PCSK9 Inhibitor for Intracranial Atherosclerosis Related Acute Ischemic Stroke (PISTIAS-3)

March 11, 2026 updated by: Wei-Hai Xu, Peking Union Medical College Hospital

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

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

1212

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Weihai Xu, MD
  • Phone Number: 86+13938912070
  • Email: xuwh@pumch.cn

Study Locations

  • China
      • Beijing, China
        • Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing 100730
        • Contact:
          • Weihai Xu, MD
          • Phone Number: 86+13651147766
          • Email: xuwh@pumch.cn
        • Principal Investigator:
          • Weihai Xu, MD
      • Chongqing, China
        • Chongqing General Hospital
      • Shanghai, China
        • Huashan Hospital, Fudan University
    • Beijing Municipality
      • Beijing, Beijing Municipality, China, 100853
        • Chinese PLA General Hospital
        • Contact:
        • Principal Investigator:
          • Shiwen Wu, MD
    • Guangdong
      • Meizhou, Guangdong, China
        • The Third Affiliated Hospital of Sun Yat-sen University, Yuedong Hospital
    • Hebei
      • Cangzhou, Hebei, China
        • Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine
      • Qinhuangdao, Hebei, China
        • Peking University Third Hospital Qinhuangdao Hospital
      • Shijiazhuang, Hebei, China, 050051
        • Hebei Provincial People's Hospital
      • Tangshan, Hebei, China, 063000
        • Tangshan Worker's Hospital
        • Contact:
        • Principal Investigator:
          • Baoquan Lu, MD
    • Heilongjiang
      • Harbin, Heilongjiang, China
        • First Affiliated Hospital of Harbin Medical University
    • Henan
      • Zhengzhou, Henan, China
        • The First Affiliated Hospital of Zhengzhou University
    • Hubei
      • Shiyan, Hubei, China
        • Affiliated Taihe Hospital of Hubei University of Medicine
      • Wuhan, Hubei, China
        • Zhongnan Hospital of Wuhan University
    • Inner Mongolia
      • Baotou, Inner Mongolia, China, 014000
        • Baotou Central Hospital
    • Jiangsu
      • Nanjing, Jiangsu, China, 210000
        • Nanjing First Hospital
    • Shandong
      • Jining, Shandong, China, 272000
        • Jining First People's Hospital
      • Liaocheng, Shandong, China, 252000
        • Liaocheng People's Hospital
      • Qingdao, Shandong, China
        • The Affiliated Hospital of Qingdao University
      • Weifang, Shandong, China, 261000
        • Weifang People's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age >=30 and <=80;2.Acute ischemic stroke within 72 hours of onset (as determined by CT/MRI in conjunction with neurological deficit symptoms)
  • Acute ischemic stroke within 72 hours of onset (diagnosed by CT/MRI in conjunction with neurological deficit symptoms)
  • NIHSS score of 4-25 at admission
  • Imaging studies (CTA/DSA/MRA) support intracranial atherosclerosis as the cause of stroke, meeting one of the following criteria: i. The culprit vessel exhibits intracranial atherosclerotic stenosis (ICAS) with a narrowing degree of 50-99%; ii. The culprit vessel exhibits intracranial atherosclerotic occlusion (ICAS-LVO), with successful recanalization achieved via mechanical thrombectomy (immediate expanded thrombolysis in cerebral infarction [eTICI] grade 2b50-3)
  • Informed consent signed

Exclusion Criteria:

  • Non-atherosclerotic intracranial arterial stenosis (such as arterial dissection, Moyamoya disease, systemic vasculitis, etc.)
  • Any identifiable source of cardiogenic embolism (such as atrial fibrillation, mechanical valves, left ventricular thrombus, patent foramen ovale, etc.)
  • Imaging findings and clinical presentation suggest that the primary pathophysiology of this event is more consistent with cerebral small vessel disease (e.g., perforator artery occlusion/lacunar infarction)
  • Pre-existing disability prior to this ischemic event (modified Rankin Scale ≥ 2 points)
  • CT or MRI findings suggest extensive cerebral infarction (e.g., ASPECTS score < 6 or infarct volume ≥ 70 ml)
  • Has undergone or is scheduled to undergo a vascular stent implantation procedure within the next three months
  • Any intracranial hemorrhage occurring within 3 months prior to enrollment;
  • Intracranial tumors, cerebral aneurysms, or arteriovenous malformations that are assessed as having indications for interventional treatment
  • Severe active bleeding tendency or coagulation disorder
  • Severe dysfunction of vital organs such as the heart, liver, and kidneys
  • Received PCSK9 monoclonal antibody inhibitor therapy within 1 month prior to enrollment or PCSK9 siRNA inhibitor therapy within 6 months prior to enrollment
  • A clear contraindication to statins or a history of intolerance to them
  • Pregnancy, breastfeeding, or planning pregnancy;14.Currently participating in another study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Recaticimab plus standard therapy group
Recaticimab in combination with standard therapy
Drug: Rucacuzumab plus standard therapy
Recaticimab (450 mg single dose, subcutaneous injection) combined with standard therapy recommended by the AHA/ASA Guidelines for Early Management of Acute Ischemic Stroke 2026 and the Chinese Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke 2023.
Placebo Comparator: Recaticimab plus placebo in combination with standard therapy grop
Recaticimab plus placebo in combination with standard therapy
Drug: Recaticimab plus placebo in combination with standard therapy
The placebo and investigational ricaximab were identical in appearance, packaging, labeling, administration method, and dosing frequency, managed through a unified production and coding system. Standard treatment followed the recommendations outlined in the "AHA/ASA Guidelines for the Early Management of Acute Ischemic Stroke 2026" and the "Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke 2023."

