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

Prior treatment

• Have received or are planned to receive intravenous thrombolysis or endovascular thrombectomy;
• Use of immunosuppressive agents, antifungal agents, fibrates, or other medications that may affect statin metabolism within 14 days prior to randomization;
• History of gastrointestinal bleeding or major surgery within the previous 90 days;
• Planned surgery or interventional procedure within 90 days that may require discontinuation of the study treatment;
• Currently participating in another clinical trial involving an investigational drug or device;
• Use of a PCSK9 inhibitor, including monoclonal antibodies or small interfering RNA (siRNA), within the previous 6 months;

Other illness

• Definite cardioembolic ischemic cerebrovascular disease, such as that associated with atrial fibrillation, prosthetic heart valves, atrial myxoma, endocarditis, etc.;
• 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.;
• Non-vascular intracranial diseases, such as intracranial tumors, multiple sclerosis, etc.;
• Pre-stroke modified Rankin Scale (mRS) score \>1;
• Known hypersensitivity to tafolecimab or any other contraindication to its use;
• History of intracranial hemorrhage, such as intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH);
• History of intracranial or extracranial angioplasty;
• Severe organic disease with an expected survival of less than 1 year;
• Unable to complete follow-up due to geographic or other reasons, such as alcohol abuse, drug abuse, dementia, or severe psychiatric disorders;

Lab values

• Creatine kinase (CK) level \>5 times the upper limit of normal (ULN) after symptom onset;
• 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;
• Thrombocytopenia (platelet count \<100 × 10⁹/L), coagulation disorders, or systemic bleeding.

Other

• Neuroimaging showing that the infarct area of the index cerebral infarction involves more than one-half of a single cerebral lobe;
• Neuroimaging showing hemorrhagic transformation of the index cerebral infarction;
• Pregnant women, or women of childbearing potential who are not using effective contraception and have no documented pregnancy test;

• Age between 35 and 80 years, regardless of gender.
• 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.
• Lp(a) ≥30 mg/dL.
• Onset of symptoms within 3 to 7 days.
• 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.