Efficacy and Safety Study of Digital Cognitive Training and PCSK9 Inhibitor-Enhanced Lipid-lowering Strategy in Patients With Intracranial Atherosclerotic Stenosis: A 2×2 Randomized Controlled Trial

Обзор

This study aims to evaluate whether digital cognitive training and/or intensive lipid-lowering therapy with a PCSK9 inhibitor 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 420 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 design: 1. No cognitive training + standard statin therapy 2. Cognitive training + standard statin therapy 3. No cognitive training + intensive statin plus PCSK9 inhibitor 4. Cognitive training + intensive statin plus PCSK9 inhibitor Cognitive training consists of 30 minutes of tablet-based exercises, 5 days per week for 12 weeks. The intensive lipid-lowering group receives a PCSK9 inhibitor (Recaticimab) injection at weeks 0, 4, and 12, on top of maximally tolerated statin. The main outcome is change in a composite cognitive score from baseline to 24 weeks. Secondary outcomes include changes in specific cognitive domains, 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.

Подробное описание

This is a national, multicenter, 2×2 factorial randomized 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: To evaluate the effect of digital cognitive training and intensive lipid-lowering (PCSK9 inhibitor) on change from baseline in a composite cognitive Z-score at 24 weeks. * Secondary: To assess effects on MoCA, domain-specific cognitive scores (memory, attention, executive function, visuospatial, language), whole-brain atherosclerotic burden, and plaque burden at the most stenotic site. * Exploratory: To test for interaction between the two interventions, and to evaluate changes in brain structure and function using advanced MRI.

Study Population:

Inclusion criteria: age 55-80 years, education ≥6 years, MRA/CTA/DSA-confirmed 50-99% intracranial arterial stenosis, no large (\>3cm) brain infarct, baseline LDL-C ≥1.8 mmol/L, subjective cognitive decline, MMSE ≥24, ADL \<18, no dementia, able to operate a tablet, pass a run-in period, agree to statin and PCSK9 inhibitor, and able to complete neuropsychological and MRI assessments.

Exclusion criteria: ≥50% extracranial stenosis, acute cerebrovascular event within 90 days, MRI contraindications, severe white matter disease (Fazekas 3), non-atherosclerotic stenosis, neurodegenerative disease, severe comorbidities, major psychiatric illness, prior PCSK9 inhibitor use, contraindications to statins or PCSK9 inhibitors, significant liver or muscle enzyme elevations, etc.

Sample Size:

A total of 420 participants will be enrolled (approximately 204 per marginal comparison after accounting for 20% dropout). Power calculation assumed a conservative effect size of Δμ=0.4 for the composite cognitive Z-score (σ=1), α=0.05 (two-sided), 1-β=0.80.

Randomization and Blinding:

Subjects are randomized 1:1:1:1 via an interactive web response system (IWRS), stratified by center and symptomatic ICAS status (prior stroke/TIA yes/no). Random block sizes are used. The study is open-label for the interventions, but outcome assessors (neuropsychological testers, MRI readers) are blinded to treatment allocation. Separate blinded and unblinded teams manage assessments and intervention delivery, respectively.

Interventions:

* Factor A (cognitive training): * Intervention group: 12 weeks of adaptive, multi-domain digital cognitive training (processing speed, attention, perception, memory, language, executive function) delivered via tablet. Participants are asked to train 30 minutes/day, 5 days/week. Minimum dose: ≥3 days/week and ≥20 minutes/session or ≥60 minutes/week. * Control group: Active control with low-difficulty standardized tasks (same device and contact time, no adaptive difficulty). * Factor B (lipid-lowering): * Both groups receive maximally tolerated statin (rosuvastatin 20mg or atorvastatin 40mg daily) with optional ezetimibe 10mg at investigator discretion. * Intervention group additionally receives subcutaneous Recaticimab (PCSK9 inhibitor) at weeks 0 (150mg), 4 (300mg), and 12 (450mg). * Control group receives no PCSK9 inhibitor.

