Intravenous rhTNK-tPA Before Stroke Thrombectomy in the Extended Time Window

Official title

Intravenous rhTNK-tPA Versus Placebo Before Endovascular Thrombectomy For Stroke Patient With Large Vessel Occlusion In The Extended Time Window: the BRIDGE-TNK EXTEND Randomized, Placebo-controlled, Double-blind Trial

Overview

This randomized, double-blind, placebo-controlled phase III clinical trial aims to evaluate the efficacy and safety of intravenous recombinant human tenecteplase (rhTNK-tPA) 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 rhTNK-tPA enhances pre-thrombectomy reperfusion rates and improves 90-day functional outcomes compared to placebo; 2) Whether rhTNK-tPA increases the risk of symptomatic intracranial hemorrhage and mortality. Participants will be randomized to receive either a single bolus of rhTNK-tPA (0.25 mg/kg, max 25 mg) or matching placebo administered intravenously over 5 seconds. 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 rhTNK-tPA 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 weight-adjusted rhTNK-tPA (0.25 mg/kg) or placebo. 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 day 1.5 MRI/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 rhTNK-tPA
  Patients will received intravenous rhTNK-tPA
• Drug Intravenous placebo
  Patients will received intravenous placebo
• Procedure Endovascular thrombectomy
  Patients will received 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 (9)

• Substantial reperfusion (defined as an eTICI grade of 2b, 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)]
• First-pass reperfusion [Time frame: Perioperative (After artery puncture, but the start of procedure)]
• Final infarct volume on day 1.5 MRI/CT [Time frame: 1.5 days post-randomization]
• Symptomatic intracranial hemorrhage within 48 hours [Time frame: within 48 hours after endovascular treatment]
• Mortality within 90 days [Time frame: 90 days post-randomization]
• Procedural-related complications [Time frame: within 90 days]
• Severe adverse events [Time frame: within 90 days]

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 ≥5;
• Imaging criteria of BOTH:

• 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.

Exclusion criteria

• Intracranial hemorrhage confirmed by CT/MRI;
• Already received intravenous thrombolytic after index stroke.;
• Pregnancy or lactation;
• Concurrent participation in other investigation drug clinical trials;
• 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 small meningiomas ≤3 cm);
• Intracranial aneurysm or arteriovenous malformation;
• Terminal illness with life expectancy <6 months;
• Anticipated inability to complete follow-up assessments.

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 · 4 centers

• Wuhan No. 1 Hospital — Wuhan
• Xiangtan Central Hospital — Xiangtan
• Jiujiang First People's Hospital — Jiujiang
• The First Affiliated Hospital of Nanchang University — Nanchang

Publications

• Albers GW, Jumaa M, Purdon B, Zaidi SF, Streib C, Shuaib A, Sangha N, Kim M, Froehler MT, Schwartz NE, Clark WM, Kircher CE, Yang M, Massaro L, Lu XY, Rippon GA, Broderick JP, Butcher K, Lansberg MG, Liebeskind DS, Nouh A, Schwamm LH, Campbell BCV; TIMELESS Investigators. Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection. N Engl J Med. 2024 Feb 22;390(8):701-711. doi: 10. PMID 38329148
• Yogendrakumar V, Campbell BC, Churilov L, Garcia-Esperon C, Choi PM, Cordato DJ, Guha P, Sharma G, Chen C, McDonald A, Thijs V, Mamun A, Dos Santos A, Balabanski AH, Kleinig TJ, Butcher KS, Devlin MJ, O'Rourke F, Donnan GA, Davis SM, Levi CR, Ma H, Parsons MW. Extending the time window for tenecteplase by effective reperfusion of penumbral tissue in patients with large vessel occlusion: Rationale PMID 39654273

Identifiers

NCT: NCT06987305 · BRIDGE-TNK EXTEND

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