Intravenous rhPro-UK Before Stroke Thrombectomy in the Extended Time Window (BRIDGE-PUK EXTEND)

Official title

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 )

Overview

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.

Detailed description

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.

Interventions

• Drug Intravenous rhPro-UK
  Patients will receive intravenous rhPro-UK
• Drug Intravenous placebo
  Patients will receive intravenous placebo
• Procedure Endovascular thrombectomy
  Patients will receive endovascular thrombectomy

Primary outcome measures

• Proportion of patients functionally independent (mRS score 0 to 2) at 90 days [Time frame: 90 days post-randomization]

Secondary outcome measures (12)

• Distribution of mRS scores at 90 days [Time frame: 90 days post-randomization]
• Shift in mRS score at 90 days [Time frame: 90 days post-randomization]
• Proportion of excellent functional outcome (mRS score 0 to 1) at 90 days [Time frame: 90 days post-randomization]
• Score on the EQ-5D-5L scale at 90 days [Time frame: 90 days post-randomization]
• Change in NIHSS score from baseline to 5-7 days post-procedure or at discharge [Time frame: 5-7 days post-procedure or at discharge]
• NIHSS score at 5-7 days post-procedure or at discharge [Time frame: 5-7 days post-procedure or at discharge]
• Final infarct volume on hour 36 NCCT [Time frame: 36 hours post-randomization]
• Substantial reperfusion (defined as an eTICI grade of 2b50, 2b67, 2c, or 3) at initial angiogram [Time frame: within 5 minutes at initial angiogram]
• Successful reperfusion (defined as an eTICI grade of 2b, 2c, or 3) at end-of-procedure angiography [Time frame: 15 minutes after initial angiogram]
• Modified first-pass reperfusion [Time frame: Perioperative (After artery puncture, but the start of procedure)]
• Time from arterial puncture to successful recanalization or final angiography [Time frame: Intraoperative]
• Proportion of balloon angioplasty or stent placement during endovascular treatment [Time frame: Intraoperative]

Eligibility criteria

Inclusion criteria

• 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; 2. 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.

6\. Plan to received endovascular thrombectomy; 7. The patient or their legal representative provides written informed consent.

Exclusion criteria

• 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.

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 · 10 centers

• The First Hospital of Lanzhou University — Lanzhou
• The Third Hospital of Hebei Medical University — Shijiazhuang
• Henan Provincial People's Hospital — Zhengzhou
• Loudi Central Hospital — Loudi
• The Second Hospital of Dalian Medical University — Dalian
• Qinghai Provincial People's Hospital — Xining
• First Affiliated Hospital of Xi'an Jiaotong University — Xi'an
• Shanxi Cardiovascular Hospital — Taiyuan
• … and 2 more centers

Identifiers

NCT: NCT07389460 · XJTU1AF2026LSYY-0065 · BRIDGE-PUK EXTEND

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