Intra-arterial Recombinant Human Tenecteplase Tissue-type Plasminogen Activator (rhTNK-tPA) Thrombolysis for Acute Medium Vessel Occlusion (MeVO-TNK Ⅱ)

Intra-arterial Recombinant Human Tenecteplase Tissue-type Plasminogen Activator (rhTNK-tPA) Thrombolysis for Acute Medium Vessel Occlusion -- A Multicenter, Prospective, Randomized, Open-label, Blinded End-point Trial

Medium vessel occlusion (MeVO) accounts for 20-45% of acute ischemic stroke (AIS). Although patients with MeVO often present with relatively low NIHSS scores, up to one-third remain functionally dependent at follow-up despite receiving standard medical therapy, including intravenous thrombolysis. Recent randomized trials (DISTAL, ESCAPE-MeVO, DISCOUNT) have not demonstrated clinical benefit of endovascular treatment (EVT) for MeVO and have suggested higher risks of symptomatic intracranial hemorrhage and mortality, underscoring the need for safer and more targeted reperfusion strategies.

Intra-arterial thrombolysis (IAT) enables localized, high-concentration thrombolytic delivery with minimal mechanical manipulation, which may be advantageous for medium and distal vessels. Recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA), a genetically engineered third-generation thrombolytic agent, has shown favorable pharmacologic properties and clinical safety in AIS, including in intra-arterial use following EVT. However, prospective evidence supporting its direct therapeutic role in MeVO-related AIS remains lacking.

This multicenter, prospective, open-label randomized controlled trial with blinded endpoint assessment is designed to evaluate the efficacy and safety of intra-arterial rhTNK-tPA thrombolysis in improving functional outcome in MeVO within 24 hours of symptom onset.

Study Overview

• Status: Recruiting
• Conditions: Acute Ischemic Stroke; Medium Vessel Occlusion
• Intervention / Treatment: Procedure: Intra-arterial Thrombolysis; Drug: Standard medical treatment

Detailed Description

This study is an investigator-initiated, multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) clinical trial designed to evaluate the efficacy and safety of intra-arterial rhTNK-tPA in improving 90-day functional outcomes in patients with MeVO stroke within 24 hours of symptom onset. The primary outcome is the proportion of patients achieving a modified Rankin Scale (mRS) score of 0-1 at 90 days. Eligible patients will be randomized in a 1:1 ratio to receive either intra-arterial rhTNK-tPA thrombolysis (0.125 mg/kg, Max 12.5mg) plus standard medical therapy or standard medical therapy alone. A total of 382 participants (191 per group) will be enrolled in this trial.

• Study Type: Interventional
• Enrollment (Estimated): 382
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Xiang Luo, PhD, MD; Phone Number: +86-13349893413; Email: flydottjh@163.com

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430000
      • Recruiting
      • Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
      • Contact: Xiang Luo; Phone Number: +86-27-83663323; Email: flydottjh@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years
2. Pre-stroke mRS score 0-1
3. Baseline NIHSS ≥4 or symptoms deemed clearly disabling by treating physician (e.g., hemianopia, aphasia, or motor dysfunction)
4. Isolated medium distal vessel occlusion (i.e., an occlusion of the co-/non-dominant M2, the M3/M4 segment of the MCA, the A1/A2/A3 segment of the ACA or the P1/P2/P3 segment of the PCA) confirmed by CT angiography (CTA) or MR angiography (MRA)
5. Acute ischemic stroke within 24 hours of symptom onset, including wake-up stroke or unwitnessed stroke; The onset time of symptoms was defined as the last time of normal performance.

