Moderate Versus Intensive Lipid-lowering for Events in Asymptomatic Intracranial Stenosis

Effect of Moderate- vs High-Intensity Lipid-Lowering Therapy in Patients With Asymptomatic Intracranial Atherosclerotic Disease: A Multicenter, Prospective, Randomized, Open-Label Trial

It is designed to compare two different strengths of cholesterol-lowering treatment in patients who have narrowing of blood vessels inside the brain (intracranial atherosclerosis) but do not currently have symptoms such as stroke.

The purpose of this study is to find out whether more intensive cholesterol-lowering treatment provides better protection against future vascular events, such as stroke, compared to moderate treatment. Cholesterol, especially LDL cholesterol, is known to contribute to the buildup of plaques in blood vessels, which can lead to serious complications.

Participants in this study are adults diagnosed with asymptomatic intracranial arterial narrowing. Because they do not yet have symptoms, this study aims to prevent future problems before they occur.

This is a multicenter study, meaning it is conducted at multiple hospitals. It is prospective, so participants are followed over time. It is also randomized, which means participants are assigned by chance (like flipping a coin) into one of two groups. One group receives moderate-intensity cholesterol-lowering therapy, while the other receives high-intensity therapy. The study is open-label, meaning both doctors and patients know which treatment is being given.

Participants will undergo regular follow-up visits during the study. These visits may include blood tests, imaging studies, and clinical assessments to monitor cholesterol levels, blood vessel condition, and overall health. The researchers will track whether participants experience any vascular events, such as stroke or transient ischemic attack (TIA).

The study will also monitor safety. Any side effects or adverse reactions to the medications will be carefully recorded. This ensures that both the effectiveness and safety of the treatments are evaluated.

1. Background and Rationale Asymptomatic intracranial atherosclerotic stenosis (aICAS) is increasingly recognized as a clinically significant condition associated with an elevated risk of ischemic stroke and systemic vascular events. Despite this, there is a paucity of randomized evidence defining optimal lipid-lowering strategies in this population. Current lipid management guidelines are predominantly informed by studies in symptomatic atherosclerosis or coronary artery disease and may not be directly generalizable to patients with aICAS.

   This study is designed to test the hypothesis that intensive lipid-lowering therapy targeting LDL70 mg/dL provides superior reduction in vascular events compared with a standard LDL-C target of <100 mg/dL.

2. Study Design This study is a multicenter, prospective, randomized, open-label, active-controlled clinical trial.

   A total of 1,626 participants will be enrolled and randomized in a 1:1 ratio to one of two treatment arms. Randomization will be performed using a centralized web-based system and stratified according to intracranial stenosis burden, baseline statin use, and the presence of diabetes mellitus.

3. Intervention Participants assigned to the moderate-intensity group will receive lipid-lowering therapy titrated to achieve and maintain LDL-C levels <100 mg/dL.

   Participants assigned to the intensive treatment group will receive statin-based therapy with additional lipid-lowering agents as needed to achieve and maintain LDL-C levels <70 mg/dL.

4. Follow-up and Assessments The enrollment period is expected to span 2 years. Participants will undergo a core follow-up period of 3 years, with study visits at 3, 12, 24, and 36 months. Extended follow-up will continue annually for up to 7 years.

Inclusion Criteria:

1. Adults aged 19 to 80 years at the time of screening

2. Presence of ≥50% stenosis in at least one major intracranial artery confirmed within 12 months prior to randomization by magnetic resonance angiography (MRA), computed tomography angiography (CTA), or conventional cerebral angiography.(Target vessels include: Middle cerebral artery (M1 or M2 segment), Anterior cerebral artery (A1 or A2 segment), Posterior cerebral artery (P1 or P2 segment), Basilar artery, Vertebral artery (V4 segment)) Stenosis severity must be assessed according to the WASID (Warfarin-Aspirin Symptomatic Intracranial Disease) method

3. Baseline low-density lipoprotein cholesterol (LDL-C) level of 100-190 mg/dL, or current use of lipid-lowering therapy

4. Presence of at least one of the following vascular risk factors:

   • Hypertension (systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or current use of antihypertensive medication)
   • Diabetes mellitus (fasting plasma glucose ≥126 mg/dL or ongoing antidiabetic treatment)
   • Current smoking
   • Family history of premature coronary artery disease (onset age <55 years in men or <65 years in women)
   • Chronic kidney disease (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m²)

Exclusion Criteria:

1. Cerebrovascular Pathologies

   • Prior history of symptomatic ischemic stroke or transient ischemic attack(TIA)
   • Previous cerebrovascular interventions, including intracranial or extracranial stenting or carotid endarterectomy
   • History of non-traumatic intracranial hemorrhage (ICH)
   • Presence of cerebral aneurysms or arteriovenous malformations (AVM)
   • Confirmed diagnosis of Moyamoya disease

2. Cardiovascular Comorbidities

   • Unstable angina pectoris or myocardial infarction (MI) within the preceding 6 months
   • Advanced heart failure, categorized as NYHA Class III or IV.
   • Severe valvular heart disease
   • Atrial fibrillation requiring chronic oral anticoagulation (CHA2DS2-VASc score ≥ 2, or persistent/permanent atrial fibrillation)

3. Contraindications to Lipid-Lowering Therapy

   • Known hypersensitivity to statins or ezetimibe
   • History of severe statin-associated muscle symptoms (SAMS), including rhabdomyolysis
   • Confirmed familial hypercholesterolemia

4. Active hepatic disease within 1 month prior to screening, or serum transaminases (ALT/AST) exceeding 3 times the upper limit of normal (ULN)

5. Type 2 diabetes mellitus requiring long-term insulin therapy, or those with established target organ damage (e.g., diabetic nephropathy, proliferative retinopathy, or clinically significant neuropathy), Type 1 diabetes mellitus with a disease duration of 20 years or more

6. Renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m²

7. Women who are currently pregnant or breastfeeding

8. Patients currently enrolled in other interventional clinical trials.