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 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.
Přehled studie
Postavení
Detailní popis
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.
Typ studie
Zápis (Odhadovaný)
Fáze
- Fáze 4
Kontakty a umístění
Studijní kontakt
- Jméno: Zijue Wang, MD
- Telefonní číslo: +86 15901586608
- E-mail: Zijue_wang@163.com
Studijní místa
-
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Beijing Municipality
-
Beijing, Beijing Municipality, Čína, 100730
- Peking Union Medical College Hospital
-
Kontakt:
- Zijue Wang, MD
- Telefonní číslo: +86 15901586608
- E-mail: Zijue_wang@163.com
-
-
Kritéria účasti
Kritéria způsobilosti
Věk způsobilý ke studiu
- Dospělý
- Starší dospělý
Přijímá zdravé dobrovolníky
Popis
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
Studijní plán
Jak je studie koncipována?
Detaily designu
- Primární účel: Léčba
- Přidělení: Randomizované
- Intervenční model: Faktorové přiřazení
- Maskování: Singl
Zbraně a zásahy
Skupina účastníků / Arm |
Intervence / Léčba |
|---|---|
|
Aktivní komparátor: Control group
No digital cognitive training + moderate-intensity statin only.
Participants receive moderate-intensity statin (rosuvastatin 10mg or atorvastatin 20mg daily, with optional ezetimibe 10mg at investigator discretion) for 24 weeks.
No digital cognitive training.
Instead, they receive science popularization and health education push notifications as active control.
|
Ezetimibe 10mg orally once daily, at investigator's discretion, in combination with statin therapy for 24 weeks.
Rosuvastatin 10mg or Atorvastatin 20mg orally once daily, at the moderate-intensity dose, for 24 weeks.
Dose may be adjusted for intolerance or safety.
Participants receive science popularization and health education push notifications.
Used to control for non-specific effects of study participation and attention.
|
|
Experimentální: Lipid-lowering intervention group
No digital cognitive training + moderate-intensity statin plus PCSK9 inhibitor.
Participants receive moderate-intensity statin (as in Arm 1) plus subcutaneous PCSK9 inhibitor (Recaticimab) injections according to the product label.
No digital cognitive training; they receive the same science popularization and health education push notifications as in Arm 1.
Total treatment duration is 24 weeks.
|
Ezetimibe 10mg orally once daily, at investigator's discretion, in combination with statin therapy for 24 weeks.
Rosuvastatin 10mg or Atorvastatin 20mg orally once daily, at the moderate-intensity dose, for 24 weeks.
Dose may be adjusted for intolerance or safety.
Participants receive science popularization and health education push notifications.
Used to control for non-specific effects of study participation and attention.
Recaticimab (PCSK9 inhibitor) subcutaneous injection according to the product label, on top of moderate-intensity statin ± ezetimibe.
Total treatment duration 24 weeks.
|
|
Experimentální: Training intervention group
Digital cognitive training + moderate-intensity statin only.
Participants receive moderate-intensity statin (as in Arm 1) for 24 weeks.
In addition, they undergo 24 weeks of digital cognitive training: adaptive, multi-domain (processing speed, attention, perception, memory, language, executive function) delivered via tablet.
The first 12 weeks are the intensive phase, followed by 12 weeks of continuation training.
Participants are asked to train 30 minutes/day, 5 days/week.
Minimum dose: ≥3 days/week and ≥20 minutes/session or ≥60 minutes/week.
|
Ezetimibe 10mg orally once daily, at investigator's discretion, in combination with statin therapy for 24 weeks.
Rosuvastatin 10mg or Atorvastatin 20mg orally once daily, at the moderate-intensity dose, for 24 weeks.
Dose may be adjusted for intolerance or safety.
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 24 weeks (first 12 weeks as the intensive phase, followed by 12 weeks continuation phase).
The system adjusts difficulty based on performance.
Ostatní jména:
|
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Experimentální: Combined intervention group
Digital cognitive training + moderate-intensity statin plus PCSK9 inhibitor.
Participants receive both interventions: moderate-intensity statin plus PCSK9 inhibitor (Recaticimab injections according to the product label as in Arm 3) and 24 weeks of digital cognitive training (same adaptive program as in Arm 2, first 12 weeks intensive phase followed by 12 weeks continuation phase).
Total treatment duration is 24 weeks.
|
Ezetimibe 10mg orally once daily, at investigator's discretion, in combination with statin therapy for 24 weeks.
Rosuvastatin 10mg or Atorvastatin 20mg orally once daily, at the moderate-intensity dose, for 24 weeks.
Dose may be adjusted for intolerance or safety.
Recaticimab (PCSK9 inhibitor) subcutaneous injection according to the product label, on top of moderate-intensity statin ± ezetimibe.
Total treatment duration 24 weeks.
