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

Phase 3

Not yet recruiting

• Conditions: Stroke, Acute Ischemic
• Interventions: Drug: Intravenous rhTNK-tPA; Drug: Intravenous placebo; Procedure: Endovascular thrombectomy

• Registration Number: NCT06987305
• Lead Sponsor: Xinqiao Hospital of Chongqing

Brief Summary

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.

Study Timeline

• Status Verified: 2025-05
• Study First Submitted: 2025-05-07
• Study First Submitted QC: 2025-05-22
• Last Update Submitted: 2025-05-22
• Study First Posted: 2025-05-23
• Last Update Posted: 2025-05-23
• Study Start: 2025-10-01
• Primary Completion: 2028-10-01
• Study Completion: 2029-01-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 820

Inclusion Criteria

1. Age ≥18 years;

2. Acute ischemic stroke presenting within 4.5-24 hours of last known well;

3. No significant pre-stroke functional disability: for age <80 years, pre-stroke modified Rankin scale (mRS) ≤2; for age ≥80 years, prestroke mRS ≤1;

4. Baseline NIHSS score ≥5;

5. 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

1. Intracranial hemorrhage confirmed by CT/MRI;
2. Already received intravenous thrombolytic after index stroke.;
3. Pregnancy or lactation;
4. Concurrent participation in other investigation drug clinical trials;
5. Arterial tortuosity or other vascular anomalies precluding endovascular access to target vessel;
6. Pre-existing neurological/psychiatric disorders interfering with neurological assessment;
7. Space-occupying intracranial tumors (except small meningiomas ≤3 cm);
8. Intracranial aneurysm or arteriovenous malformation;
9. Terminal illness with life expectancy <6 months;
10. Anticipated inability to complete follow-up assessments.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
rhTNK-tPA group	Intravenous rhTNK-tPA	Patients in this group will be treated with intravenous rhTNK-tPA and endovascular thrombectomy
rhTNK-tPA group	Endovascular thrombectomy	Patients in this group will be treated with intravenous rhTNK-tPA and endovascular thrombectomy
Placebo group	Intravenous placebo	Patients in this group will be treated with intravenous placebo and endovascular thrombectomy
Placebo group	Endovascular thrombectomy	Patients in this group will be treated with intravenous placebo and endovascular thrombectomy

Primary Outcome Measures

Name	Time	Method
Proportion of patients functionally independent (mRS score 0 to 2) at 90 days	90 days post-randomization	functional independence

Secondary Outcome Measures

Name	Time	Method
First-pass reperfusion	Perioperative (After artery puncture, but the start of procedure)	defined as Expanded Treatment in Cerebral Infarction 2c, or 3 after the first thrombectomy pass
Final infarct volume on day 1.5 MRI/CT	1.5 days post-randomization	Infarct volume quantified via MRI/CT , with manual correction by certified radiologists.
Symptomatic intracranial hemorrhage within 48 hours	within 48 hours after endovascular treatment	evaluate intracranial hemorrhage (Heidelberg classification)
Mortality within 90 days	90 days post-randomization	evaluate death rate of the two treatment groups
Procedural-related complications	within 90 days	evaluate complications
Severe adverse events	within 90 days	evaluate any adverse events
Substantial reperfusion (defined as an eTICI grade of 2b, 2c, or 3) at initial angiogram	within 5 minutes at initial angiogram	The expanded Thrombolysis In Cerebral Infarction (eTICI) reperfusion grading system is a 6-point scale: 0 indicates no reperfusion noted; 1, reduction in thrombus without filling of distal arterial branches; 2a, reperfusion of \<50% of the territory; 2b, a reperfusion of ≥50% of the territory; 2c, near-complete perfusion with distal slow flow or presence of small cortical emboli; and 3, complete reperfusion. Successful reperfusion at initial angiogram prior to thrombectomy was defined as an eTICI grade of 2b, 2c, or 3 on the first intracranial angiogram.
Successful reperfusion (defined as an eTICI grade of 2b, 2c, or 3) at end-of-procedure angiography	15 minutes after initial angiogram	The expanded Thrombolysis In Cerebral Infarction (eTICI) reperfusion grading system is a 6-point scale: 0 indicates no reperfusion noted; 1, reduction in thrombus without filling of distal arterial branches; 2a, reperfusion of \<50% of the territory; 2b, a reperfusion of ≥50% of the territory; 2c, near-complete perfusion with distal slow flow or presence of small cortical emboli; and 3, complete reperfusion. This outcome will be evaluate at the end of procedure.
Modified first-pass reperfusion	Perioperative (After artery puncture, but the start of procedure)	defined as Expanded Treatment in Cerebral Infarction 2b, 2c, or 3 after the first thrombectomy pass