Intravenous rhPro-UK Versus Placebo Before Endovascular Thrombectomy For Stroke Patient With Large Vessel Occlusion In The Extended Time Window: the Randomized, Placebo-controlled, Double-blind Trial (BRIDGE-PUK EXTEND )
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 820
- 试验地点
- 20
- 主要终点
- Proportion of patients functionally independent (mRS score 0 to 2) at 90 days
研究概览
简要总结
This randomized, double-blind, placebo-controlled phase III clinical trial aims to evaluate the efficacy and safety of intravenous recombinant human Prourokinase (rhPro-UK) in acute ischemic stroke patients with large vessel occlusion presenting 4.5-24 hours after last known well. The study will address two primary questions: 1) Whether rhPro-UK enhances pre-thrombectomy reperfusion rates and improves 90-day functional outcomes compared to placebo; 2) Whether rhPro-UK increases the risk of symptomatic intracranial hemorrhage and mortality.
Participants will be randomized to receive an intravenous bolus of rhPro-UK or matching placebo, with a total dose of 35mg (15mg administered as an intravenous push within 5 minutes, and the remaining 20mg continuously infused intravenously over 30 minutes). Key assessments include repeat neuroimaging (CT/CTA or MRI/MRA) at 24 hours post-treatment to evaluate reperfusion, NIH Stroke Scale score at day 5-7, and modified Rankin Scale score assessment at 90 days. Safety monitoring will focus on hemorrhagic transformation and mortality events throughout the study period.
详细描述
This multicenter, phase III trial employs a randomized, double-blind, placebo-controlled design to investigate the therapeutic window extension for rhPro-UK in large vessel occlusion stroke. Eligible participants are adults with large vessel occlusion confirmed by vascular imaging (CTA/MRA), and salvageable brain tissue demonstrated by perfusion imaging (CTP/MRP) mismatch. Exclusion criteria include contraindications to thrombolysis, and large core infarction (>70 mL on CTP).
Patients will be randomized 1:1 to receive either rhPro-UK or placebo, with a total dose of 35mg (15mg administered as an intravenous push within 5 minutes, followed by the remaining 20 mg continuously infused intravenously over 30 minutes) . All participants will undergo endovascular thrombectomy.
The primary outcome is functional independence (mRS 0-2) at 90 days. Secondary outcomes include substantial reperfusion at initial angiogram, first-pass reperfusion, final infarct volume on hour 36 CT, etc. Safety outcomes include symptomatic intracranial hemorrhage per Heidelberg Bleeding Classification criteria within 36 hours, and 90-day mortality.
Safety monitoring includes independent adjudication of hemorrhagic events and all-cause mortality. A sample size of 820 participants provides 80% power to detect a 10% absolute difference in functional independence (α=0.05).
The trial incorporates centralized blinded outcome assessment and intention-to-treat analysis, with data oversight by an independent clinical events committee and data safety monitoring board.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years;
- •Acute ischemic stroke presenting within 4.5-24 hours of last known well;
- •No significant pre-stroke functional disability: for age <80 years, pre-stroke modified Rankin scale (mRS) ≤2; for age ≥80 years, prestroke mRS ≤1;
- •Baseline NIHSS score ≥6;
- •Imaging criteria of BOTH:
- •1. Occlusion on CTA/MRA in one of the following vessels: M1/M2 segment of middle cerebral artery, A1 segment of anterior cerebral artery, V4 segment of vertebral artery, basilar artery, or P1 segment of posterior cerebral artery. For A1, or P1 occlusions, vessel diameter must be ≥0.75 mm;
- •For anterior circulation occlusion: CTP/MRP demonstrating mismatch ratio ≥1.8, absolute mismatch volume ≥15 mL, and ischemic core volume <70 mL; OR have a mismatch between the presence of an abnormal signal on MRI diffusion-weighted imaging and no visible signal change on FLAIR. For posterior circulation occlusion: pc-ASPECTS score ≥
- •6. Plan to received endovascular thrombectomy;
- •The patient or their legal representative provides written informed consent.