6. Acute ischemic stroke within 6-24 hours of onset, meeting at least one of the following imaging criteria:

   1. Evidence of a hypoperfusion-ischemic core mismatch on CT or MRI perfusion, defined as an ischemic core volume <50mL, hypoperfused tissue volume to ischemic core volume ratio ≥1.2, and mismatch volume ≥10 mL
   2. Evidence of a diffusion-hyperintensity mismatch, defined as absence of hyperintensity on fluidattenuated inversion recovery (FLAIR) imaging within ≥ 90% of the area of the diffusion weighted imaging (DWI) lesion)
7. The participant or legally authorized representative is capable of providing informed consent

Exclusion Criteria:

1. Evidence of intracranial hemorrhage
2. Any active bleeding (gastrointestinal, urinary, hemorrhagic retinopathy, etc.) or parenchymal organ surgery or biopsy within 30 days before stroke; Severe head trauma or stroke within the past 3 months
3. Persistent and uncontrolled hypertension, defined as systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg
4. Inherited or acquired hemorrhagic tendancy; deficiency of anticoagulant factors; or on oral anticoagulant with an INR> 1.7
5. Blood glucose <2.8 mmol/L (50 mg/dl) or > 22.2mmol/L (400 mg/dl), platelets count <100*109/L, or hemoglobin <70g/L
6. Severe hepatic insufficiency, chronic hemodialysis and severe renal insufficiency (or recent blood tests suggesting a glomerular filtration rate <30 ml/min or blood creatinine> 200 mmol/L (2.5 mg/dl)
7. Women who are pregnant or breastfeeding
8. Allergy to rhTNK-tPA or radiocontrast agent
9. Participation in other clinical trials
10. Expected survival time less than 6 months (e.g., due to malignancy, severe cardiopulmonary disease, etc.)
11. Other conditions deemed by the investigator to make the patient unsuitable for participation or pose significant risks (e.g., inability to understand and/or comply with study procedures and/or follow-up due to mental illness, cognitive or emotional disorders)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention group; Patients of this group will receive intra-arterial rhTNK-tPA thrombolysis plus standard medical treatment	Procedure: Intra-arterial Thrombolysis; rhTNK-tPA（Tenecteplase）dose: 0.125 mg/kg, maximum dose: 12.5mg.; Drug: Standard medical treatment; Standard medical treatment
Active Comparator: Control group; Patients of this group will receive standard medical treatment alone	Drug: Standard medical treatment; Standard medical treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Excellent outcome	Rate of modified Rankin scale (mRS) 0-1 at 90±7 days	90±7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ordinal distribution of mRS	The shift analysis of mRS at 90±7 days (mRS 5 and 6 merged)	90±7 days
Functional independence	Rate of mRS 0-2 at 90±7 days	90±7 days
Infarct core volume change from baseline	Infarct core volume change from baseline at 7±1 days or discharge if earlier	7±1 days or discharge if earlier
Quality of life (EQ-5D-5L)	The EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L) index score at 90±7 days The EQ-5D-5L is a standardized, preference-based measure of health-related quality of life covering five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with five severity levels. The EQ-5D-5L index score typically ranges from less than 0 (health states worse than death) to 1.0 (full health), with higher scores indicating better quality of life.	90±7 days
Neurologic deficit (NIHSS score) changes	The change of the National Institutes of Health Stroke Scale (NIHSS) score from baseline to 36±12 hours The NIHSS is a standardized clinical scale used to quantify neurologic impairment in stroke patients. The total score ranges from 0 to 42, with higher scores indicating more severe neurologic deficit. The outcome is defined as the change in NIHSS score from baseline, where a greater negative change reflects greater neurologic improvement.	36±12 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptomatic intracranial hemorrhage (sICH)	Rate of sICH within 48 hours after randomization (Heidelberg Bleeding Classification)	48 hours
All-caused mortality	All cause mortality at 90±7 days	90±7 days
Any intracranial hemorrhage	Rate of any intracranial hemorrhage within 48 hours after randomization (Heidelberg Bleeding Classification)	48 hours

Collaborators and Investigators

• Sponsor: Xiang Luo
• Investigators: Principal Investigator: Xiang Luo, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 450001

