PCSK9 Inhibitor with Statin Therapy for Asymptomatic Intracranial Atherosclerosis

Phase 4

Not yet recruiting

• Conditions: Intracranial Atherosclerosis; Intracranial Artery Stenosis; Atherosclerotic Plaque
• Interventions: Drug: Recaticimab and Statin; Drug: Statin

• Registration Number: NCT06902740
• Lead Sponsor: Peking Union Medical College Hospital

Brief Summary

This is a prospective, multicenter, open-label, blinded-endpoint, randomized controlled trial designed to evaluate the efficacy of intensive lipid-lowering therapy with a PCSK9 inhibitor plus statin versus statin alone in reversing asymptomatic intracranial atherosclerotic plaques, , assessed using high-resolution magnetic resonance imaging of the intracranial vessel walls.

Detailed Description

Intracranial atherosclerotic stenosis (ICAS) is a leading cause of ischemic stroke worldwide. The global prevalence of asymptomatic ICAS was reported to be 6%-13%, depending on the different racial populations, characteristics of the study population, and the diagnostic methods.Among patients with cardiovascular risk factors, the prevalence was as high as 29.6% in China. Although patients with asymptomatic ICAS do not exhibit clinical symptoms, their potential risk for stroke and cognitive impairment should not be overlooked. Asymptomatic ICAS increases long-term stroke risk, and when these patients progress to symptomatic ICAS after their first stroke event, the risk of recurrent stroke significantly rises. Even with current intervention strategies or intensive medical treatments, the annual recurrence rate remains as high as 10-20%, making it difficult to control. Moreover, asymptomatic ICAS can lead to sustained hypo-perfusion in specific brain regions, adversely affecting brain health. An increasing evidence suggests that asymptomatic ICAS is independently associated with cognitive decline and the onset of dementia. A prospective cohort study found that asymptomatic ICAS may accelerate the progression of mild cognitive impairment to Alzheimer's disease. Therefore, addressing the disease burden of asymptomatic ICAS and reducing the secondary impact of cerebral ischemia events remain critical clinical needs.

The progression of ICAS plaques can be viewed as a key transition from a subclinical state of early, uncomplicated atherosclerosis to an acute phase. Substantial evidence has demonstrated that intensive lipid-lowering therapy, which controls low-density lipoprotein cholesterol (LDL-C) levels below 70 mg/dL, effectively inhibits plaque progression in patients with atherosclerotic cardiovascular disease. Plaque progression has become an improvable aspect of coronary atherosclerosis. Similarly, multiple cohort studies have shown that intensive lipid-lowering therapy can reverse asymptomatic ICAS. A prospective follow-up study based on transcranial Doppler (TCD) evaluation showed that in the lipid-controlled group (LDL-C ≤ 1.8 mmol/L), the plaque reversal rates were 26.3% in the first year and 34.7% in the second year, with significant differences compared to the non-controlled group. Another single-arm study based on CT angiography (CTA) evaluation demonstrated that daily administration of 20 mg of rosuvastatin significantly reduced total cholesterol and LDL-C levels in patients with asymptomatic ICAS, with 30 out of 48 patients (62.5%) showing ICAS reversal during a 6-month follow-up period. With the advancement of intracranial vascular imaging technologies, high-resolution magnetic resonance imaging (HRMRI) now enables sub-millimeter evaluation of the arterial wall, providing more precise insights into the process of atherosclerotic reversal.

However, traditional statin therapy exhibits only a "6% effect" in lipid-lowering, meaning that doubling the statin dosage results in only a 6% increase in the reduction of cholesterol and LDL-C levels. Moreover, higher doses of statins significantly increase the risks of liver and muscle damage, creating a pressing need to explore new, more effective lipid-lowering agents. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, as novel lipid-lowering drugs, lower LDL-C levels by enhancing LDL receptor degradation. Recent studies have demonstrated their significant effects in reducing cardiovascular events and combating atherosclerosis, with good safety profiles. Several randomized controlled trials have shown that PCSK9 inhibitors, either alone or in combination with statins, effectively control LDL-C levels and reduce cardiovascular adverse events. In patients with atherosclerotic cardiovascular disease but no history of ischemic events, PCSK9 inhibitors have been shown to stabilize and reverse plaques, offering excellent primary prevention effects. However, high-level evidence supporting the use of PCSK9 inhibitors in treating patients with asymptomatic ICAS remains limited.

This prospective, multicenter, open-label, blinded-endpoint, randomized controlled trial will enroll asymptomatic patients with intracranial artery stenosis who meet the inclusion and exclusion criteria. Participants will be centrally randomized into two groups, with 150 patients in each group: (1) Intensive lipid-lowering therapy group: Recaticimab 450 mg every 12 weeks combined with rosuvastatin 10 mg q.n. or atorvastatin 20 mg q.n., with or without ezetimibe 10 mg q.d. (2) Conventional lipid-lowering therapy group: Rosuvastatin 10 mg q.n. or atorvastatin 20 mg q.n., with or without ezetimibe 10 mg q.d.

