Clinical trial NCT06902740: PCSK9 Inhibitor With Statin Therapy for Asymptomatic Intracranial Atherosclerosis
Official title: PCSK9 Inhibitor With Statin Therapy for Asymptomatic Intracranial Atherosclerosis (PISTIAS-2): A Multicenter, Open-label, Blinded-endpoint, Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Intracranial Atherosclerosis
Intracranial Artery Stenosis
Atherosclerotic Plaque
Keywords: Intracranial Atherosclerosis
intracranial artery stenosis
atherosclerotic plaque
high-resolution magnetic resonance imaging
PCSK9 inhibitor
statin
Recaticimab
Lead sponsor: Peking Union Medical College Hospital
Sponsor class: OTHER
Collaborators: name: Chinese PLA General Hospital
name: Hebei General Hospital
name: Taihe Hospital
name: Weifang People's Hospital
name: Nanjing First Hospital, Nanjing Medical University
name: Baotou Central Hospital
name: Jining First People's Hospital
name: Liaocheng People's Hospital
name: Tangshan Worker's Hospital
First posted: 2025-03-30
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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) 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.

Primary outcomes:
measure: Percentage change in plaque burden
timeFrame: at 24 weeks of treatment
Secondary outcomes:
measure: Percentage change in stenosis degree
timeFrame: at 24 weeks of treatment
measure: Ischemic stroke or transient ischemic attack
timeFrame: at 24 weeks of treatment
measure: Major adverse cardiovascular events
timeFrame: at 24 weeks of treatment
measure: Silent cerebral infarction
timeFrame: at 24 weeks of treatment
measure: Changes in Plasma marker Aβ40/Aβ42
timeFrame: at 24 weeks of treatment
measure: Changes in Plasma marker GFAP
timeFrame: at 24 weeks of treatment
measure: Percentage of patients who achieved LDL-C goal
timeFrame: at 24 weeks of treatment
measure: Percentage change in LDL-C relative to baseline
timeFrame: at 24 weeks of treatment
Other outcomes:
measure: Any stroke during 24 weeks of treatment
timeFrame: at 24 weeks of treatment
measure: Any death during 24 weeks of treatment
timeFrame: at 24 weeks of treatment
measure: Changes in cognitive scale scores
timeFrame: at 24 weeks of treatment
measure: Changes in traditional lipid parameters
timeFrame: at 24 weeks of treatment
measure: Changes in Lipoprotein (a) level
timeFrame: at 24 weeks of treatment
measure: Visit-to-visit lipid variability of LDL-C
timeFrame: at 24 weeks of treatment
measure: Changes in high-sensitivity C-reactive protein
timeFrame: at 24 weeks of treatment
measure: Changes in plasma marker Neurofilament light
timeFrame: at 24 weeks of treatment
measure: Changes in plasma marker pTau217
timeFrame: at 24 weeks of treatment
measure: Changes in length of plaque
timeFrame: at 24 weeks of treatment
measure: Changes in plaque enhancement
timeFrame: at 24 weeks of treatment
measure: Changes in remodeling index of the plaque
timeFrame: at 24 weeks of treatment
measure: Changes in brain volume
timeFrame: at 24 weeks of treatment
measure: Changes in cortical thickness
timeFrame: at 24 weeks of treatment
measure: Changes in white matter hyperintensity
timeFrame: at 24 weeks of treatment
measure: Changes in DNA methylation status of peripheral blood cells
timeFrame: at 24 weeks of treatment
measure: Changes in Senescence-Associated Secretory Phenotype SA-β-gal
timeFrame: at 24 weeks of treatment
measure: Adverse events
timeFrame: at 24 weeks of treatment
Locations:
city: Beijing
country: China
facility: Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
state: Beijing
city: Beijing
country: China
facility: Chinese PLA General Hospital
state: Beijing
city: Shijiazhuang
country: China
facility: Hebei Provincial People's Hospital
state: Hebei
city: Tangshan
country: China
facility: Tangshan Worker's Hospital
state: Hebei
city: Shiyan
country: China
facility: Taihe Hospital
state: Hubei
city: Baotou
country: China
facility: Baotou Central Hospital
state: Inner Mongolia Autonomous Region
city: Nanjing
country: China
facility: Nanjing First Hospital
state: Jiangsu
city: Jining
country: China
facility: Jining First People's Hospital
state: Shandong
city: Liaocheng
country: China
facility: Liaocheng People's Hospital
state: Shandong
city: Weifang
country: China
facility: Weifang People's Hospital
state: Shandong
Study officials:
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