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ClinicalTrials.gov ID

NCT07466251

Lead Sponsor

Peking Union Medical College HospitalOTHER

Overall Status

Not yet recruiting

Study Type

Interventional

Phase

Phase 4

Enrollment

1,212Estimated

Last Update Posted

Jul 15, 2026Actual

Start Date

Sep 1, 2026Estimated

Primary Completion Date

Dec 31, 2028Estimated

Completion Date

Dec 31, 2029Estimated

Official Title

PCSK9 Inhibitor for Intracranial Atherosclerosis Related Acute Ischemic Stroke (PISTIAS-3): a Randomized, Double-blind, Placebo-controlled Trial

Brief Summary

This study is a prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial designed to evaluate whether early administration of PCSK9 inhibitors can effectively improve functional outcomes at 90 days in patients with ischemic stroke (AIS) associated with intracranial atherosclerotic stenosis (ICAS), primarily assessed using the modified Rankin Scale at 90 days.

Detailed Description

Acute ischemic stroke (AIS) remains one of the leading causes of death and disability worldwide. Although intravenous thrombolysis and endovascular therapies have significantly improved reperfusion success rates, three critical challenges persist in clinical practice that determine prognosis: First, only a limited proportion of patients can actually receive reperfusion therapy within the therapeutic time window; Second, even with successful reperfusion, secondary injuries such as microcirculatory perfusion failure, inflammatory cascades, and thrombus reformation may still occur. Third, acute phase fluctuations, particularly early neurological deterioration and the risk of early recurrence, remain prominent, directly limiting improvements in functional outcomes. 3 Intracranial atherosclerotic stenosis (ICAS) accounts for up to 50% of ischemic stroke etiologies in China. Its pathological chain-"plaque instability-thrombosis-microcirculatory impairment"-permeates both the acute and subacute phases, closely correlating with early recurrence and poor outcomes.Proprotein convertase subtilisin/kexin type 9 (PCSK9) classically promotes the degradation of low-density lipoprotein cholesterol (LDL-C) receptors and elevates LDL-C levels, thereby driving atherosclerosis progression. More importantly, growing basic and translational research suggests that PCSK9 may not only function as a "lipid metabolism protein" but also participate in processes such as endothelial activation, inflammatory cascades, platelet reactivity, and microcirculatory dysfunction. This positions it as a potential hub connecting the "plaque-thrombus-inflammation" axis. Consequently, PCSK9 inhibitors may offer additional neurovascular protective benefits beyond lipid-lowering effects during the acute phase of acute ischemic stroke (AIS).Existing basic and clinical evidence suggests that PCSK9 inhibitors may exert a combined intervention effect on key pathological processes driving atherosclerosis during the acute phase of AIS through a dual mechanism involving both lipid-dependent and non-lipid-dependent pathways. Mechanistic studies reveal that PCSK9 inhibition simultaneously modulates inflammatory responses, endothelial activation, dysfunction, and thrombogenic tendencies. In ischemia-reperfusion models, it demonstrates neuroprotective signaling by mitigating brain injury and improving neurological function. Clinically, large randomized trials confirm its ability to rapidly enhance lipid-lowering effects beyond statins and reduce ischemic stroke risk. Further translational evidence in cerebrovascular disease indicates that in symptomatic ICAS populations, PCSK9 inhibitor plus statin-enhanced lipid-lowering therapy reduces plaque burden, alleviates stenosis, and increases plaque stability. In the acute phase of AIS, early addition of PCSK9 inhibitors correlates with reduced neurological deterioration within 7 days, decreased recurrence risk within 30 days, and improved functional outcomes at 90 days. Collectively, this evidence chain spanning mechanisms to clinical practice provides clear scientific rationale and clinical necessity for adding PCSK9 inhibitors to the treatment of ICAS-associated AIS.This study is a nationwide, prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial. It will enroll 1,212 patients meeting inclusion and exclusion criteria. Patients will be randomly assigned to two groups using a randomized allocation method: (1) Experimental group: 450 mg of Recaticimab for Injection (3 vials) administered as a single subcutaneous injection. (2) Control group: Placebo of Recaticimab for Injection 450 mg (3 vials) administered as a single subcutaneous injection. Each group will include 606 patients. Both groups will receive standard guideline-recommended treatment in addition to the study drug. Long-term efficacy was assessed through patient visits and evaluations at 0 hours, 24 hours (±2 or ±12 hours), 7 days (±2 days) or at discharge, 90 days (±7 days), and 1 year.Primary outcome measures included: Analysis based on the intention-to-treat principle using an ANCOVA model for all randomized patients with baseline HRMRI and a modified Rankin Scale (mRS) score of 0-2 at 90 days. Secondary outcome measures included: (1) mRS score of 0-1 at 90 days (indicating good patient function); (2) Distribution of 90-day mRS scores; (3) Any stroke (including ischemic and hemorrhagic) within 90 days; (4) Ischemic stroke within 90 days; (5) Composite vascular events (including stroke, myocardial infarction, and vascular death) within 90 days; (6) 90-day European Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) score; (7) 90-day Barthel Index (BI) score.Details are provided in the "Outcome Measures" section.The sample size is calculated based on the primary outcome and a total of 1212 participants are anticipated. An independent Data Safety Monitoring Board will oversee the overall conduct of the trial.