Publications and helpful links

General Publications

• Miao Z, Luo G, Song L, Sun D, Chen W, Yao X, Pan Y, Liu Y, Yuan G, Wen C, Wei M, Cai X, Yang Q, Zhou Z, Chang M, Nan G, Wang J, Xiang G, Zhou L, Gao W, Zhang H, Hao J, Xu C, Sun Y, Yi T, Feng G, Han H, Gao F, Ma N, Mo D, Sun X, Deng Y, Tong X, Li X, Jia B, Wang B, He Z, Yang M, Zhao X, Zhang X, Zhang L, Li S, Tong X, Jing J, Xiong Y, Liu T, Li Z, Ren Z, Wang Y, Liebeskind DS, Jovin TG, Nguyen TN, Wang Y, Liu L, Yan B, Huo X; ANGEL-TNK Investigators. Intra-arterial Tenecteplase for Acute Stroke After Successful Endovascular Therapy: The ANGEL-TNK Randomized Clinical Trial. JAMA. 2025 Aug 19;334(7):582-591. doi: 10.1001/jama.2025.10800.
• Goyal M, Ospel JM, Ganesh A, Dowlatshahi D, Volders D, Mohlenbruch MA, Jumaa MA, Nimjee SM, Booth TC, Buck BH, Kennedy J, Shankar JJ, Dorn F, Zhang L, Hametner C, Nardai S, Zafar A, Diprose W, Vatanpour S, Stebner A, Bosshart S, Singh N, Sebastian I, Uchida K, Ryckborst KJ, Fahed R, Hu SX, Vollherbst DF, Zaidi SF, Lee VH, Lynch J, Rempel JL, Teal R, Trivedi A, Bode FJ, Ogungbemi A, Pham M, Orosz P, Abdalkader M, Taschner C, Tarpley J, Poli S, Singh RJ, De Leacy R, Lopez G, Sahlas D, Chen M, Burns P, Schaafsma JD, Marigold R, Reich A, Amole A, Field TS, Swartz RH, Settecase F, Lenzser G, Ortega-Gutierrez S, Asdaghi N, Lobotesis K, Siddiqui AH, Berrouschot J, Mokin M, Ebersole K, Schneider H, Yoo AJ, Mandzia J, Klostranec J, Jadun C, Patankar T, Sauvageau E, Lenthall R, Peeling L, Huynh T, Budzik R, Lee SK, Makalanda L, Levitt MR, Perry RJ, Hlaing T, Jahromi BS, Singh P, Demchuk AM, Hill MD; ESCAPE-MeVO Investigators. Endovascular Treatment of Stroke Due to Medium-Vessel Occlusion. N Engl J Med. 2025 Apr 10;392(14):1385-1395. doi: 10.1056/NEJMoa2411668. Epub 2025 Feb 5.
• Psychogios M, Brehm A, Ribo M, Rizzo F, Strbian D, Raty S, Arenillas JF, Martinez-Galdamez M, Hajdu SD, Michel P, Gralla J, Piechowiak EI, Kaiser DPO, Puetz V, Van den Bergh F, De Raedt S, Bellante F, Dusart A, Hellstern V, Khanafer A, Parrilla G, Morales A, Kirschke JS, Wunderlich S, Fiehler J, Thomalla G, Lemmens R, Peluso JP, Bolognese M, von Hessling A, van Es A, Kruyt ND, Coutinho JM, Castano C, Minnerup J, van Zwam W, Dhondt E, Nolte CH, Machi P, Loehr C, Mattle HP, Buhk JH, Kaesmacher J, Dobrocky T, Papanagiotou P, Alonso A, Holtmannspoetter M, Zini A, Renieri L, Keil F, van den Wijngaard I, Kagi G, Terceno M, Wiesmann M, Amaro S, Rommers N, Balmer L, Fragata I, Katan M, Leker RR, Saver JL, Staals J, Fischer U; DISTAL Investigators. Endovascular Treatment for Stroke Due to Occlusion of Medium or Distal Vessels. N Engl J Med. 2025 Apr 10;392(14):1374-1384. doi: 10.1056/NEJMoa2408954. Epub 2025 Feb 5.

Study record dates

Study Major Dates

• Study Start (Actual): December 30, 2025
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: December 11, 2025
• First Submitted That Met QC Criteria: December 11, 2025
• First Posted (Actual): December 24, 2025

Study Record Updates

• Last Update Posted (Actual): January 21, 2026
• Last Update Submitted That Met QC Criteria: January 19, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Acute Ischemic Stroke; Tenecteplase; medium vessel occlusion; Intra-arterial thrombolysis
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Stroke; Ischemic Stroke
• Other Study ID Numbers: TJ-IRB202512087

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No