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

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.

• Incidence of new stroke (including hemorrhagic and ischemic stroke) within 90 days. [Срок оценки: From baseline to 90 days after randomization]
• Incidence of composite clinical endpoint events within 90 days [Срок оценки: From baseline to 90 days after randomization]
• Incidence of myocardial infarction within 90 days. [Срок оценки: From baseline to 90 days after randomization]
• Incidence of vascular death within 90 days. [Срок оценки: From baseline to 90 days after randomization]
• Incidence of all-cause death within 90 days. [Срок оценки: From baseline to 90 days after randomization]
• Proportion of patients with poor functional outcome (mRS score 2-6) at 90 days. [Срок оценки: From baseline to 90 days after randomization]
• Proportion of patients with Lp(a) <30 mg/dL at 90 days [Срок оценки: From baseline to 90 days after randomization]
• Percent reduction in ApoB and LDL-C levels from baseline to 90 days [Срок оценки: From baseline to 90 days after randomization]
• LDL-C goal attainment rate (<1.8 mmol/L or reduction ≥ 50%) at 90 days [Срок оценки: From baseline to 90 days after randomization]
• Moderate and severe bleeding events (GUSTO classification) [Срок оценки: From baseline to 90 days after randomization]
• Hepatotoxicity: Post-treatment ALT or AST levels exceeding 3 times the upper limit of normal upon re-measurement [Срок оценки: From baseline to 90 days after randomization]
• Muscle toxicity [Срок оценки: From baseline to 90 days after randomization]