PCSK9 Inhibitor With Statin Therapy for Asymptomatic Intracranial Atherosclerosis

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.

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 80 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.

Inclusion Criteria:

1. Age ≥18 and ≤80, 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 ≥ 1.8 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.