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 24 weeks (first 12 weeks as the intensive phase, followed by 12 weeks continuation phase).
The system adjusts difficulty based on performance.
Ostatní jména:
|
Co je měření studie?
Primární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
|
Change from baseline in composite cognitive Z-score at week 24
Časové okno: Baseline to 24 weeks
|
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
|
Sekundární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
|
Change from baseline in composite cognitive score at week 12
Časové okno: Baseline to 12 weeks
|
Same composite Z-score as primary outcome, derived from memory, executive, visuospatial, attention, and language domains.
Outcome is change from baseline to week 12.
|
Baseline to 12 weeks
|
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Change from baseline in five cognitive domain Z-scores at week 12 and week 24
Časové okno: Baseline to 12 weeks and Baseline to 24 weeks
|
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.
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Baseline to 12 weeks and Baseline to 24 weeks
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Change from baseline in plaque burden at the most stenotic site at week 24
Časové okno: Baseline to 24 weeks
|
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.
|
Baseline to 24 weeks
|
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Change from baseline in MoCA total score at week 12 and week 24
Časové okno: Baseline to 12 weeks and Baseline to 24 weeks
|
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.
|
Baseline to 12 weeks and Baseline to 24 weeks
|
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Change from baseline in whole-brain atherosclerotic burden at week 24
Časové okno: Baseline to 24 weeks
|
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.
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Baseline to 24 weeks
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Change from baseline in serum LDL-C at week 12 and week 24
Časové okno: Baseline to 12 weeks and Baseline to 24 weeks
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Serum LDL-C levels.
Outcome is change from baseline at week 12 and week 24.
Higher values indicate worse lipid control.
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Baseline to 12 weeks and Baseline to 24 weeks
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Další výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
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Change from baseline in vascular stenosis severity at week 24
Časové okno: Baseline to 24 weeks
|
Intracranial arterial stenosis severity assessed by TOF-MRA.
Outcome is change from baseline to week 24.
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Baseline to 24 weeks
|
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Change from baseline in brain structure and function at week 24
Časové okno: Baseline to 24 weeks
|
Brain structure (DTI, 3D T1WI) and function (resting-state fMRI) changes.
Outcome is change from baseline to week 24.
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Baseline to 24 weeks
|
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Change from baseline in other lipid parameters at week 24
Časové okno: Baseline to 24 weeks
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Other lipid parameters including TC, non-HDL-C, Lp(a), TG, and HDL-C.
Outcome is change from baseline to week 24.
|
Baseline to 24 weeks
|
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Change from baseline in plasma biomarkers at week 24
Časové okno: Baseline to 24 weeks
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Plasma biomarkers including Aβ42/Aβ40, p-tau217, NfL, and GFAP.
Outcome is change from baseline to week 24.
|
Baseline to 24 weeks
|
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Interaction between digital cognitive training and PCSK9 inhibitor-enhanced lipid-lowering at week 24
Časové okno: Baseline to 24 weeks
|
Test for interaction between the two interventions on composite cognitive Z-score at week 24.
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Baseline to 24 weeks
|
Spolupracovníci a vyšetřovatelé
Publikace a užitečné odkazy
Obecné publikace
- 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.
- Risk Reduction of Cognitive Decline and Dementia: WHO Guidelines. Geneva: World Health Organization; 2019. Available from http://www.ncbi.nlm.nih.gov/books/NBK542796/
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Termíny studijních záznamů
Hlavní termíny studia
Začátek studia (Odhadovaný)
Primární dokončení (Odhadovaný)
Dokončení studie (Odhadovaný)
Termíny zápisu do studia
První předloženo
První předloženo, které splnilo kritéria kontroly kvality
První zveřejněno (Aktuální)
Aktualizace studijních záznamů
Poslední zveřejněná aktualizace (Aktuální)
Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality
Naposledy ověřeno
Více informací
Termíny související s touto studií
Klíčová slova
Další relevantní podmínky MeSH
- Cerebrovaskulární poruchy
- Onemocnění mozku
- Onemocnění centrálního nervového systému
- Nemoci nervového systému
- Cévní onemocnění
- Kardiovaskulární choroby
- Duševní poruchy
- Neurokognitivní poruchy
- Poruchy kognice
- Arterioskleróza
- Arteriální okluzivní onemocnění
- Intrakraniální arteriální onemocnění
- Kognitivní dysfunkce
- Intrakraniální arterioskleróza
- Sloučeniny síry
- Organické chemikálie
- Heterocyklické sloučeniny, 1 kruh
- Heterocyklické sloučeniny
- Uhlovodíky
- Amidy
- Pyrimidiny
- Uhlovodíky, halogenované
- Sulfonamidy
- Sulfony
- Azetidiny
- Azetiny
- Fluorobenzenes
- Uhlovodíky, fluorované
- Rosuvastatin Vápník
- Ezetimib
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