Outcome Measures:

* Primary endpoint: Change in composite cognitive Z-score (average of memory, executive, visuospatial, attention, language domain Z-scores) from baseline to week 24. * Secondary endpoints: Change in composite Z-score at week 12; change in MoCA total score at weeks 12 and 24; change in each cognitive domain Z-score; change in whole-brain atherosclerotic burden (11-segment MRA score) and plaque burden (HRMRI) at week 24. * Exploratory endpoints: Interaction between training and lipid-lowering; changes in brain structure (DTI, 3D T1), function (resting-state fMRI), perfusion (ASL, optional), and lipid parameters (TC, non-HDL-C, Lp(a), TG, HDL-C). * Safety endpoints: Adverse events related to cognitive training (headache, eye strain, fatigue, sleep disturbance, etc.) and to lipid-lowering (myalgia, liver enzyme elevation, CK elevation, injection site reactions, allergic reactions).

Study Schedule:

* Screening/run-in (day -7 to 0): informed consent, medical history, physical exam, labs, MRI, neuropsychological assessment, and a run-in compliance check (3 simple tasks). * Baseline (day 0): randomization, start interventions (PCSK9 injection, dispense training device if assigned). * Follow-up visits: week 4 (±7 days), week 12 (±7 days), week 24 (±7 days). At each visit, labs, adverse event monitoring, and compliance assessment are performed. Full neuropsychological battery and MRI are repeated at week 24 (MRI also at baseline; cognitive battery also at week 12). * Early termination: if a participant withdraws, an early termination visit includes the full set of outcome assessments.

Statistical Analysis:

Primary analysis will use a linear mixed-effects model (LMM) with subject as random effect, time as repeated measure, and fixed effects: factor A (training), factor B (PCSK9 inhibitor), time, A×B, A×time, B×time, and A×B×time. Baseline cognitive status and other prespecified covariates (center, age, education) will be adjusted. The primary inference is the marginal mean difference at week 24 with 95% CI. Intention-to-treat (ITT) analysis is primary; per-protocol and sensitivity analyses will be performed. Secondary outcomes will be analyzed similarly. Safety data will be summarized descriptively.

Data Monitoring and Quality:

The study will be monitored by independent clinical research associates. All serious adverse events (SAEs) will be reported within 24 hours to the sponsor and the ethics committee. Data will be collected using an electronic data capture (EDC) system. The database will be locked after data cleaning, and statistical analysis will follow a pre-specified SAP (Statistical Analysis Plan).

Ethics and Dissemination:

The protocol has been approved by the ethics committee of Peking Union Medical College Hospital (I-26PJ0926). Written informed consent will be obtained from all participants. Results will be submitted for publication in peer-reviewed journals, regardless of the outcome.

Вмешательства

• Препарат Rosuvastatin
  Rosuvastatin 20mg or Atorvastatin 40mg orally once daily, at the maximally tolerated dose, for 24 weeks. Dose may be adjusted for intolerance or safety.
• Препарат Ezetimibe
  Ezetimibe 10mg orally once daily, at investigator's discretion, in combination with statin therapy for 24 weeks.
• Препарат Recaticimab
  Recaticimab (PCSK9 inhibitor) subcutaneous injection: 150mg at week 0, 300mg at week 4, 450mg at week 12, on top of maximally tolerated statin ± ezetimibe. Total treatment duration 24 weeks.
• Поведенческое Digital Cognitive Training
  Tablet-based adaptive cognitive training covering six domains: processing speed, attention, perception, memory, language, and executive function. Participants are instructed to train 30 minutes/day, 5 days/week for 12 weeks. The system adjusts difficulty based on performance.
• Поведенческое Active Control
  Participants receive low-difficulty standardized tasks on the same tablet platform, with similar contact time and push frequency as the intervention group. No adaptive multi-domain training is provided. Used to control for non-specific effects of device use and attention.