• Acute Ischemic Stroke AIS
• Intracranial Atherosclerosis ICAS
• Atherosclerotic Plaque

• Recaticimab plus standard therapy
• Recaticimab's placebo in combination with standard therapy

Ages Eligible for Study

Adult (18-64)Older Adult (65+)

Sexes Eligible for Study

All

Accepts Healthy Volunteers

No

Eligibility Criteria

Inclusion Criteria

1. Age 30 to 80 years, inclusive.
2. Acute ischemic stroke with symptom onset within 72 hours before screening, diagnosed on the basis of neurological deficits and CT or MRI findings.
3. National Institutes of Health Stroke Scale (NIHSS) score of 4 to 25 at hospital admission.
4. CTA, DSA, or MRA evidence that the culprit intracranial artery has atherosclerotic stenosis of 50% to 99%.

Exclusion Criteria

1. Intracranial arterial stenosis attributable to a nonatherosclerotic cause, such as arterial dissection, moyamoya disease, or systemic vasculitis.
2. Any definite source of cardioembolism, such as atrial fibrillation, a mechanical prosthetic heart valve, left ventricular thrombus, or patent foramen ovale.
3. Clinical and imaging findings suggesting that the index ischemic event is primarily attributable to cerebral small vessel disease.
4. Pre-stroke disability, defined as a modified Rankin Scale score of 2 or higher before the index ischemic event.
5. Extensive cerebral infarction on CT or MRI, such as an Alberta Stroke Program Early CT Score (ASPECTS) below 6 or an infarct volume of 70 mL or greater.
6. Previous stent implantation in the culprit vessel or planned stent implantation in the culprit vessel within 3 months after enrollment.
7. Any intracranial hemorrhage within 3 months before enrollment.
8. An intracranial tumor; or a cerebral aneurysm or arteriovenous malformation judged to require interventional treatment.
9. Severe active bleeding tendency or coagulation disorder.
10. Severe cardiac, hepatic, renal, or other major organ dysfunction.
11. Treatment with a PCSK9 monoclonal antibody inhibitor within 1 month before enrollment or with a PCSK9-targeting small interfering RNA therapy within 6 months before enrollment.
12. A definite contraindication to statin therapy or a history of statin intolerance.
13. Pregnant or breastfeeding, or planning to become pregnant during the study.
14. Current participation in another clinical trial.

Primary Purpose

Treatment

Allocation

Randomized

Interventional Model

Parallel Assignment

Masking

Quadruple

Lead Sponsor

Peking Union Medical College HospitalOTHER

Collaborators

Chinese PLA General HospitalOTHER

Hebei General HospitalOTHER

Taihe HospitalOTHER

Weifang People's HospitalOTHER

Nanjing First Hospital, Nanjing Medical UniversityOTHER

Baotou Central HospitalOTHER

Jining First People's HospitalOTHER

Liaocheng People's HospitalOTHER

Tangshan Worker's HospitalOTHER

Chongqing General HospitalOTHER

First Affiliated Hospital of Harbin Medical UniversityOTHER

Cangzhou Hospital of Integrated Traditional Chinese and Western MedicineOTHER

The First Affiliated Hospital of Zhengzhou UniversityOTHER

The Affiliated Hospital of Qingdao UniversityOTHER

Zhongnan HospitalOTHER

Huashan HospitalOTHER

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