The primary outcome is the percentage change in asymptomatic intracranial atherosclerotic plaque burden after 24 weeks of lipid-lowering treatment, assessed using high-resolution magnetic resonance imaging of the intracranial vessel walls.The secondary outcomes include: the percentage of patients who achieved the LDL-C target, ischemic cerebrovascular events(ischemic stroke or transient ischemic attack), major adverse cardiovascular events(ischemic stroke, myocardial infarction, or all-cause mortality), and changes in neuroimaging biomarkers(the number of cerebral microbleeds, volume of white matter hyperintensities, or the presence of subclinical cerebral infarctions).

Following the intervention phase, all participants will enter a prospective observational period, during which they may continue with either lipid-lowering regimen at their discretion. Clinical or telephone follow-ups will be conducted every six months, encouraging routine lipid profile assessments and HRMRI follow-ups to evaluate long-term effects.

Study Timeline

• Status Verified: 2025-03
• Study First Submitted: 2025-03-16
• Study First Submitted QC: 2025-03-24
• Last Update Submitted: 2025-03-24
• Study First Posted: 2025-03-30
• Last Update Posted: 2025-03-30
• Study Start: 2025-05-01
• Primary Completion: 2027-12-31
• Study Completion: 2028-12-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 300

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) 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. 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. Retinal hemorrhage Active bleeding diathesis or coagulopathy; active peptic ulcer disease, major systemic hemorrhage within 30 days, active bleeding diathesis, platelets count <125,000, hematocrit <30, Hgb <10 g/dl, uncorrected INR >1.5, bleeding time >1 minute beyond ULN at screening, or heparin associated thrombocytopenia that increases the risk of bleeding.
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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Recaticimab plus Statin Group	Recaticimab and Statin	Recaticimab (450mg every 12 weeks subcutaneously) combined with rosuvastatin 10mg qn or atorvastatin 20mg qn, with or without ezetimibe 10mg qd
Statin Group	Statin	Rosuvastatin 10mg qn or atorvastatin 20mg qn, with or without ezetimibe 10mg qd

Primary Outcome Measures

Name	Time	Method
Percentage change in plaque burden	at 24 weeks of treatment	Intracranial plaque burden was assessed at maximum stenosis site by high-resolution magnetic resonance imaging, performed at baseline and the end of the 24-week treatment period. Plaque burden = (vessel wall cross-sectional area - lumen cross-sectional area ) / vessel wall cross-sectional area ×100%. Percentage change in plaque burden=plaque burden at 24 weeks - plaque burden at baseline.

Secondary Outcome Measures

Name	Time	Method
Percentage change in stenosis degree	at 24 weeks of treatment	The degree of stenosis is calculated using the formula:1-（Ds/Dn）×100%, Ds represents the vessel diameter at the most stenotic site of the intracranial artery, and Dn represents the normal vessel diameter at a reference site.
Percentage of patients who achieved LDL-C goal	at 24 weeks of treatment	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.
Percentage change in LDL-C relative to baseline	at 24 weeks of treatment	Percentage change in LDL-C level at 24 weeks of treatment relative to baseline
Ischemic stroke or transient ischemic attack	at 24 weeks of treatment	New-Onset 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. Imaging findings must confirm that the infarct lesion is located within the vascular territory of the culprit artery responsible for the initial stroke.; 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.
Major adverse cardiovascular events	at 24 weeks of treatment	Composite endpoints includes ischemic stroke, myocardial infarction, and cardiovascular mortality as a cluster
Silent cerebral infarction	at 24 weeks of treatment	Silent cerebral infarction is defined as an imaging-detected infarct without acute clinical symptoms.
Changes in Plasma marker Aβ40/Aβ42	at 24 weeks of treatment	Changes in plasma markers Aβ40/Aβ42 from baseline at week 24 of treatment
Changes in Plasma marker GFAP	at 24 weeks of treatment	Changes in plasma marker GFAP from baseline at 24 weeks of treatment

Trial Locations

Locations (10)

Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; 🇨🇳 Beijing, Beijing, China

Chinese PLA General Hospital; 🇨🇳 Beijing, Beijing, China

Hebei Provincial People's Hospital; 🇨🇳 Shijiazhuang, Hebei, China

Tangshan Worker's Hospital; 🇨🇳 Tangshan, Hebei, China

Taihe Hospital; 🇨🇳 Shiyan, Hubei, China

Baotou Central Hospital; 🇨🇳 Baotou, Inner Mongolia Autonomous Region, China

Nanjing First Hospital; 🇨🇳 Nanjing, Jiangsu, China

Jining First People's Hospital; 🇨🇳 Jining, Shandong, China

Liaocheng People's Hospital; 🇨🇳 Liaocheng, Shandong, China

Weifang People's Hospital; 🇨🇳 Weifang, Shandong, China