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

NCT07605130 | Not Yet Recruiting Phase 4

• 1 other identifier: K10526
• Study Type: interventional
• Target: 420
• Locations: 1 country
• Sites: 1

Brief Summary

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. 1.No cognitive training + standard statin therapy
2. 2.Cognitive training + standard statin therapy
3. 3.No cognitive training + intensive statin plus PCSK9 inhibitor
4. 4.Cognitive training + intensive statin plus PCSK9 inhibitor

Conditions

Intracranial Arteriosclerosis; Cognitive Impairment

Keywords

Cognitive Dysfunction; Cognitive Training; Artificial Intelligence; Computerised Cognitive Training

Outcome Measures

Primary Outcomes (1)

• 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.

  Baseline to 24 weeks

Secondary Outcomes (5)

• Change from baseline in composite cognitive score at week 12

  Baseline to 12 weeks

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

  Baseline to 12 weeks and Baseline to 24 weeks

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

  Baseline to 12 weeks and Baseline to 24 weeks

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

  Baseline to 24 weeks

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

  Baseline to 24 weeks

Study Arms (4)

Control group

ACTIVE COMPARATOR

No digital cognitive training + maximum statin tolerance only Participants receive maximally tolerated statin (rosuvastatin 20mg or atorvastatin 40mg daily, with optional ezetimibe 10mg at investigator discretion) for 24 weeks. No digital cognitive training. Instead, they receive low-difficulty standardized tasks as active control (same tablet, contact time, and push frequency but no adaptive multi-domain training).

Drug: Rosuvastatin; Drug: Ezetimibe; Behavioral: Active Control

Lipid-lowering intervention group

EXPERIMENTAL

No digital cognitive training + maximum tolerance statin plus PCSK9 inhibitor Participants receive maximally tolerated statin (as in Arm 1) plus subcutaneous PCSK9 inhibitor (Recaticimab) injections: 150mg at week 0, 300mg at week 4, 450mg at week 12. No digital cognitive training; they receive the same low-difficulty active control as in Arm 1. Total treatment duration is 24 weeks.

Drug: Rosuvastatin; Drug: Ezetimibe; Drug: Recaticimab; Behavioral: Active Control

Training intervention group

EXPERIMENTAL

Digital cognitive training + maximum statin tolerance only Participants receive maximally tolerated statin (as in Arm 1) for 24 weeks. In addition, they undergo 12 weeks of digital cognitive training: adaptive, multi-domain (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.

Drug: Rosuvastatin; Drug: Ezetimibe; Behavioral: Digital Cognitive Training

Combined intervention group

EXPERIMENTAL

Digital cognitive training + maximum tolerance statin plus PCSK9 inhibitor Participants receive both intensive interventions: maximally tolerated statin plus PCSK9 inhibitor (Recaticimab injections at weeks 0,4,12 as in Arm 3) \*\*and\*\* 12 weeks of digital cognitive training (same adaptive program as in Arm 2). Total treatment duration is 24 weeks.

Drug: Rosuvastatin; Drug: Ezetimibe; Drug: Recaticimab; Behavioral: Digital Cognitive Training

Interventions

Rosuvastatin DRUG

Rosuvastatin 20mg or Atorvastatin 40mg orally once daily, at the maximally tolerated dose, for 24 weeks. Dose may be adjusted for intolerance or safety.

Combined intervention group; Control group; Lipid-lowering intervention group; Training intervention group

Ezetimibe DRUG

Ezetimibe 10mg orally once daily, at investigator's discretion, in combination with statin therapy for 24 weeks.

Combined intervention group; Control group; Lipid-lowering intervention group; Training intervention group

Recaticimab DRUG

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.

Combined intervention group; Lipid-lowering intervention group

Digital Cognitive Training BEHAVIORAL

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.

Also known as: Computerized Cognitive Training (CCT)

Combined intervention group; Training intervention group

Active Control BEHAVIORAL

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.

Control group; Lipid-lowering intervention group

Eligibility Criteria

• Age: 55 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 55-80 years old
• The number of years of education is greater than or equal to 6 years
• %-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

You may not qualify if:

• 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

Sponsors & Collaborators

• Peking Union Medical College Hospital: lead

Study Sites (1)

Peking Union Medical College Hospital

Beijing, Beijing Municipality, 100730, China

Location

Related Publications (10)

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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.0000000000004826. Epub 2017 Dec 27.

  PMID: 29282327 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• Qureshi AI, Caplan LR. Intracranial atherosclerosis. Lancet. 2014 Mar 15;383(9921):984-98. doi: 10.1016/S0140-6736(13)61088-0. Epub 2013 Sep 2.

  PMID: 24007975 BACKGROUND

• Yang WJ, Wong KS, Chen XY. Intracranial Atherosclerosis: From Microscopy to High-Resolution Magnetic Resonance Imaging. J Stroke. 2017 Sep;19(3):249-260. doi: 10.5853/jos.2016.01956. Epub 2017 Sep 6.

  PMID: 28877564 BACKGROUND

MeSH Terms

Conditions

Intracranial Arteriosclerosis; Cognitive Dysfunction

Interventions

Rosuvastatin Calcium; Ezetimibe

Condition Hierarchy (Ancestors)

Intracranial Arterial Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Fluorobenzenes; Hydrocarbons, Fluorinated; Hydrocarbons, Halogenated; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azetidines; Azetines

Central Study Contacts

Zijue Wang, MD

CONTACT

+86 15901586608; Zijue_wang@163.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: The study adopted a design featuring open-label intervention and blinded endpoint assessment (PROBE). The blinded group investigator is only responsible for the evaluation and judgment related to the endpoint. The blinded group researchers did not obtain or ask the subjects about intervention allocation information during the entire study period, and did not participate in informed consent, random assignment, intervention implementation, adherence management, and medication adjustment. The unblinded investigator is responsible for all study implementation except for endpoint assessment. Non-blind monitors are responsible for research process monitoring and quality control. The non-blind auditor is responsible for handling issues related to the digital cognitive intervention system, providing technical/process advice, and reviewing the monitoring report of the non-blinded monitor.
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Researcher

Model Details: This study was randomized for 2×2 factors: factor A (digital cognitive training: with/without) and factor B (intensive lipid-lowering: PCSK9 addition/no addition), a total of 4 groups. Randomization was performed using a centralized randomization system with 1:1:1:1 allocation to four intervention combinations. In order to balance implementation feasibility with key prognostic factors, randomization stratification factors were limited to the study center and symptomatic ICAS status (previous ischemic stroke or TIA: yes/no), and block randomization with variable block size was used within each stratum to keep allocation hidden.

Study Record Dates

• First Submitted: May 17, 2026
• First Posted: May 22, 2026
• Study Start: May 25, 2026
• Primary Completion (Estimated): September 30, 2028
• Study Completion (Estimated): July 31, 2029
• Last Updated: May 22, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)