A Phase 4 interventional study of Recaticimab plus standard therapy and Recaticimab's placebo in combination with standard therapy in Acute Ischemic Stroke AIS, Intracranial Atherosclerosis ICAS and Atherosclerotic Plaque, sponsored by Peking Union Medical College Hospital. Not yet recruiting at 19 sites in China. Open to participants aged 30 Years to 80 Years. Per ClinicalTrials.gov, last updated 2026-07-15.
Sponsored by Peking Union Medical College Hospital · Phase 4, Interventional, and Treatment
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.
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.
Exclusion Criteria
Recaticimab in combination with standard therapy
Drug: Recaticimab plus standard therapy
Recaticimab's placebo in combination with standard therapy
Drug: Recaticimab's placebo in combination with 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.
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."
Proportion of participants with functional independence, defined as a modified Rankin Scale score of 0-2, at Day 90
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.
Time frame: Day 90 (±7 days) after randomization
Proportion of participants with an excellent functional outcome, defined as an mRS score of 0-1, at Day 90
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.
Time frame: Day 90 (±7 days) after randomization
Distribution of modified Rankin Scale (mRS) scores at Day 90
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.
Time frame: Day 90 (±7 days) after randomization
Incidence of any stroke 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.
Time frame: From randomization through Day 90
Incidence of ischemic stroke 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.
Time frame: From randomization through Day 90
Incidence of composite vascular events 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.
Time frame: From randomization through Day 90
Barthel Index score at Day 90
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.
Time frame: Day 90 (±7 days) after randomization
Health-related quality of life assessed using the EQ-5D-5L at Day 90
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).
Time frame: Day 90 (±7 days) after randomization
National Institutes of Health Stroke Scale score at Day 7 or hospital discharge
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.
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
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.
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
Proportion of participants whose measured low-density lipoprotein cholesterol (LDL-C) concentration is below 1.4 mmol/L at the scheduled assessment.
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
Proportion of participants whose measured low-density lipoprotein cholesterol (LDL-C) concentration is below 1.8 mmol/L at the scheduled assessment.
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
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.
Time frame: From baseline to Day 7 (±2 days) after randomization or hospital discharge, whichever occurs first
Change from baseline in NIHSS score at 24 hours
Change in NIHSS score will be calculated as the 24-hour 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.
Time frame: From baseline to 24 hours after randomization, with an allowable assessment window of -2 to +12 hours
Cerebral infarct volume at Day 7 or hospital discharge
Cerebral infarct volume will be quantified in milliliters using follow-up CT or MRI and assessed by a blinded core imaging laboratory. Lower infarct volumes indicate less extensive ischemic brain injury.
Time frame: Day 7 (±2 days) after randomization or at hospital discharge, whichever occurs first
Cerebral perfusion parameters at Day 7 or hospital discharge
Prespecified quantitative cerebral perfusion parameters derived from CT perfusion or MR perfusion imaging will be assessed by a blinded core imaging laboratory.
Time frame: Day 7 (±2 days) after randomization or at hospital discharge, whichever occurs first
Serum interleukin-6 concentration at Day 7 or hospital discharge
Serum interleukin-6 concentration will be measured as a marker of systemic inflammation. Higher concentrations indicate greater inflammatory activity. Testing will be performed according to the prespecified laboratory procedures.
Time frame: Day 7 (±2 days) after randomization or at hospital discharge, whichever occurs first
High-sensitivity C-reactive protein concentration at Day 7 or hospital discharge
High-sensitivity C-reactive protein concentration will be measured as a marker of systemic inflammation. Higher concentrations indicate greater inflammatory activity.
Time frame: Day 7 (±2 days) after randomization or at hospital discharge, whichever occurs first
Incidence of any stroke through 1 year
Proportion of participants who experience an adjudicated ischemic or hemorrhagic stroke after randomization. Events will be reviewed by an independent Clinical Event Committee blinded to treatment allocation.
Time frame: From randomization through 1 year
Incidence of ischemic stroke through 1 year
Proportion of participants who experience an adjudicated ischemic stroke after randomization. Events will be reviewed by an independent Clinical Event Committee blinded to treatment allocation.
Time frame: From randomization through 1 year
Incidence of composite vascular events through 1 year
Proportion of participants who experience at least one component of the composite endpoint, defined as any stroke, myocardial infarction, or vascular death. Events will be adjudicated by an independent blinded Clinical Event Committee.
Time frame: From randomization through 1 year
Health-related quality of life assessed using the EQ-5D-5L at 1 year
Health-related quality of life will be assessed using the EQ-5D-5L descriptive system, covering mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Overall self-rated health will also be assessed using the EQ visual analogue scale ranging from 0 to 100, with higher scores indicating better perceived health.
Time frame: At 1 year after randomization
Barthel Index score at 1 year
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 and better functional status.
Time frame: At 1 year after randomization
Incidence of moderate-to-severe symptomatic intracranial hemorrhage within 72 hours
Proportion of participants with symptomatic intracranial hemorrhage according to the modified Heidelberg criteria. The event must include imaging-confirmed intracranial hemorrhage, an increase of at least 4 points in the total NIHSS score compared with baseline or a previously recorded NIHSS score, and neurological deterioration that cannot be explained by a cause other than the intracranial hemorrhage. Qualifying hemorrhage types include parenchymal hematoma type 1 or 2, remote intracranial hemorrhage, subarachnoid hemorrhage, intraventricular hemorrhage, or subdural hemorrhage.
Time frame: From randomization through 72 hours after randomization
All-cause mortality through Day 90
Proportion of participants who die from any cause after randomization and through Day 90. Death will be recorded as an mRS score of 6.
Time frame: From randomization through Day 90
Incidence of adverse events through Day 90
Proportion of participants who experience at least one adverse event after administration of the study intervention. Adverse events will be recorded with respect to onset, duration, severity, relationship to the study intervention, action taken, and outcome, and will be coded using the Medical Dictionary for Regulatory Activities.
Time frame: From administration of the study intervention through Day 90 after randomization
Incidence of serious adverse events through Day 90
Proportion of participants who experience at least one serious adverse event. A serious adverse event is an event that results in death, is life-threatening, requires inpatient hospitalization or prolongation of hospitalization, results in persistent or significant disability, causes a congenital anomaly or birth defect, or is considered an important medical event requiring intervention to prevent a serious outcome.
Time frame: From administration of the study intervention through Day 90 after randomization
Plan to share: Undecided
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Peking Union Medical College Hospital