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
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 入组人数
- 440
- 试验地点
- 1
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 55 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Rosuvastatin (Drug)
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.
干预措施: Digital Cognitive Training (Behavioral)
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.
干预措施: Active Control (Behavioral)
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.
干预措施: Active Control (Behavioral)
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.
干预措施: Digital Cognitive Training (Behavioral)
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.
干预措施: Recaticimab (Drug)
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.
干预措施: Ezetimibe (Drug)
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.
干预措施: Ezetimibe (Drug)
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.
干预措施: Recaticimab (Drug)
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.
干预措施: Ezetimibe (Drug)
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.
干预措施: Rosuvastatin (Drug)
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.
干预措施: Rosuvastatin (Drug)
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.
干预措施: Ezetimibe (Drug)
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.
干预措施: Rosuvastatin (Drug)
结局指标
主要结局
未指定
次要结局
- 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 whole-brain atherosclerotic burden at week 24(Baseline to 24 weeks)
- Change from baseline in serum LDL-C at week 12 and week 24(Baseline to 12 weeks and Baseline to 24 weeks)
研究者
ZijueWang
Assistant Researcher
Peking Union Medical College Hospital