 86+13997833207; Email: aizhibing1@126.com
      • Principal Investigator: Zhibing Ai, MD
    • Wuhan, Hubei, China
      • Not yet recruiting
      • Zhongnan Hospital of Wuhan University
      • Contact: Bin Mei, MD; Phone Number: 86+13037196699; Email: neuromei20@163.com
      • Principal Investigator: Bin Mei, MD
  • Inner Mongolia Autonomous Region
    • Baotou, Inner Mongolia Autonomous Region, China, 014000
      • Not yet recruiting
      • Baotou Central Hospital
      • Contact: Jingfen Zhang, MD; Phone Number: 86+13947253466; Email: 1846224761@qq.com
      • Principal Investigator: Jingfen Zhang, MD
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • Not yet recruiting
      • Nanjing First Hospital
      • Contact: Qiwen Deng, MD; Phone Number: 86+15366110212; Email: qiw_deng@njmu.edu.cn
      • Principal Investigator: Qiwen Deng, MD
  • Shandong
    • Jining, Shandong, China, 272000
      • Not yet recruiting
      • Jining First People's Hospital
      • Contact: Zhongrui Yan, MD; Phone Number: 86+15910000699; Email: zhongruiy@163.com
      • Principal Investigator: Zhongrui Yan, MD
    • Liaocheng, Shandong, China, 252000
      • Not yet recruiting
      • Liaocheng People's Hospital
      • Contact: Guanzeng Li, MD; Phone Number: 86+13396350996; Email: 13396350996@163.com
      • Principal Investigator: Guanzeng Li, MD
    • Qingdao, Shandong, China
      • Not yet recruiting
      • The Affiliated Hospital Of Qingdao University
      • Contact: Naidong Wang, MD; Phone Number: 86+18661809550; Email: wangnaidong163@163.com
      • Principal Investigator: Naidong Wang, MD
    • Weifang, Shandong, China, 261000
      • Not yet recruiting
      • Weifang People's Hospital
      • Contact: Li Zhou, MD; Phone Number: 86+13869621818; Email: weifangzhou003@163.com
      • Principal Investigator: Li Zhou, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 and ≤60, male or female;
2. Asymptomatic intracranial artery stenosis (50%-99%) in the internal carotid artery (C6-7 segments), middle cerebral artery (M1 segment), vertebral artery (V4 segment), or basilar artery, confirmed by angiography (MRA, CTA, or DSA);
3. Atherosclerosis identified as the cause of intracranial artery stenosis by high-resolution magnetic resonance imaging;
4. No previous ischemic cerebrovascular events (including ischemic stroke or transient ischemic attack).
5. Baseline low-density lipoprotein cholesterol ≥ 2.6 mmol/L;
6. Informed consent signed.

Exclusion Criteria:

