NCT07605130 - 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 | Crick | Crick

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

Phase 4Not Yet RecruitingNCT07605130

Peking Union Medical College Hospital440 enrolled

Overview

This study aims to evaluate whether digital cognitive training and/or PCSK9 inhibitor-enhanced lipid-lowering therapy on top of moderate-intensity statin can improve cognitive function in patients with intracranial atherosclerosis (ICAS). ICAS is a common cause of stroke and is also linked to thinking and memory problems. The study will enroll 440 adults aged 55-80 years who have 50-99% narrowing of an intracranial artery, subjective memory complaints, and LDL cholesterol ≥1.8 mmol/L, but who are not demented. Participants will be randomly assigned to one of four groups in a 2×2 factorial, parallel-group design: No cognitive training + moderate-intensity statin therapy Cognitive training + moderate-intensity statin therapy No cognitive training + moderate-intensity statin plus PCSK9 inhibitor Cognitive training + moderate-intensity statin plus PCSK9 inhibitor Cognitive training consists of 30 minutes of tablet-based exercises, 5 days per week for 24 weeks (first 12 weeks as the intensive phase, followed by 12 weeks continuation phase). The PCSK9 inhibitor (Recaticimab) is administered subcutaneously according to the product label, on top of moderate-intensity statin. The main outcome is change in a composite cognitive score from baseline to 24 weeks. Secondary outcomes include changes in specific cognitive domains, serum LDL-C, MRI markers of brain structure and function, and safety measures. The study is multicenter, open-label with blinded outcome assessment, and is conducted under the approval of the ethics committee of Peking Union Medical College Hospital.

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.

Eligibility

Sex: ALLMin age: 55 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age 55-80 years old 2. The number of years of education is greater than or equal to 6 years 3. 50%-99% stenosis of the intracranial artery confirmed by MRA, CTA or DSA 4. Head CT or MRI confirmed that there were no infarct lesions/softening foci larger than 3 cm in the brain 5. LDL-C ≥ 1.8mmol/L at baseline 6. Decline in cognitive function of the complainant 7. 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) 8. Proficient in operating electronic products such as mobile phones and tablets 9. Complete the operation evaluation through the introduction period (see the definition of the introduction period) 10. Agree to receive moderate-intensity statin and PCSK9 inhibitor therapy during the study period 11. Able to cooperate with neuropsychological and multimodal magnetic resonance examinations Exclusion Criteria: 1. Extracranial cervical artery stenosis ≥ 50% 2. Acute cerebrovascular events within 90 days 3. Contraindications to MRI (metal implants in the body, claustrophobia, etc.) 4. Visual and auditory impairments, as well as communication difficulties, that affect cognitive training 5. Clinically diagnosed vascular dementia 6. Neuroimaging showing significant white matter lesions (Fazekas grade 3) or multiple microbleeds 7. Non-atherosclerotic intracranial artery stenosis (such as vasculitis, moyamoya disease, dissection, etc.) 8. Neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, etc.) 9. Severe comorbidities (tumors, multiple sclerosis, severe cardiopulmonary and renal diseases, intracranial aneurysms) 10. 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% 11. 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 12. Having a clear contraindication or severe intolerance to PCSK9 inhibitors or statins (such as a history of severe allergic reactions) 13. 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) 14. Other circumstances deemed inappropriate for enrollment by the investigator

Outcomes

Primary Outcomes

Change from baseline in composite cognitive Z-score at week 24

The composite cognitive Z-score is derived from five cognitive domains: memory, executive function, visuospatial ability, attention, and language. Each individual test score is first standardized to a Z-score using normative mean and SD, with direction aligned so that higher scores indicate better function (reaction times are reverse-coded). Domain Z-scores are the equally weighted average of the prespecified core tests within each domain. The overall composite Z-score is the equally weighted average of the five domain Z-scores. The outcome is the change from baseline to week 24, with positive values indicating improvement.

Time frame: Baseline to 24 weeks

Secondary Outcomes

Change from baseline in composite cognitive score at week 12

Same composite Z-score as primary outcome, derived from memory, executive, visuospatial, attention, and language domains. Outcome is change from baseline to week 12.

Time frame: Baseline to 12 weeks

Change from baseline in MoCA total score at week 12 and week 24

Montreal Cognitive Assessment (MoCA) total score. The MoCA scale ranges from 0 to 30, with higher scores indicating better cognitive function. Outcome is change from baseline at week 12 and week 24.

Time frame: Baseline to 12 weeks and Baseline to 24 weeks

Change from baseline in five cognitive domain Z-scores at week 12 and week 24

Domain-specific Z-scores for memory, executive function, visuospatial ability, attention, and language. Each domain Z-score is the equally weighted average of prespecified core tests within that domain. Outcome is change from baseline at week 12 and week 24.

Time frame: Baseline to 12 weeks and Baseline to 24 weeks

Change from baseline in whole-brain atherosclerotic burden at week 24

Whole-brain atherosclerotic burden is assessed by TOF-MRA, summing stenosis scores (0, 1, 2, 3, 4) across 11 intracranial arterial segments (range 0-44, higher indicates greater burden). Outcome is change from baseline to week 24.

Time frame: Baseline to 24 weeks

Change from baseline in plaque burden at the most stenotic site at week 24

Plaque burden measured by high-resolution MRI (HRMRI) at the most stenotic intracranial artery site. Plaque burden = (vessel wall area - lumen area)/vessel wall area × 100%. Outcome is change from baseline to week 24.

Time frame: Baseline to 24 weeks

Change from baseline in serum LDL-C at week 12 and week 24

Serum LDL-C levels. Outcome is change from baseline at week 12 and week 24. Higher values indicate worse lipid control.

Time frame: Baseline to 12 weeks and Baseline to 24 weeks