Acute Ischemic Stroke AIS, Atherosclerotic Plaque, Intracranial Atherosclerosis ICAS
Conditions
Keywords
Intracranial Atherosclerosis, intracranial artery stenosis, atherosclerotic plaque, PCSK9 inhibitor, Recaticimab
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.
Interventions
DRUGRecaticimab 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.
DRUGRecaticimab'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."
Sponsors
Peking Union Medical College Hospital
Chinese PLA General Hospital
Hebei General Hospital
Taihe Hospital
Weifang People's Hospital
Nanjing First Hospital, Nanjing Medical University
Baotou Central Hospital
Jining First People's Hospital
Liaocheng People's Hospital
Tangshan Worker's Hospital
Chongqing General Hospital
First Affiliated Hospital of Harbin Medical University
Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine
The First Affiliated Hospital of Zhengzhou University
The Affiliated Hospital of Qingdao University
Zhongnan Hospital
Huashan Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Subjects, clinical investigators, outcome assessors, imaging evaluators, laboratory technicians, data management personnel, and statistical analysts remained blinded to treatment allocation throughout the entire study.
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants with functional independence, defined as a modified Rankin Scale score of 0-2, at Day 90 | Day 90 (±7 days) after randomization | The modified Rankin Scale (mRS) is a 7-category ordinal scale ranging from 0 (no symptoms) to 6 (death), with lower scores indicating better functional status. This outcome is the proportion of participants with an mRS score of 0-2, representing functional independence. Participants who die before the Day 90 assessment will be assigned an mRS score of 6. The assessment will be performed by trained assessors blinded to treatment allocation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants with an excellent functional outcome, defined as an mRS score of 0-1, at Day 90 | Day 90 (±7 days) after randomization | The mRS ranges from 0 (no symptoms) to 6 (death), with lower scores indicating better functional status. This outcome is the proportion of participants with an mRS score of 0-1, representing an excellent functional outcome. Participants who die before the assessment will be assigned an mRS score of 6. |
| Distribution of modified Rankin Scale (mRS) scores at Day 90 | Day 90 (±7 days) after randomization | The ordinal distribution of mRS scores across all seven categories will be assessed. The mRS ranges from 0 (no symptoms) to 6 (death), with lower scores indicating better functional status. The outcome will evaluate a shift toward better functional outcomes across the full mRS distribution. |
| Incidence of any stroke through Day 90 | From randomization through Day 90 | Proportion of participants who experience an adjudicated stroke after randomization, including either ischemic stroke or hemorrhagic stroke. Suspected events will be reviewed by an independent Clinical Event Committee blinded to treatment allocation. |
| Incidence of ischemic stroke through Day 90 | From randomization through Day 90 | Proportion of participants who experience an adjudicated ischemic stroke after randomization. Ischemic stroke is defined as a new focal neurological injury attributable to cerebral ischemia, supported by clinical findings and/or imaging evidence of acute cerebral infarction, and not explained by a nonischemic cause. Events will be adjudicated by an independent blinded Clinical Event Committee. |
| Incidence of composite vascular events through Day 90 | From randomization through Day 90 | Proportion of participants who experience at least one component of the composite endpoint after randomization. The composite endpoint includes any stroke, myocardial infarction, or vascular death. Events will be adjudicated by an independent Clinical Event Committee blinded to treatment allocation. |
| Barthel Index score at Day 90 | Day 90 (±7 days) after randomization | Activities of daily living will be assessed using the Barthel Index. The total score ranges from 0 to 100, with higher scores indicating greater independence in activities of daily living and better functional status. |
| Health-related quality of life assessed using the EQ-5D-5L at Day 90 | Day 90 (±7 days) after randomization | Health-related quality of life will be assessed using the European Quality of Life 5-Dimension 5-Level instrument. The descriptive system assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, with five levels of severity for each dimension. Overall self-rated health will also be assessed using the EQ visual analogue scale, ranging from 0 (worst imaginable health) to 100 (best imaginable health). |
| National Institutes of Health Stroke Scale score at Day 7 or hospital discharge | Day 7 (±2 days) after randomization or at hospital discharge, whichever occurs first | Neurological impairment will be assessed using the National Institutes of Health Stroke Scale (NIHSS). The NIHSS ranges from 0 to 42, with higher scores indicating greater neurological impairment. |
| Change from baseline in NIHSS score at Day 7 or hospital discharge | From baseline to Day 7 (±2 days) after randomization or hospital discharge, whichever occurs first | Change in NIHSS score will be calculated as the follow-up NIHSS score minus the baseline NIHSS score. The NIHSS ranges from 0 to 42, with higher scores indicating greater neurological impairment. A negative change indicates neurological improvement, whereas a positive change indicates neurological worsening. |
| Proportion of participants achieving an LDL-C level below 1.4 mmol/L at Day 7 or hospital discharge | Day 7 (±2 days) after randomization or at hospital discharge, whichever occurs first | Proportion of participants whose measured low-density lipoprotein cholesterol (LDL-C) concentration is below 1.4 mmol/L at the scheduled assessment. |
| Proportion of participants achieving an LDL-C level below 1.8 mmol/L at Day 7 or hospital discharge | Day 7 (±2 days) after randomization or at hospital discharge, whichever occurs first | Proportion of participants whose measured low-density lipoprotein cholesterol (LDL-C) concentration is below 1.8 mmol/L at the scheduled assessment. |
| Change from baseline in LDL-C level at Day 7 or hospital discharge | From baseline to Day 7 (±2 days) after randomization or hospital discharge, whichever occurs first | Change in LDL-C concentration will be calculated as the follow-up LDL-C value minus the baseline value and reported in mmol/L. A negative value indicates a reduction in LDL-C from baseline. |
Countries
China
Contacts
CONTACTWeihai Xu, MD
CONTACTYiyang Liu, PhD
Outcome results
None listed