PCSK9 inhibitor plus statin for reversing asymptomatic intracranial artery plaque

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

This trial will test whether adding a PCSK9 inhibitor to statin therapy can shrink plaque and improve narrowing in adults aged 18–60 with asymptomatic intracranial artery stenosis (≥50%).

Quick facts

• Phase: Phase 4
• Study type: Interventional
• Enrollment: 300 (estimated)
• Ages: 18 Years to 60 Years
• Sex: All
• Sponsor: Peking Union Medical College Hospital (Academic / other)
• Drugs / interventions: radiation, evolocumab, alirocumab, Recaticimab
• Locations: 19 sites (Beijing, Beijing Municipality and 18 other locations)
• Trial ID: NCT06902740 on ClinicalTrials.gov

What this trial studies

This prospective, multicenter, open-label, blinded-endpoint randomized Phase 4 trial compares recaticimab plus statin versus statin alone in adults with asymptomatic intracranial atherosclerotic stenosis (50–99%). Participants are randomized to combination therapy or statin monotherapy and undergo high-resolution intracranial vessel-wall MRI to measure plaque burden and vessel changes over time. Eligible participants have no prior ischemic stroke or TIA and baseline LDL-C ≥2.6 mmol/L. The primary focus is imaging-based plaque regression and concurrent safety monitoring.

Who should consider this trial

Good fit: Adults 18–60 with asymptomatic intracranial atherosclerotic stenosis of 50–99% confirmed by angiography and vessel-wall MRI, LDL-C ≥2.6 mmol/L, and no prior stroke or TIA are ideal candidates.

Not a fit: Patients with symptomatic stenosis (prior stroke/TIA), non-atherosclerotic causes of narrowing, LDL-C below 2.6 mmol/L, or outside the 18–60 age range are unlikely to qualify or benefit from this protocol.

Why it matters

Potential benefit: If successful, adding a PCSK9 inhibitor could reduce intracranial plaque burden and lower the future risk of stroke and cognitive decline.

How similar studies have performed: PCSK9 inhibitors have produced large LDL-C reductions and reduced cardiovascular events in large trials, and lipid-lowering has shown plaque regression in extracranial arteries, but randomized data specifically demonstrating plaque regression in asymptomatic intracranial atherosclerosis are limited.

Eligibility criteria

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.

Where this trial is running

Beijing, Beijing Municipality and 18 other locations

• Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College — Beijing, Beijing Municipality, China (Recruiting)
• Chinese PLA General Hospital — Beijing, Beijing Municipality, China (Not_yet_recruiting)
• The Third Affiliated Hospital of Sun Yat-sen University, Yuedong Hospital — Meizhou, Guangdong, China (Not_yet_recruiting)
• Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine — Cangzhou, Hebei, China (Not_yet_recruiting)
• Peking University Third Hospital Qinhuangdao Hospital — Qinhuangdao, Hebei, China (Not_yet_recruiting)
• Hebei Provincial People's Hospital — Shijiazhuang, Hebei, China (Recruiting)
• Tangshan Worker's Hospital — Tangshan, Hebei, China (Not_yet_recruiting)
• First Affiliated Hospital of Harbin Medical University — Harbin, Heilongjiang, China (Not_yet_recruiting)
• The first affiliated hospital of zhengzhou university — Zhengzhou, Henan, China (Not_yet_recruiting)
• Taihe Hospital — Shiyan, Hubei, China (Not_yet_recruiting)
• Zhongnan Hospital of Wuhan University — Wuhan, Hubei, China (Not_yet_recruiting)
• Baotou Central Hospital — Baotou, Inner Mongolia, China (Not_yet_recruiting)
• Nanjing First Hospital — Nanjing, Jiangsu, China (Not_yet_recruiting)
• Jining First People's Hospital — Jining, Shandong, China (Not_yet_recruiting)
• Liaocheng People's Hospital — Liaocheng, Shandong, China (Not_yet_recruiting)
• The Affiliated Hospital of Qingdao University — Qingdao, Shandong, China (Not_yet_recruiting)
• Weifang People's Hospital — Weifang, Shandong, China (Not_yet_recruiting)
• Chongqing General Hospital — Chongqing, China (Not_yet_recruiting)
• Huashan Hospital, Fudan University — Shanghai, China (Not_yet_recruiting)

Study contacts

• Study coordinator: Weihai Xu, MD

Conditions Intracranial Atherosclerosis; Intracranial Artery Stenosis; Atherosclerotic Plaque; intracranial artery stenosis; atherosclerotic plaque; high-resolution magnetic resonance imaging; PCSK9 inhibitor; statin