PCSK9 Inhibitor for Intracranial Atherosclerosis Related Acute Ischemic Stroke

Official title

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

Overview

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.

Interventions

• Drug Recaticimab 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.
• Drug Recaticimab's 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."

Primary outcome measures

• Proportion of participants with functional independence, defined as a modified Rankin Scale score of 0-2, at Day 90 [Time frame: Day 90 (±7 days) after randomization]

Secondary outcome measures (12)

• Proportion of participants with an excellent functional outcome, defined as an mRS score of 0-1, at Day 90 [Time frame: Day 90 (±7 days) after randomization]
• Distribution of modified Rankin Scale (mRS) scores at Day 90 [Time frame: Day 90 (±7 days) after randomization]
• Incidence of any stroke through Day 90 [Time frame: From randomization through Day 90]
• Incidence of ischemic stroke through Day 90 [Time frame: From randomization through Day 90]
• Incidence of composite vascular events through Day 90 [Time frame: From randomization through Day 90]
• Barthel Index score at Day 90 [Time frame: Day 90 (±7 days) after randomization]
• Health-related quality of life assessed using the EQ-5D-5L at Day 90 [Time frame: Day 90 (±7 days) after randomization]
• National Institutes of Health Stroke Scale score at Day 7 or hospital discharge [Time frame: Day 7 (±2 days) after randomization or at hospital discharge, whichever occurs first]
• Change from baseline in NIHSS score at Day 7 or hospital discharge [Time frame: From baseline to Day 7 (±2 days) after randomization or hospital discharge, whichever occurs first]
• Proportion of participants achieving an LDL-C level below 1.4 mmol/L at Day 7 or hospital discharge [Time frame: Day 7 (±2 days) after randomization or at hospital discharge, whichever occurs first]
• Proportion of participants achieving an LDL-C level below 1.8 mmol/L at Day 7 or hospital discharge [Time frame: Day 7 (±2 days) after randomization or at hospital discharge, whichever occurs first]
• Change from baseline in LDL-C level at Day 7 or hospital discharge [Time frame: From baseline to Day 7 (±2 days) after randomization or hospital discharge, whichever occurs first]

Eligibility criteria

Inclusion criteria

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

Exclusion criteria

• Intracranial arterial stenosis attributable to a nonatherosclerotic cause, such as arterial dissection, moyamoya disease, or systemic vasculitis.
• Any definite source of cardioembolism, such as atrial fibrillation, a mechanical prosthetic heart valve, left ventricular thrombus, or patent foramen ovale.
• Clinical and imaging findings suggesting that the index ischemic event is primarily attributable to cerebral small vessel disease.
• Pre-stroke disability, defined as a modified Rankin Scale score of 2 or higher before the index ischemic event.
• 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.
• Previous stent implantation in the culprit vessel or planned stent implantation in the culprit vessel within 3 months after enrollment.
• Any intracranial hemorrhage within 3 months before enrollment.
• An intracranial tumor; or a cerebral aneurysm or arteriovenous malformation judged to require interventional treatment.
• Severe active bleeding tendency or coagulation disorder.
• Severe cardiac, hepatic, renal, or other major organ dysfunction.
• 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.
• A definite contraindication to statin therapy or a history of statin intolerance.
• Pregnant or breastfeeding, or planning to become pregnant during the study.
• Current participation in another clinical trial.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 19 centers

• Chinese PLA General Hospital — Beijing
• The Third Affiliated Hospital of Sun Yat-sen University, Yuedong Hospital — Meizhou
• Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine — Cangzhou
• Peking University Third Hospital Qinhuangdao Hospital — Qinhuangdao
• Hebei Provincial People's Hospital — Shijiazhuang
• Tangshan Worker's Hospital — Tangshan
• First Affiliated Hospital of Harbin Medical University — Harbin
• The first affiliated hospital of zhengzhou university — Zhengzhou
• … and 11 more centers

