INtensive liPid-lowering Therapy for Acute High-risk IntracRanial or Extracranial atheroSclerosis -II (INSPIRES-2)

INtensive liPid-lowering Therapy for Acute High-risk IntracRanial or Extracranial atheroSclerosis -II (INSPIRES-2)：A Multicenter, Randomized, Double-blind, Placebo-controlled Clinical Trial

The research team is conducting a randomized, double-blind, placebo-controlled, multicenter clinical study aimed at evaluating the impact of adding Tolecilimab (a PCSK9 inhibitor) to standard lipid-lowering therapy (statins ± ezetimibe) on serum lipoprotein(a) [Lp(a)] levels and the risk of stroke recurrence within 90 days in patients with ischemic stroke or high-risk TIA (ABCD² ≥ 4) accompanied by elevated lipoprotein(a) levels (≥50 mg/dL).

Atherosclerotic stroke, particularly the large-artery atherosclerosis (LAA) subtype, carries a high risk of recurrence despite standard lipid-lowering therapy with statins. Elevated Lipoprotein(a) [Lp(a)] is a key genetic, pro-atherogenic risk factor largely unaffected by conventional statins and is independently associated with an increased risk of LAA-type stroke recurrence, representing a significant unmet residual risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors provide a dual-pathway approach by potently lowering both low-density lipoprotein cholesterol (LDL-C) and Lp(a) levels.Evidence on the benefits of early, intensive lipid-lowering with PCSK9 inhibitors specifically for secondary stroke prevention in high-risk LAA patients with elevated Lp(a) is lacking. The primary purpose of this study is to evaluate the efficacy and safety of adding tafolecimab, a novel PCSK9 inhibitor, to standard lipid-lowering therapy in reducing Lp(a) levels at 90 days in patients with acute ischemic stroke or high-risk transient ischemic attack (TIA) of LAA etiology and elevated Lp(a). Secondary objectives include assessing its impact on LDL-C control, preliminary clinical outcomes (stroke recurrence, composite vascular events), safety, and exploring biomarker associations. This is a multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 242 patients from multiple centers in China will be enrolled. Key eligibility criteria include: age 35-80 years, acute ischemic stroke or high-risk TIA (ABCD² ≥4) of large-artery atherosclerosis (LAA) etiology occurring 3-7 days before randomization, and lipoprotein(a) [Lp(a)] ≥50 mg/dL. Patients will be stratified by site and randomly assigned in a 1:1 ratio to receive either standard lipid-lowering therapy (statin ± ezetimibe) plus tafolecimab (a PCSK9 monoclonal antibody) or standard therapy plus matching placebo for 90 days. Study treatment will be initiated as soon as possible after randomization. Face-to-face visits are scheduled at baseline, day 7 (or hospital discharge), and months 1, 2, and 3 after randomization. At each visit, neurological status (NIHSS, mRS), vital signs, concomitant medications, and adverse events will be recorded. Fasting blood samples will be collected at baseline, month 1, month 2, and month 3 for central laboratory measurement of Lp(a), LDL-C, apolipoprotein B, high-sensitivity C-reactive protein, and interleukin-6. Additional safety laboratories (liver function, renal function, creatine kinase, complete blood count) will be performed at baseline, day 7, and month 3. The primary efficacy endpoint is the percent change in Lp(a) from baseline to 90 days, analyzed using a repeated-measures mixed-effects model (MMRM) with adjustment for baseline value. The key secondary efficacy endpoints include: percent change in LDL-C at 90 days, proportion of patients achieving LDL-C goal (<1.8 mmol/L or ≥50% reduction), and the occurrence of stroke recurrence, composite vascular events (ischemic stroke, myocardial infarction, hospitalization for unstable angina or heart failure, cardiovascular death), and all-cause death within 90 days. Safety endpoints comprise the incidence of adverse events, serious adverse events, bleeding events (GUSTO classification), hepatotoxicity (ALT/AST >3× ULN), myotoxicity (CK >10× ULN or clinical muscle symptoms), and injection-site reactions. The sample size was calculated to provide 80% power to detect a 25% between-group difference in Lp(a) reduction at 90 days, assuming a standard deviation of 67.34% and a two-sided alpha of 0.05, with an anticipated 5% dropout rate. Efficacy analyses will be performed on the intention-to-treat (ITT) population, while safety analyses will include all patients who received at least one dose of study drug. Time-to-event endpoints will be analyzed using Kaplan-Meier estimates and Cox proportional-hazards models. Continuous secondary endpoints will be assessed using MMRM or analysis of covariance.

Inclusion Criteria:

1. Age between 35 and 80 years, regardless of gender.
2. For patients with prior lipid-lowering treatment: screening LDL-C ≥1.8 mmol/L; for treatment-naïve patients: screening LDL-C ≥2.6 mmol/L.
3. Lp(a) ≥50 mg/dL.
4. Onset of symptoms within 3 to 7 days.
5. Diagnosis of ischemic stroke (NIHSS score ≤20) or high-risk TIA with ABCD² score ≥4; and meeting at least one of the following imaging criteria:

(1) Large-artery atherosclerosis (LAA) subtype per TOAST classification: vascular imaging confirms ≥50% atherosclerotic stenosis of the intracranial or extracranial culprit artery.

(2) Head CT or MRI demonstrates acute multiple infarcts, with etiology consistent with large-artery atherosclerosis (including nonstenotic vulnerable plaques).

6.The patient or their legally authorized representative has provided written informed consent.

Exclusion Criteria:

1. Patients who have undergone or are scheduled to undergo thrombolysis or thrombectomy therapy.
2. Definite cardiogenic ischemic cerebrovascular disease (e.g., accompanied by atrial fibrillation, prosthetic heart valves, atrial myxoma, infective endocarditis, etc.).
3. Other clearly identified etiologies of ischemic cerebrovascular disease (e.g., aortic dissection, cervical/cerebral arterial dissection, vasculitis, vascular malformations, moyamoya disease/syndrome, fibromuscular dysplasia, etc.).
4. Non-vascular intracranial diseases (e.g., intracranial tumors, multiple sclerosis, etc.).
5. Imaging findings indicating that the current cerebral infarction area exceeds 1/2 of a single brain lobe.
6. Imaging findings indicating hemorrhagic transformation of the current cerebral infarction.
7. Pre-stroke mRS score > 2.
8. Patients with known allergies to Tafolecimab or other contraindications for its use.
9. Use of immunosuppressive drugs, antifungal drugs, or fibrates (which affect statin metabolism) within 14 days prior to randomization.
10. Creatine kinase levels exceeding 5 times the upper limit of normal after the onset of the event.
11. Severe hepatic or renal insufficiency prior to randomization (Note: Severe hepatic insufficiency is defined as ALT >2×ULN or AST >2×ULN; severe renal insufficiency is defined as serum creatinine >1.5×ULN or GFR <40 ml/min/1.73m²).
12. History of intracranial hemorrhage (e.g., ICH, SAH).
13. History of intracranial or extracranial vascular angioplasty.
14. History of gastrointestinal bleeding or major surgery within 90 days prior to enrollment.
15. Planned surgical or interventional procedures within the next 90 days that may necessitate discontinuation of the investigational drug.
16. Suffering from severe organic diseases with an expected survival time of less than 1 year.
17. Pregnant women, or women of childbearing potential who are not using effective contraception and lack documented pregnancy test results.
18. Currently participating in other investigational drug or device trials.
19. Inability to cooperate with follow-up due to geographic, social, or other reasons (e.g., alcohol abuse, substance abuse, dementia, severe psychiatric disorders, etc.).