1. Non-atherosclerotic intracranial artery stenosis, including arterial dissection; moya moya disease; systemic vasculitis and primary central nervous system vasculitis; varicella-zoster vasculopathy or other viral vasculopathy; neurosyphilis and other intracranial infections, radiation vasculopathy; fibromuscular dysplasia, sickle cell disease, neurofibromatosis; reversible cerebral vasoconstriction syndrome; postpartum vasculopathy; suspected vasospasm, suspected reperfusion after vessel occlusion.
2. Upstream tandem extracranial vessel stenosis (≥50%) adjacent to the target intracranial stenotic vessel.
3. Previous treatment of target intracranial lesion with endovascular intervention or plan to perform endovascular intervention within 6 months, including intracranial stenting, endovascular angioplasty, and thrombectomy.
4. Any intracranial hemorrhage (parenchymal, subarachnoid, subdural, extradural, intraventricular) within 90 days prior to enrollment.
5. Presence of intracranial tumors.
6. Presence of cerebral aneurysms or arteriovenous malformations with indications for interventional therapy.
7. Major surgery (including open femoral, aortic, or carotid surgery) within previous 30 days or planned in the next 6 months after enrollment.
8. Presence of any of the following unequivocal cardiac sources of embolism: mitral stenosis, mechanical valve, endocarditis, intracardiac clot or vegetation, myocardial infarction within 3 months, dilated cardiomyopathy, chronic or paroxysmal atrial fibrillation.
9. New York Heart Association (NYHA) class III or IV, or known left ventricular ejection fraction < 30%.
10. Severe liver dysfunction or severe kidney dysfunction: AST and/or ALT > 3 times the ULN; creatinine clearance < 0.6 mL/s and/or serum creatinine > 265 μmol/L (>3.0 mg/dL); CK >5 times the ULN at screening.
11. Active bleeding diathesis or coagulopathy (e.g., active peptic ulcer disease, major systemic hemorrhage within 30 days, active bleeding diathesis, platelets count < 125,000 / uL, hematocrit < 30%, Hgb < 10 g/dl, international normalized ratio >1.5, bleeding time > 1 minute beyond normal value upper limit).
12. Presence of systemic autoimmune diseases: systemic sclerosis, systemic lupus erythematosus, Sjögren's syndrome, Behçet's disease, mixed connective tissue disease, IgG4-related disease.
13. Dementia or psychiatric problem that hinder their ability to consistently adhere to an outpatient program. Co-morbid conditions that may limit the life expectancy to less than 3 years.
14. Relative/absolute contraindications to magnetic resonance imaging (MRI) (such as presence of internal metallic objects, claustrophobia, contrast agent allergy, severe renal impairment, epilepsy, hypotension, asthma, and other hypersensitivity respiratory diseases).
15. Uncontrolled hypertension during the screening period, defined as seated systolic blood pressure (SBP) > 180 mmHg or diastolic blood pressure (DBP) > 110 mmHg.
16. Prior use of PCSK9 inhibitor before this recruitment.
17. Known intolerance or allergy to statin.
18. Pregnancy, lactation, or planning pregnancy.
19. Currently participating in another study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Recaticimab plus Statin Group; Recaticimab (450mg every 12 weeks subcutaneously) combined with rosuvastatin 10mg qn or atorvastatin 20mg qn	Drug: Recaticimab and Statin; Recaticimab (450mg every 12 weeks subcutaneously) combined with rosuvastatin 10mg qn or atorvastatin 20mg qn
Active Comparator: Statin Group; Rosuvastatin 10mg qn or atorvastatin 20mg qn	Drug: Statin; Rosuvastatin 10mg qn or atorvastatin 20mg qn