Publications

• Zhao W, Li S, Li C, Wu C, Wang J, Xing L, Wan Y, Qin J, Xu Y, Wang R, Wen C, Wang A, Liu L, Wang J, Song H, Feng W, Ma Q, Ji X; TREND Investigators. Effects of Tirofiban on Neurological Deterioration in Patients With Acute Ischemic Stroke: A Randomized Clinical Trial. JAMA Neurol. 2024 Jun 1;81(6):594-602. doi: 10.1001/jamaneurol.2024.0868. PMID 38648030
• Tao C, Liu T, Cui T, Liu J, Li Z, Ren Y, Zhao X, Xie F, Li J, Wang H, Huang L, Li J, Wen J, Zeng J, Zhu J, Li Z, Li D, Hu X, Huang B, Wang J, Zhang C, Ye B, Hou Y, Gan Y, Sun H, Guan F, Shao Y, Liu Z, Ou Z, Fan S, Wang Y, Zhai H, Ni C, Wang H, Zhang C, Zhao Y, Wang G, Zhu Y, Li R, Sun J, Hu H, Cui J, Wang L, Zhang C, Song J, Jing X, Wang A, Wang J, Xu P, Qureshi AI, Nguyen TN, Nogueira RG, Saver J PMID 40616232
• Wang C, Gu H, Huo X, Yuan B, Li S, Xu J, Jiang Y, Jing J, Yao X, Li Z, Long F, Ma Z, Zhuang X, Xu L, Jin Y, Huang W, Zhang Y, Wen J, Wang A, Pan Y, Ye W, Yu W, Cheng A, Wang M, Dong Q, Xu A, Wang N, Yang Y, Meng X, Liu L, Zhao X, Li H, Miao Z, Li Z, Wang Y; TASTE-2 investigators. Edaravone dexborneol versus placebo on functional outcomes in patients with acute ischaemic stroke undergoing endovascu PMID 41500725
• Writing Committee for the PEARL Investigators; Yang X, He X, Xu Y, Pan D, Li K, Chen Y, Zhu Y, Pan Y, Yi T, Zhang M, Peng H, Huang W, Li D, Feng J, Chen J, Lu W, Liao B, Xie Y, Liao B, Yang L, Tang L, Han B, Liu Y, Lin P, Chen J, Liang Y, Li D, Weng G, Huang H, Li H, Li C, Peng Z, Li H, He B, Xue R, Bao M, Sun H, Hou H, Zhou H, Xiao Y, Li J, Zhang W, Chen X, Yan W, Pi Y, Deng Z, Wang J, Xie D, Liu PMID 42262770
• Kim J, Hong U, Yoon CW, Bae JW, Rha JH, Park HK. PCSK9 inhibitor in acute ischemic stroke patient receiving mechanical thrombectomy: early outcomes and safety. Front Neurol. 2024 May 16;15:1375609. doi: 10.3389/fneur.2024.1375609. eCollection 2024. PMID 38817546
• Liu L, Chen W, Zhou H, Duan W, Li S, Huo X, Xu W, Huang L, Zheng H, Liu J, Liu H, Wei Y, Xu J, Wang Y; Chinese Stroke Association Stroke Council Guideline Writing Committee. Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of clinical management of ischaemic cerebrovascular diseases. Stroke Vasc Neurol. 2020 Jun;5(2):159- PMID 32561535
• Prabhakaran S, Gonzalez NR, Zachrison KS, Adeoye O, Alexandrov AW, Ansari SA, Chapman S, Czap AL, Dumitrascu OM, Ishida K, Jadhav AP, Johnson B, Johnston KC, Khatri P, Kimberly WT, Lee VH, Leslie-Mazwi TM, Mac Grory B, Madsen TE, Menon B, Mistry EA, Park S, Parker S, Perez de la Ossa N, Reeves M, Saiz T, Scott PA, Schwartzberg D, Sheth SA, Sporns PB, Times S, Tjoumakaris S, Wolfe SQ, Yaghi S; Peer PMID 41582814
• Sun Y, Lv Q, Guo Y, Wang Z, Huang R, Gao X, Han Y, Yao Z, Zheng M, Luo S, Li Y, Gu X, Zhang Y, Wang J, Hong L, Ma X, Su G, Sheng J, Lai C, Shen A, Wang M, Zhang W, Wu S, Zheng Z, Li J, Zhong T, Wang Y, He L, Du X, Ma CS. Recaticimab as Add-On Therapy to Statins for Nonfamilial Hypercholesterolemia: The Randomized, Phase 3 REMAIN-2 Trial. J Am Coll Cardiol. 2024 Nov 12;84(20):2037-2047. doi: 10.101 PMID 39505412

Identifiers

NCT: NCT07466251 · 1-24PJ2600 · 2024ZD0521605 · 82025013

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