Первичные конечные точки

• Change from baseline in composite cognitive Z-score at week 24 [Срок оценки: Baseline to 24 weeks]

Вторичные конечные точки (5)

• Change from baseline in composite cognitive score at week 12 [Срок оценки: Baseline to 12 weeks]
• Change from baseline in MoCA total score at week 12 and week 24 [Срок оценки: Baseline to 12 weeks and Baseline to 24 weeks]
• Change from baseline in five cognitive domain Z-scores at week 12 and week 24 [Срок оценки: Baseline to 12 weeks and Baseline to 24 weeks]
• Change from baseline in whole-brain atherosclerotic burden at week 24 [Срок оценки: Baseline to 24 weeks]
• Change from baseline in plaque burden at the most stenotic site at week 24 [Срок оценки: Baseline to 24 weeks]

Критерии участия

Критерии включения

• 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 maximally tolerated statin and PCSK9 inhibitor therapy during the study period
• Able to cooperate with neuropsychological and multimodal magnetic resonance examinations

Критерии исключения

• Extracranial vascular 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Факторный дизайн

Маскирование

Простое слепое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Peking Union Medical College Hospital — Пекин

Публикации

• Giugliano RP, Sabatine MS, Ott BR. Cognitive Function in a Randomized Trial of Evolocumab. N Engl J Med. 2017 Nov 16;377(20):1997. doi: 10.1056/NEJMc1712102. No abstract available. PMID 29141161
• Tang Y, Xing Y, Zhu Z, He Y, Li F, Yang J, Liu Q, Li F, Teipel SJ, Zhao G, Jia J. The effects of 7-week cognitive training in patients with vascular cognitive impairment, no dementia (the Cog-VACCINE study): A randomized controlled trial. Alzheimers Dement. 2019 May;15(5):605-614. doi: 10.1016/j.jalz.2019.01.009. Epub 2019 Mar 17. PMID 30894299
• Chapman SB, Aslan S, Spence JS, Hart JJ Jr, Bartz EK, Didehbani N, Keebler MW, Gardner CM, Strain JF, DeFina LF, Lu H. Neural mechanisms of brain plasticity with complex cognitive training in healthy seniors. Cereb Cortex. 2015 Feb;25(2):396-405. doi: 10.1093/cercor/bht234. Epub 2013 Aug 28. PMID 23985135
• Risk Reduction of Cognitive Decline and Dementia: WHO Guidelines. Geneva: World Health Organization; 2019. Available from http://www.ncbi.nlm.nih.gov/books/NBK542796/ PMID 31219687
• Chan ATC, Ip RTF, Tran JYS, Chan JYC, Tsoi KKF. Computerized cognitive training for memory functions in mild cognitive impairment or dementia: a systematic review and meta-analysis. NPJ Digit Med. 2024 Jan 3;7(1):1. doi: 10.1038/s41746-023-00987-5. PMID 38172429
• Petersen RC, Lopez O, Armstrong MJ, Getchius TSD, Ganguli M, Gloss D, Gronseth GS, Marson D, Pringsheim T, Day GS, Sager M, Stevens J, Rae-Grant A. Practice guideline update summary: Mild cognitive impairment [RETIRED]: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018 Jan 16;90(3):126-135. doi: 10.1212/WNL.000 PMID 29282327
• Graessel E, Jank M, Scheerbaum P, Scheuermann JS, Pendergrass A. Individualised computerised cognitive training (iCCT) for community-dwelling people with mild cognitive impairment (MCI): results on cognition in the 6-month intervention period of a randomised controlled trial (MCI-CCT study). BMC Med. 2024 Oct 15;22(1):472. doi: 10.1186/s12916-024-03647-x. PMID 39407328
• Sabayan B, Goudarzi R, Ji Y, Borhani-Haghighi A, Olson-Bullis BA, Murray AM, Sedaghat S. Intracranial Atherosclerosis Disease Associated With Cognitive Impairment and Dementia: Systematic Review and Meta-Analysis. J Am Heart Assoc. 2023 Nov 21;12(22):e032506. doi: 10.1161/JAHA.123.032506. Epub 2023 Nov 20. PMID 37955546

Идентификаторы

NCT: NCT07605130 · K10526

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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