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
90-day modified Rankin Scale (mRS) score of 0-2
Time Frame: Day 90 of patient enrollment
Scoring using the modified Rankin Scale (mRS)
Day 90 of patient enrollment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
90-day modified Rankin Scale (mRS) score of 0-1
Time Frame: Day 90 of patient enrollment
Scoring using the modified Rankin Scale (mRS)
Day 90 of patient enrollment
Distribution of modified Rankin Scale (mRS) scores at 90 days
Time Frame: Day 90 of patient enrollment
Scoring using the modified Rankin Scale (mRS)
Day 90 of patient enrollment
Time from randomization to the first-ever stroke
Time Frame: From randomization to Day 90 of enrollment
Stroke is a general term for acute cerebrovascular diseases, referring to brain tissue damage or death caused by rupture or blockage of intracranial blood vessels due to various causes. It can be classified into two major categories: hemorrhagic and ischemic, as determined by the project's Clinical Events Committee.
From randomization to Day 90 of enrollment
Time from randomization to the first-ever ischemic stroke
Time Frame: From randomization to Day 90 of enrollment
Ischemic Stroke: Defined as an acute cerebral infarction with clinical signs or imaging evidence of a new acute focal neurological injury persisting for more than 24 hours, excluding other non-ischemic causes.
From randomization to Day 90 of enrollment
Time from randomization to the occurrence of major adverse cardiovascular events
Time Frame: From randomization to Day 90 of enrollment
Composite major adverse cardiovascular endpoints includes ischemic stroke, myocardial infarction, and cardiovascular mortality as a cluster
From randomization to Day 90 of enrollment
Barthel Index (BI) Score
Time Frame: On Day 90 and at 1 year after enrollment
Scoring using the Barthel Index (BI) for activities of daily living
On Day 90 and at 1 year after enrollment
European Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) Score
Time Frame: On Day 90 and at 1 year after enrollment
Scoring using the European Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L)
On Day 90 and at 1 year after enrollment

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
NIHSS at 24 hours, 7 days, and discharge
Time Frame: At 24 hours, 7 days, and at discharge
Assessment using the National Institutes of Health Stroke Scale
At 24 hours, 7 days, and at discharge
Cerebral infarction volume or perfusion status at 7 days post-enrollment or at discharge
Time Frame: At 7 days post-enrollment or upon discharge
Evaluate using CT/CTP or MRI/PWI
At 7 days post-enrollment or upon discharge
Inflammation levels at 7 days post-group assignment or at discharge
Time Frame: At 7 days post-enrollment or upon discharge
Evaluated through markers such as interleukin IL-6 and high-sensitivity C-reactive protein
At 7 days post-enrollment or upon discharge
The proportion of subjects with moderate to severe symptomatic intracranial hemorrhage(sICH)
Time Frame: From randomization to Day 90 of enrollment

The diagnosis of symptomatic intracranial hemorrhage will be assessed based on the modified Heidelberg hemorrhage classification criteria, requiring simultaneous fulfillment of the following conditions:

  1. Imaging confirmation of any of the following types of intracranial hemorrhage: parenchymal hemorrhage type 1, parenchymal hemorrhage type 2, distant intracranial hemorrhage, subarachnoid hemorrhage, intraventricular hemorrhage, or subdural hemorrhage;
  2. An increase in total NIHSS score of ≥4 points compared to baseline NIHSS or any previously recorded NIHSS score;
  3. Symptom deterioration cannot be explained by causes other than the intracranial hemorrhage itself.
From randomization to Day 90 of enrollment
Adverse events
Time Frame: From randomization to Day 90 of enrollment
An Adverse Event (AE) is any untoward medical occurrence in clinical trial subject administered a pharmaceutical product and which does not necessarily have a causal relationship with the treatment.
From randomization to Day 90 of enrollment
Serious Adverse Events
Time Frame: From randomization to Day 90 of enrollment
A Serious Adverse Event (SAE) is any untoward medical occurrence that, at any dose: (1) results in death; (2) is life-threatening; (3) requires inpatient hospitalization or prolongation of existing hospitalization; (4)results in persistent or significant disability/incapacity; (5) is a congenital anomaly/birth defect; (6) is otherwise considered medically significant by the investigator.
From randomization to Day 90 of enrollment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Peking Union Medical College Hospital

Collaborators

Chinese PLA General Hospital
Huashan Hospital
Hebei General Hospital
The Affiliated Hospital of Qingdao University
Nanjing First Hospital, Nanjing Medical University
The First Affiliated Hospital of Zhengzhou University
Zhongnan Hospital
First Affiliated Hospital of Harbin Medical University
Taihe Hospital
Liaocheng People's Hospital
Weifang People's Hospital
Baotou Central Hospital
Chongqing General Hospital
Tangshan Worker's Hospital
Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine
Jining First People's Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

September 1, 2026

Primary Completion (Estimated)

December 31, 2028

Study Completion (Estimated)

December 31, 2029

Study Registration Dates

First Submitted

March 7, 2026

First Submitted That Met QC Criteria

March 11, 2026

First Posted (Actual)

March 12, 2026

Study Record Updates

Last Update Posted (Actual)

March 12, 2026

Last Update Submitted That Met QC Criteria

March 11, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1-24PJ2600
  • 2024ZD0521605 (Other Grant/Funding Number: the Noncommunicable Chronic Diseases-National Science and Technology Major Project)
  • 82025013 (Other Grant/Funding Number: the National Science Fund for Distinguished Young Scholars)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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