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in plaque burden from baseline to week 24	Intracranial plaque burden was assessed at maximum stenosis site by high-resolution magnetic resonance imaging, performed at baseline and the end of the treatment period (24 [±1] week) on the same machine. The plaque burden is calculated according to the following formula: plaque burden = [(vessel wall cross-sectional area - lumen cross-sectional area ) / vessel wall cross-sectional area] ×100%. The outcome will be centrally assessed by an independent core imaging laboratory blinded to treatment allocation according to a predefined imaging analysis protocol.	From baselie to the end of treatment at 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in stenosis degree from baseline to week 24	The degree of stenosis is calculated according to the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) criteria using the formula: [1-(Dstenosis/Dnormal)]×100%. Dstenosis represents the vessel diameter at the most stenotic site of the intracranial artery, and Dnormal represents the normal vessel diameter at a reference site.	From baseline to the end of treatment at 24 weeks
Time from randomization to the first-ever ischemic stroke or transient ischemic attack	Ischemic Stroke: Defined as an acute cerebral infarction with clinical signs or imaging evidence of a new acute focal neurological injury persisting for more than 24 hours, excluding other non-ischemic causes. Transient Ischemic Attack (TIA): Defined as a sudden onset of focal neurological deficit due to cerebral or retinal ischemia, which completely resolves within 24 hours. Imaging (CT or MRI) must show no evidence of a new cerebral infarction. Other non-ischemic causes, such as brain infection, trauma, tumor, epilepsy, severe metabolic disorders, or progressive neurological diseases, must be excluded.	From baseline to the end of treatment at 24 weeks
Change in plasma marker glial fibrillary acidic protein(GFAP)	Change in plasma marker glial fibrillary acidic protein(GFAP) quantified using the Single Molecule Array platform from baseline to the end of treatment at 24 weeks	From baseline to the end of treatment at 24 weeks
Change in plasma marker neurofilament light(NfL)	Change in plasma marker Neurofilament light(NfL) quantified using the Single Molecule Array platform from baseline to the end of treatment at 24 weeks	From baseline to the end of treatment at 24 weeks
Time from randomization to the occurrence of major adverse cardiovascular events	Composite major adverse cardiovascular endpoints includes ischemic stroke, myocardial infarction, and cardiovascular mortality as a cluster	From baseline to the end of treatment at 24 weeks
Silent cerebral infarction	New-onset silent cerebral infarction is defined as an imaging-detected infarct without acute clinical symptoms	at 24 weeks of treatment
Percentage of patients who achieved LDL-C goal at week 24	Percentage of patients achieving the LDL-C target at week 24 of treatment, defined as LDL-C < 1.8 mmol/L or LDL-C < 2.6 mmol/L based on ASCVD risk assessment.	at 24 weeks of treatment
Percentage change in LDL-C relative to baseline	Percentage change in LDL-C level at 24 weeks of treatment relative to baseline	From baseline to the end of treatment at 24 weeks
Change in Plasma marker Aβ42/Aβ40	Change in plasma markers Aβ42/Aβ40 from baseline to the end of treatment at 24 weeks	From baseline to the end of treatment at 24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time from randomization to the time of the first occurrence of transient ischemic attack	Transient Ischemic Attack (TIA): Defined as a sudden onset of focal neurological deficit due to cerebral or retinal ischemia, which completely resolves within 24 hours. Imaging (CT or MRI) must show no evidence of a new cerebral infarction. Other non-ischemic causes, such as brain infection, trauma, tumor, epilepsy, severe metabolic disorders, or progressive neurological diseases, must be excluded.	From baseline to the end of treatment at 24 weeks
Time from randomization to the time of the first occurrence of ischemic stroke	Ischemic Stroke: Defined as an acute cerebral infarction with clinical signs or imaging evidence of a new acute focal neurological injury persisting for more than 24 hours, excluding other non-ischemic causes.	From baseline to the end of treatment at 24 weeks
Time from randomization to the time of the occurrence of any stroke	Any stroke includes ischemic and hemorrhagic stroke	From baseline to the end of treatment at 24 weeks
Time from randomization to the time of the occurrence of myocardial infarction	Time from randomization to the time of the occurrence of myocardial infarction	From baseline to the end of treatment at 24 weeks
