Efficacy and Safety Study of Digital Cognitive Training and PCSK9 Inhibitor-Enhanced Lipid-lowering Strategy in Patients With Intracranial Atherosclerotic Stenosis: A 2x2 Factorial, Randomized, Parallel-Group, Multicenter Trial

This is a national, multicenter, 2×2 factorial, randomized, parallel-group controlled trial with a PROBE design (Prospective, Randomized, Open-label, Blinded Endpoint assessment). The study is conducted in China and is approved by the Institutional Review Board of Peking Union Medical College Hospital.

Background and Rationale:

Intracranial atherosclerotic stenosis (ICAS) is highly prevalent in Asian populations and is associated with both ischemic stroke and vascular cognitive impairment. Chronic hypoperfusion, microemboli, and white matter damage contribute to cognitive decline. While digital cognitive training has shown benefit in mild cognitive impairment, and PCSK9 inhibitors profoundly lower LDL-C and stabilize plaque, no trial has directly tested their combined effect on cognition in ICAS patients. This study aims to fill that gap.

Study Objectives:

Primary Objective A: To evaluate the effect of digital cognitive training versus active control on change from baseline in a composite cognitive Z-score at 24 weeks.

Primary Objective B: To evaluate the effect of adding a PCSK9 inhibitor to moderate-intensity statin therapy versus not adding it on change from baseline in a composite cognitive Z-score at 24 weeks.

Secondary and exploratory objectives include assessing effects on cognitive domains, serum LDL-C, MRI markers, plasma biomarkers, and testing the interaction between the two interventions.

Sample Size:

A total of 440 participants will be enrolled (110 per group, 1:1:1:1). Power calculation assumes a standardized effect size dΔ = 0.30 for the composite cognitive Z-score change, two-sided α = 0.05, power = 80%, and 20% missing primary outcome at week 24. Both marginal comparisons are powered at 80%.

Randomization and Blinding:

Subjects are randomized 1:1:1:1 via an interactive web response system (IWRS), stratified by center and prior stroke/TIA status. Random block sizes are used. The study is open-label for interventions, but outcome assessors (neuropsychological testers, MRI readers) are blinded. Separate blinded and unblinded teams manage assessments and intervention delivery.

Interventions:

Factor A (cognitive training): The intervention group receives 24 weeks of adaptive, multi-domain digital cognitive training (first 12 weeks intensive phase, followed by 12 weeks continuation phase), 30 minutes/day, 5 days/week. The control group receives active control consisting of science popularization and health education push notifications.

Factor B (lipid-lowering): Both groups receive moderate-intensity statin (rosuvastatin 10 mg or atorvastatin 20 mg daily) with optional ezetimibe. The intervention group additionally receives subcutaneous PCSK9 inhibitor (Recaticimab) according to the product label.

Statistical Analysis:

Primary analysis will use a mixed model for repeated measures (MMRM) jointly analyzing the change from baseline in composite cognitive Z-score at weeks 12 and 24. Fixed effects include Factor A, Factor B, visit, A×visit, B×visit, and randomization stratification factors. Factor A and Factor B are tested at two-sided α = 0.05 without fixed sequence. The primary model does not include the A×B interaction term; interaction is assessed in an exploratory model. Intention-to-treat analysis is primary, with per-protocol and sensitivity analyses (including cLDA and MNAR scenarios).

Data Monitoring and Ethics:

The study is monitored by independent clinical research associates. Serious adverse events are reported within 24 hours. Data is collected via EDC. Written informed consent will be obtained from all participants.

Inclusion criteria

• Age 55-80 years old
• The number of years of education is greater than or equal to 6 years
• 50%-99% stenosis of the intracranial artery confirmed by MRA, CTA or DSA
• Head CT or MRI confirmed that there were no infarct lesions/softening foci larger than 3 cm in the brain
• LDL-C ≥ 1.8mmol/L at baseline
• Decline in cognitive function of the complainant
• MMSE ≥ 24 points; no severe impairment of daily living and social functioning, and the daily living ability scale (ADL, 14-item BADL and IADL combined version, total score range of 14-56 points) <=18; and the investigator's clinical assessment does not meet the diagnosis of dementia (DSM-V or NIA-AA diagnostic criteria)
• Proficient in operating electronic products such as mobile phones and tablets
• Complete the operation evaluation through the introduction period (see the definition of the introduction period)
• Agree to receive moderate-intensity statin and PCSK9 inhibitor therapy during the study period
• Able to cooperate with neuropsychological and multimodal magnetic resonance examinations

Exclusion criteria

• Extracranial cervical artery stenosis ≥ 50%
• Acute cerebrovascular events within 90 days
• Contraindications to MRI (metal implants in the body, claustrophobia, etc.)
• Visual and auditory impairments, as well as communication difficulties, that affect cognitive training
• Clinically diagnosed vascular dementia
• Neuroimaging showing significant white matter lesions (Fazekas grade 3) or multiple microbleeds
• Non-atherosclerotic intracranial artery stenosis (such as vasculitis, moyamoya disease, dissection, etc.)
• Neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, etc.)
• Severe comorbidities (tumors, multiple sclerosis, severe cardiopulmonary and renal diseases, intracranial aneurysms)
• Other diseases that may affect cognition have been ruled out; severe anxiety, depression, or schizophrenia; a new stroke occurring within the 3 months prior to baseline; hereditary or inflammatory small vessel diseases; presence of any of the following clear sources of cardioembolic events: mitral stenosis, mechanical heart valves, endocarditis, intracardiac clots or vegetations, dilated cardiomyopathy, chronic or paroxysmal atrial fibrillation, ejection fraction less than 30%
• Planning to use medications that may affect cognitive function within the past 3 months or in the following 24 weeks, including large amounts of sedatives, anti-anxiety drugs, cognitive enhancers, and cholinergic agents.(12) Previously treated with a PCSK9 inhibitor
• Having a clear contraindication or severe intolerance to PCSK9 inhibitors or statins (such as a history of severe allergic reactions)
• Presence of significant liver or muscle safety abnormalities at baseline, or the investigator deems the patient unsuitable for intensive lipid-lowering therapy (for example, significantly elevated ALT or AST, significantly elevated CK, etc.; the thresholds can be based on the reference ranges of each center's laboratory and specified in the protocol in advance)
• Other circumstances deemed inappropriate for enrollment by the investigator