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

Official title

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

Overview

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.

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.

Interventions

• Procedure Intra-arterial Thrombolysis
  rhTNK-tPA（Tenecteplase）dose: 0.125 mg/kg, maximum dose: 12.5mg.
• Drug Standard medical treatment
  Standard medical treatment

Primary outcome measures

• Excellent outcome [Time frame: 90±7 days]

Secondary outcome measures (5)

• Ordinal distribution of mRS [Time frame: 90±7 days]
• Functional independence [Time frame: 90±7 days]
• Quality of life (EQ-5D-5L) [Time frame: 90±7 days]
• Neurologic deficit (NIHSS score) changes [Time frame: 36±12 hours]
• Infarct core volume change from baseline [Time frame: 7±1 days or discharge if earlier]

Eligibility criteria

Inclusion criteria

• Age ≥18 years
• Pre-stroke mRS score 0-1
• Baseline NIHSS ≥4 or symptoms deemed clearly disabling by treating physician (e.g., hemianopia, aphasia, or motor dysfunction)
• 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)
• 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.
• Acute ischemic stroke within 6-24 hours of onset, meeting at least one of the following imaging criteria:

• 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
• 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)
• The participant or legally authorized representative is capable of providing informed consent

Exclusion criteria

• Evidence of intracranial hemorrhage
• 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
• Persistent and uncontrolled hypertension, defined as systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg
• Inherited or acquired hemorrhagic tendancy; deficiency of anticoagulant factors; or on oral anticoagulant with an INR> 1.7
• 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
• 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)
• Women who are pregnant or breastfeeding
• Allergy to rhTNK-tPA or radiocontrast agent
• Participation in other clinical trials
• Expected survival time less than 6 months (e.g., due to malignancy, severe cardiopulmonary disease, etc.)
• 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)

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

Single blind

Primary purpose

Treatment

Study locations

China · 1 center

• Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology — Wuhan

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, PMID 40616323
• 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 PMID 39908448
• 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 PMID 39908430

Identifiers

NCT: NCT07302854 · TJ-IRB202512087

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