Time from randomization to the time of the occurrence of vascular death	Time from randomization to the time of the occurrence of vascular death	From baseline to the end of treatment at 24 weeks
Time from randomization to the time of the occurrence of any death	All-cause mortality will be calculated between two arms	From baseline to the end of treatment at 24 weeks
Changes in cognitive scale scores	Cognitive function will be evaluated via MMSE and MOCA at baseline and week 24	From baseline to the end of treatment at 24 weeks
Changes in traditional lipid parameters	Changes in traditional lipid profiles, especially total cholesterol (TC), triglycerides (TG) and HDL-C.	From baseline to the end of treatment at 24 weeks
Change in Lipoprotein (a) level	Non-traditional lipid parameters such as Lipoprotein (a) level will be detected at baseline and week 24	From baseline to the end of treatment at 24 weeks
Visit-to-visit lipid variability of LDL-C	Lipid variability during the treatment period, which can be evaluated by the following indicators: coefficient of variation (CV), standard deviation (SD), variability independent of the mean (VIM), average real variability (ARV).	From baseline to the end of treatment at 24 weeks
Change in high-sensitivity C-reactive protein	Inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP) will be detected at baseline and week 24	From baseline to the end of treatment at 24 weeks
Change in plasma marker pTau217	Markers of neurological disorders such asplasma marker pTau217 will be detected at baseline and week 24	From baseline to the end of treatment at 24 weeks
Changes in DNA methylation status of peripheral blood cells	DNA methylation, particularly RNF213, an important epigenetic factor, may play a role in the progression of ICAS.	From baseline to the end of treatment at 24 weeks
Changes in Senescence-Associated Secretory Phenotype	Previous studies have shown that lipid-lowering has an obvious scavenging effect on senescent cells. Senescence associated β-galactosidase, SA-β-gal, is thought to be a sign of aging	From baseline to the end of treatment at 24 weeks
Change in length of plaque	length of plaque was evaluated by high-resolution MRI at baseline and week 24	From baseline to the end of treatment at 24 weeks
Change in plaque maximum thickness	the maximum thickness of plaque was evaluated by high-resolution MRI at baseline and week 24	From baseline to the end of treatment at 24 weeks
Change in the outer-wall boundary area at the maximal stenotic site	the outer-wall boundary area at the maximal stenotic site was evaluated by high-resolution MRI at baseline and week 24	From baseline to the end of treatment at 24 weeks
Change in remodeling index of the plaque	Remodeling index of the plaque is calculated by the ratio of the diameter of the lumen at the most severe lesion to the diameter of the proximal reference lumen, positive remodeling defined as remodeling index > 1.1	From baseline to the end of treatment at 24 weeks
Change in plaque enhancement	plaque enhancement will be detected via contrast enhanced high- resolution MRI	From baseline to the end of treatment at 24 weeks
Change in brain volume	Total brain volume will be evaluated by MRI 3D-T1WI at baseline and week 24	From baseline to the end of treatment at 24 weeks
Change in cortical thickness	The thickness and surface area of cerebral cortex in all and different brain regions were quantitatively determined based on MRI	From baseline to the end of treatment at 24 weeks
Change in cerebral small vessel disease burden	cerebral small vessel disease burden were quantitatively determined based on MRI at baseline and week 24	From baseline to the end of treatment at 24 weeks
Change in white matter hyperintensity	White matter hyperintensity (WMH) in all and different brain regions were quantitatively determined based on MRI	From baseline to the end of treatment at 24 weeks
Change in collateral circulation status	Collateral circulation status will be assessed using standardized imaging-based grading scales to evaluate the extent and quality of collateral blood flow.	From baseline to the end of treatment at 24 weeks
Adverse events	An Adverse Event (AE) is any untoward medical occurrence in clinical trial subject administered a pharmaceutical product and which does not necessarily have a causal relationship with the treatment.	From baseline to the end of treatment at 24 weeks
Serious Adverse Events	A Serious Adverse Event (SAE) is any untoward medical occurrence that, at any dose: (1) results in death; (2) is life-threatening; (3) requires inpatient hospitalization or prolongation of existing hospitalization; (4)results in persistent or significant disability/incapacity; (5) is a congenital anomaly/birth defect; (6) is otherwise considered medically significant by the investigator.	From baseline to the end of treatment at 24 weeks