排除标准
- •Intracranial hemorrhage confirmed by CT/MRI;
- •Onset accompanied by epileptic seizures, resulting in questionable stroke diagnosis and inability to obtain an accurate baseline NIHSS score;
- •Women who are pregnant or breastfeeding, or have a positive serum β-HCG test upon admission;
- •Already received intravenous thrombolytic after index stroke;
- •History of prior intracranial hemorrhage, including cerebral parenchymal hemorrhage, subarachnoid hemorrhage, and subdural/extradural hematoma;
- •Active bleeding or bleeding tendency, such as gastrointestinal bleeding, urinary tract bleeding, retinal hemorrhage, etc., or presence of coagulation dysfunction;
- •History of major recent surgery or trauma, such as intracranial or spinal surgery within the past 3 months, major surgery within the past 2 weeks, or severe head trauma within the past 3 weeks;
- •Baseline blood glucose <2.8 mmol/L or >22.2 mmol/L;
- •Received low molecular weight heparin within 24 hours, or oral anticoagulants with an International Normalized Ratio (INR) >1.7, or thrombin inhibitors within 48 hours, among others;
- •Arterial tortuosity or other vascular anomalies precluding endovascular access to target vessel;
- •Pre-existing neurological/psychiatric disorders interfering with neurological assessment;
- •Space-occupying intracranial tumors (except for small meningiomas);
- •Intracranial aneurysm or arteriovenous malformation;
- •Terminal illness with life expectancy <6 months;
- •Concurrent participation in other investigation clinical trials;
- •Presence of other conditions deemed by the investigator as unsuitable for participation in the study.
研究组 & 干预措施
Placebo group
Patients in this group will be treated with intravenous placebo and endovascular thrombectomy
干预措施: Intravenous placebo (Drug)
rhPro-UK group
Patients in this group will be treated with intravenous rhPro-UK and endovascular thrombectomy
干预措施: Intravenous rhPro-UK (Drug)
rhPro-UK group
Patients in this group will be treated with intravenous rhPro-UK and endovascular thrombectomy
干预措施: Endovascular thrombectomy (Procedure)
Placebo group
Patients in this group will be treated with intravenous placebo and endovascular thrombectomy
干预措施: Endovascular thrombectomy (Procedure)
结局指标
主要结局
Proportion of patients functionally independent (mRS score 0 to 2) at 90 days
时间窗: 90 days post-randomization
The modified Rankin Scale (mRS) is employed to assess patients' activities of daily living and the degree of disability. It grades patients' functional ability on a scale from 0 to 6, with a score of 0 indicating no symptoms and 6 representing death. An mRS score of 0-2 indicates functional independence.
次要结局
- Distribution of mRS scores at 90 days(90 days post-randomization)
- Shift in mRS score at 90 days(90 days post-randomization)
- Proportion of excellent functional outcome (mRS score 0 to 1) at 90 days(90 days post-randomization)
- Score on the EQ-5D-5L scale at 90 days(90 days post-randomization)
- Change in NIHSS score from baseline to 5-7 days post-procedure or at discharge(5-7 days post-procedure or at discharge)
- NIHSS score at 5-7 days post-procedure or at discharge(5-7 days post-procedure or at discharge)
- Final infarct volume on hour 36 NCCT(36 hours post-randomization)
- Substantial reperfusion (defined as an eTICI grade of 2b50, 2b67, 2c, or 3) at initial angiogram(within 5 minutes at initial angiogram)
- Successful reperfusion (defined as an eTICI grade of 2b, 2c, or 3) at end-of-procedure angiography(15 minutes after initial angiogram)
- Modified first-pass reperfusion(Perioperative (After artery puncture, but the start of procedure))
- Time from arterial puncture to successful recanalization or final angiography(Intraoperative)
- Proportion of balloon angioplasty or stent placement during endovascular treatment(Intraoperative)
- Proportion of patients planned for but ultimately not receiving endovascular treatment(Perioperative (After artery puncture, but the start of procedure))
- Symptomatic intracranial hemorrhage within 36 hours(within 36 hours after endovascular treatment)
- Proportion of patients with parenchymal hematoma at 36 hours post-procedure(within 36 hours after endovascular treatment)
- Mortality within 90 days(90 days post-randomization)
- Procedural-related complications(within 90 days)
- Severe adverse events(within 90 days)