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) \[Lp(a)\] ≥30 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.

• Tafolecimab (Drug): Treatment should be initiated as soon as possible after randomization, with Tafolecimab administered subcutaneously once every two weeks for a total duration of 90 days. All patients received standard lipid-lowering therapy as recommended by stroke secondary prevention guidelines, including intensive statin treatment with or without ezetimibe, administered at maximally tolerated doses.
• Placebo (Drug): Treatment should be initiated as soon as possible after randomization, with Tafolecimab placebo administered subcutaneously once every two weeks for a total duration of 90 days. All patients received standard lipid-lowering therapy as recommended by stroke secondary prevention guidelines, including intensive statin treatment with or without ezetimibe, administered at maximally tolerated doses.

Primary outcomes

• Percentage change in Lp(a) from baseline at 90 days. [From baseline to 90 days after randomization]

Secondary outcomes

• Incidence of new stroke (including hemorrhagic and ischemic stroke) within 90 days. [From baseline to 90 days after randomization]: Symptoms and signs of acute neurological deficits caused by sudden focal or whole brain, spinal cord or retinal vascular damage, which are related to cerebral circulatory disorders, including hemorrhagic and ischemic stroke
• Incidence of composite clinical endpoint events within 90 days [From baseline to 90 days after randomization]: Including recurrent ischemic stroke, myocardial infarction, rehospitalization for unstable angina or heart failure, and cardiovascular death
• Incidence of myocardial infarction within 90 days. [From baseline to 90 days after randomization]: Acute myocardial infarction is diagnosed by the third edition of the international general diagnostic criteria (Glob Heart. 2012 Dec;7(4):275-95)
• Incidence of vascular death within 90 days. [From baseline to 90 days after randomization]: Vascular death includes stroke, sudden cardiac death, acute myocardial infarction, heart failure, pulmonary embolism, heart / cerebrovascular intervention or surgery (death unrelated to acute MI) and other cardiovascular causes of death \[such as: Arrhythmia irrelevant with sudden cardiac death, aortic aneurysm rupture, or peripheral artery disease. Any death of unknown/unclear cause that occurs within 30 days after stroke, myocardial infarction, or cardio-cerebrovascular operation/surgery will be regarded as death due to stroke, myocardial infarction, or cardio-cerebrovascular operation/surgery, respectively.
• Incidence of all-cause death within 90 days. [From baseline to 90 days after randomization]
• Proportion of patients with poor functional outcome (mRS score 2-6) at 90 days. [From baseline to 90 days after randomization]: The Modified Rankin Scale (mRS) score ranges from 0 to 6, with higher scores indicating worse functional outcome. The modified Rankin Scale (mRS)= 2-6: poor functional outcome
• Proportion of patients with Lp(a) <30 mg/dL at 90 days [From baseline to 90 days after randomization]
• Percent reduction in ApoB and LDL-C levels from baseline to 90 days [From baseline to 90 days after randomization]
• LDL-C goal attainment rate (<1.8 mmol/L or reduction ≥ 50%) at 90 days [From baseline to 90 days after randomization]
• Moderate and severe bleeding events (GUSTO classification) [From baseline to 90 days after randomization]: The GUSTO classification provides a three-tiered (severe, moderate, mild), criteria-driven framework for consistently reporting bleeding complications in clinical research, with a focus on hemodynamic impact and objective laboratory/transfusion data.
• Hepatotoxicity: Post-treatment ALT or AST levels exceeding 3 times the upper limit of normal upon re-measurement [From baseline to 90 days after randomization]: Hepatotoxicity in this context is defined as a confirmed elevation of liver enzymes after treatment. Specifically, it means that a follow-up blood test shows either ALT or AST levels to be more than three times higher than the normal limit. This is a standard safety criterion for detecting potential drug-induced liver injury in clinical trials.
• Muscle toxicity [From baseline to 90 days after randomization]: Post-treatment creatine kinase levels exceeding 10 times the upper limit of normal upon re-measurement, or occurrence of skeletal muscle adverse events (myalgia, myopathy, or rhabdomyolysis)
• Upper Respiratory Tract Infection (URTI): [From baseline to 90 days after randomization]: Common infections affecting the nose, sinuses, throat, or larynx (e.g., common cold, sinusitis). These are general illnesses, not necessarily treatment-related.
• Urinary Tract Infection (UTI) [From baseline to 90 days after randomization]: An infection in any part of the urinary system (bladder, urethra, kidneys). It is monitored as a common potential infection during trials.
• Injection Site Reactions: [From baseline to 90 days after randomization]: Including papules, bleeding, discoloration, pain, itching, rash, induration, erythema, swelling, etc., at the injection site
• Allergic Reactions: [From baseline to 90 days after randomization]: Undesirable immune system responses to the treatment, ranging from mild (rash, itching) to severe, life-threatening anaphylaxis.
• Other Adverse Events/Serious Adverse Events (AEs/SAEs): [From baseline to 90 days after randomization]: Other Adverse Events/Serious Adverse Events (AEs/SAEs):

Sex: All, ages: 35 Years to 80 Years

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) ≥30 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. Have received or are planned to receive intravenous thrombolysis or endovascular thrombectomy;
2. Definite cardioembolic ischemic cerebrovascular disease, such as that associated with atrial fibrillation, prosthetic heart valves, atrial myxoma, endocarditis, etc.;
3. Ischemic cerebrovascular disease with other definite etiologies, such as aortic dissection, cervical or intracranial arterial dissection, vasculitis, vascular malformation, moyamoya disease/moyamoya syndrome, fibromuscular dysplasia, etc.;
4. Non-vascular intracranial diseases, such as intracranial tumors, multiple sclerosis, etc.;
5. Neuroimaging showing that the infarct area of the index cerebral infarction involves more than one-half of a single cerebral lobe;
6. Neuroimaging showing hemorrhagic transformation of the index cerebral infarction;
7. Pre-stroke modified Rankin Scale (mRS) score >1;
8. Known hypersensitivity to tafolecimab or any other contraindication to its use;
9. Use of immunosuppressive agents, antifungal agents, fibrates, or other medications that may affect statin metabolism within 14 days prior to randomization;
10. Creatine kinase (CK) level >5 times the upper limit of normal (ULN) after symptom onset;
11. Severe hepatic or renal impairment prior to randomization. Severe hepatic impairment is defined as alanine aminotransferase (ALT) >2 times the ULN or aspartate aminotransferase (AST) >2 times the ULN; severe renal impairment is defined as serum creatinine >1.5 times the ULN or glomerular filtration rate (GFR) <40 mL/min/1.73 m²;
12. History of intracranial hemorrhage, such as intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH);
13. History of intracranial or extracranial angioplasty;
14. History of gastrointestinal bleeding or major surgery within the previous 90 days;
15. Planned surgery or interventional procedure within 90 days that may require discontinuation of the study treatment;
16. Severe organic disease with an expected survival of less than 1 year;
17. Pregnant women, or women of childbearing potential who are not using effective contraception and have no documented pregnancy test;
18. Currently participating in another clinical trial involving an investigational drug or device;
19. Unable to complete follow-up due to geographic or other reasons, such as alcohol abuse, drug abuse, dementia, or severe psychiatric disorders;
20. Use of a PCSK9 inhibitor, including monoclonal antibodies or small interfering RNA (siRNA), within the previous 6 months;
21. Thrombocytopenia (platelet count <100 × 10⁹/L), coagulation disorders, or systemic bleeding.