Collaborators and Investigators

• Sponsor: Peking Union Medical College Hospital
• Collaborators: Chinese PLA General Hospital; Huashan Hospital; Hebei General Hospital; The Affiliated Hospital of Qingdao University; Nanjing First Hospital, Nanjing Medical University; The First Affiliated Hospital of Zhengzhou University; Zhongnan Hospital; First Affiliated Hospital of Harbin Medical University; Taihe Hospital; Liaocheng People's Hospital; Weifang People's Hospital; Baotou Central Hospital; Chongqing General Hospital; Tangshan Worker's Hospital; Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine; Jining First People's Hospital

Publications and helpful links

General Publications

• Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR; FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722. doi: 10.1056/NEJMoa1615664. Epub 2017 Mar 17.
• Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ, Koenig W, Somaratne R, Kassahun H, Yang J, Wasserman SM, Scott R, Ungi I, Podolec J, Ophuis AO, Cornel JH, Borgman M, Brennan DM, Nissen SE. Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA. 2016 Dec 13;316(22):2373-2384. doi: 10.1001/jama.2016.16951.
• Gao P, Wang T, Wang D, Liebeskind DS, Shi H, Li T, Zhao Z, Cai Y, Wu W, He W, Yu J, Zheng B, Wang H, Wu Y, Dmytriw AA, Krings T, Derdeyn CP, Jiao L; CASSISS Trial Investigators. Effect of Stenting Plus Medical Therapy vs Medical Therapy Alone on Risk of Stroke and Death in Patients With Symptomatic Intracranial Stenosis: The CASSISS Randomized Clinical Trial. JAMA. 2022 Aug 9;328(6):534-542. doi: 10.1001/jama.2022.12000.
• Perez de Isla L, Diaz-Diaz JL, Romero MJ, Muniz-Grijalvo O, Mediavilla JD, Argueso R, Sanchez Munoz-Torrero JF, Rubio P, Alvarez-Banos P, Ponte P, Manas D, Suarez Gutierrez L, Cepeda JM, Casanas M, Fuentes F, Guijarro C, Angel Barba M, Saltijeral Cerezo A, Padro T, Mata P; SAFEHEART Study Group. Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients with Familial Hypercholesterolemia: The ARCHITECT Study. Circulation. 2023 May 9;147(19):1436-1443. doi: 10.1161/CIRCULATIONAHA.122.062557. Epub 2023 Apr 3.
• Kim BS, Lim JS, Jeong JU, Mun JH, Kim SH. Regression of asymptomatic intracranial arterial stenosis by aggressive medical management with a lipid-lowering agent. J Cerebrovasc Endovasc Neurosurg. 2019 Sep;21(3):144-151. doi: 10.7461/jcen.2019.21.3.144. Epub 2019 Sep 30.
• Miao H, Yang Y, Wang H, Huo L, Wang M, Zhou Y, Hua Y, Ren M, Ren C, Ji X, Yang Q, Guo X. Intensive Lipid-Lowering Therapy Ameliorates Asymptomatic Intracranial Atherosclerosis. Aging Dis. 2019 Apr 1;10(2):258-266. doi: 10.14336/AD.2018.0526. eCollection 2019 Apr.
• Zhu J, Wang Y, Li J, Deng J, Zhou H. Intracranial artery stenosis and progression from mild cognitive impairment to Alzheimer disease. Neurology. 2014 Mar 11;82(10):842-9. doi: 10.1212/WNL.0000000000000185. Epub 2014 Jan 31.
• Zhao D, Guallar E, Qiao Y, Knopman DS, Palatino M, Gottesman RF, Mosley TH Jr, Wasserman BA. Intracranial Atherosclerotic Disease and Incident Dementia: The ARIC Study (Atherosclerosis Risk in Communities). Circulation. 2024 Sep 10;150(11):838-847. doi: 10.1161/CIRCULATIONAHA.123.067003. Epub 2024 Aug 1.
• Li S, Tang M, Zhang D, Han F, Zhou L, Yao M, Li M, Cui L, Zhang S, Peng B, Jin Z, Zhu Y, Ni J. The prevalence and prognosis of asymptomatic intracranial atherosclerosis in a community-based population: Results based on high-resolution magnetic resonance imaging. Eur J Neurol. 2023 Dec;30(12):3761-3771. doi: 10.1111/ene.16057. Epub 2023 Sep 22.
• Gutierrez J, Khasiyev F, Liu M, DeRosa JT, Tom SE, Rundek T, Cheung K, Wright CB, Sacco RL, Elkind MSV. Determinants and Outcomes of Asymptomatic Intracranial Atherosclerotic Stenosis. J Am Coll Cardiol. 2021 Aug 10;78(6):562-571. doi: 10.1016/j.jacc.2021.05.041.
• Wong KS, Ng PW, Tang A, Liu R, Yeung V, Tomlinson B. Prevalence of asymptomatic intracranial atherosclerosis in high-risk patients. Neurology. 2007 Jun 5;68(23):2035-8. doi: 10.1212/01.wnl.0000264427.09191.89.
• Wong KS, Huang YN, Yang HB, Gao S, Li H, Liu JY, Liu Y, Tang A. A door-to-door survey of intracranial atherosclerosis in Liangbei County, China. Neurology. 2007 Jun 5;68(23):2031-4. doi: 10.1212/01.wnl.0000264426.63544.ee.
• Chimowitz MI, Lynn MJ, Derdeyn CP, Turan TN, Fiorella D, Lane BF, Janis LS, Lutsep HL, Barnwell SL, Waters MF, Hoh BL, Hourihane JM, Levy EI, Alexandrov AV, Harrigan MR, Chiu D, Klucznik RP, Clark JM, McDougall CG, Johnson MD, Pride GL Jr, Torbey MT, Zaidat OO, Rumboldt Z, Cloft HJ; SAMMPRIS Trial Investigators. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011 Sep 15;365(11):993-1003. doi: 10.1056/NEJMoa1105335. Epub 2011 Sep 7.

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: March 16, 2025
• First Submitted That Met QC Criteria: March 24, 2025
• First Posted (Actual): March 30, 2025

Study Record Updates

• Last Update Posted (Actual): August 7, 2025
• Last Update Submitted That Met QC Criteria: August 3, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: statin; PCSK9 inhibitor; atherosclerotic plaque; Intracranial Atherosclerosis; intracranial artery stenosis; high-resolution magnetic resonance imaging; Recaticimab
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Arteriosclerosis; Arterial Occlusive Diseases; Intracranial Arterial Diseases; Plaque, Atherosclerotic; Intracranial Arteriosclerosis; Atherosclerosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Other Study ID Numbers: I-24PJ2601; 2024ZD0521605 (Other Grant/Funding Number: the Noncommunicable Chronic Diseases-National Science and Technology Major Project); 82025013 (Other Grant/Funding Number: the National Science Fund for Distinguished Young Scholars)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No