A Phase 4 interventional study of Rosuvastatin and Ezetimibe in Intracranial Arteriosclerosis and Cognitive Impairment, sponsored by Peking Union Medical College Hospital. Not yet recruiting at 1 site in China. Open to participants aged 55 Years to 80 Years. Per ClinicalTrials.gov, last updated 2026-09-15.
Sponsored by Peking Union Medical College Hospital · Phase 4, Interventional, and Treatment
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.
102 studies on the registry are indexed under Intracranial Arteriosclerosis; 48 are open to participants now.
This study's planned enrollment of 440 is above the median of 194 across 61 interventional studies indexed under Intracranial Arteriosclerosis.
Browse Intracranial Arteriosclerosis studies →Peking Union Medical College Hospital is the lead sponsor of 1,155 studies on the registry; 475 are open to participants now.
Of its 5 completed or terminated interventional studies of FDA-regulated products, 0 (0%) have results posted.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Short tests of memory and thinking, each scored out of 30. Lower scores suggest more difficulty; criteria give a range, either to include people with memory problems or to leave them out.
The American Psychiatric Association’s manual of mental health diagnoses. DSM-5 (2013, revised as DSM-5-TR in 2022) replaced DSM-IV, and some studies still name the older edition. “Meets DSM criteria for …” means diagnosed by that edition’s diagnostic criteria, usually by a clinician in an interview.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
The share of blood the heart’s main pumping chamber (the left ventricle) pushes out with each beat, measured by an echocardiogram (heart ultrasound) or a MUGA scan. About 50–70% is normal.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
MMSE and MoCA
Short tests of memory and thinking, each scored out of 30. Lower scores suggest more difficulty; criteria give a range, either to include people with memory problems or to leave them out.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
DSM diagnostic criteria
The American Psychiatric Association’s manual of mental health diagnoses. DSM-5 (2013, revised as DSM-5-TR in 2022) replaced DSM-IV, and some studies still name the older edition. “Meets DSM criteria for …” means diagnosed by that edition’s diagnostic criteria, usually by a clinician in an interview.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
LVEF (left ventricular ejection fraction)
The share of blood the heart’s main pumping chamber (the left ventricle) pushes out with each beat, measured by an echocardiogram (heart ultrasound) or a MUGA scan. About 50–70% is normal.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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.
Drug: Rosuvastatin · Drug: Ezetimibe · Behavioral: Active Control
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.
Drug: Rosuvastatin · Drug: Ezetimibe · Drug: Recaticimab · Behavioral: Active Control
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.
Drug: Rosuvastatin · Drug: Ezetimibe · Behavioral: Digital Cognitive Training
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.
Drug: Rosuvastatin · Drug: Ezetimibe · Drug: Recaticimab · Behavioral: Digital Cognitive Training
Rosuvastatin 10mg or Atorvastatin 20mg orally once daily, at the moderate-intensity dose, for 24 weeks. Dose may be adjusted for intolerance or safety.
Ezetimibe 10mg orally once daily, at investigator's discretion, in combination with statin therapy for 24 weeks.
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.
Also known as: Computerized Cognitive Training (CCT)
Participants receive science popularization and health education push notifications. Used to control for non-specific effects of study participation and attention.
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
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
Change from baseline in vascular stenosis severity at week 24
Intracranial arterial stenosis severity assessed by TOF-MRA. Outcome is change from baseline to week 24.
Time frame: Baseline to 24 weeks
Change from baseline in brain structure and function at week 24
Brain structure (DTI, 3D T1WI) and function (resting-state fMRI) changes. Outcome is change from baseline to week 24.
Time frame: Baseline to 24 weeks
Change from baseline in other lipid parameters at week 24
Other lipid parameters including TC, non-HDL-C, Lp(a), TG, and HDL-C. Outcome is change from baseline to week 24.
Time frame: Baseline to 24 weeks
Change from baseline in plasma biomarkers at week 24
Plasma biomarkers including Aβ42/Aβ40, p-tau217, NfL, and GFAP. Outcome is change from baseline to week 24.
Time frame: Baseline to 24 weeks
Interaction between digital cognitive training and PCSK9 inhibitor-enhanced lipid-lowering at week 24
Test for interaction between the two interventions on composite cognitive Z-score at week 24.
Time frame: Baseline to 24 weeks
Plan to share: No — No plan to share IPD due to absence of consent for data sharing and institutional policies protecting participant confidentiality.
Start is estimated for Sep 2026; primary completion for Sep 2028, 24 months later.
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Studies of the drug tested here: Recaticimab
Intracranial Arteriosclerosis →
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