Intra-arterial Recombinant Human TNK Tissue-type Plasminogen Activator (rhTNK-tPA) Thrombolysis for Acute Large Vascular Occlusion After Successful Mechanical Thrombectomy Recanalization

Study Overview
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Brief Summary
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The goal of this clinical trial is to evaluate whether intra-arterial (IA) rhTNK-tPA thrombolysis can improve neurological outcomes in acute large vessel occlusion patients after successful mechanical thrombectomy (MT) recanalization between 4.5- 24 hours from symptom onset. Participants enrolled will be randomly assigned to study or control arm with a 1:1ratio. Study group will receive IA rhTNK-tPA thrombolysis (0.125 mg/kg, Max 12.5mg) plus best medical management, and control receive best medical management alone.

Official Title
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Intra-arterial Recombinant Human Tenecteplase Tissue-type Plasminogen Activator rhTNK-tPA) Thrombolysis for Acute Large Vessel Occlusion After Successful Mechanical Thrombectomy Recanalization -- A Multicenter, Prospective, Randomized, Open-label, Blinded End-point Trial (ANGEL-TNK)

Conditions
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Ischemic Stroke, Acute

Intervention / Treatment
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* Drug: Recombinant Human tenecteplase Tissue-type Plasminogen Activator (rhTNK-tPA)
* Other: Best Medical Management


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical Inclusion Criteria: Age >18 years; NIHSS ≥2; Onset of symptoms to baseline CT imaging time: 4.5 to 24 hours, including wake-up stroke and unwitnessed stroke; Time of onset of symptoms is defined as last known well (LKW); Pre-stroke mRS score 0-1; Signed informed consent from patient or their health care proxy. Neuroimaging Inclusion Criteria: CTA/MRA proven intracranial artery occlusion: Intracranial Internal Carotid Artery (ICA)、M1 of Middle cerebral artery (MCA)、dominant M2 of MCA; ASPECTS ≥6 on non-contrast CT (NCCT) scan or DWI MRI; CT perfusion or MR perfusion: ischemic infarct core <70ml, mismatch ratio≥1.2, mismatch volume ≥15ml; Treated with MT resulting in an eTICI score 2b50-3 at end of the procedure. Patients with an eTICI score 2b50-3 on the diagnostic cerebral angiography before the onset of MT are also eligible for the study. Exclusion Criteria: Clinical Exclusion Criteria: IV thrombolysis used on admission; Contraindications to intravenous thrombolysis; Balloon angioplasty, permanent stenting and other situations during the endovascular procedure that require antiplatelet therapy or anticoagulant within the first 24h; IV heparin (heparinized saline allowed); Females who are pregnant, or those of child-bearing potential with positive urine or serum beta Human Chorionic Gonadotropin (HCG) test; Brain tumor (with mass effect); Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency Known coagulopathy, INR>1.7 or use of novel anticoagulants < 48h from symptom onset Platelets < 50*109/L; Suspicion of septic emboli or endocarditis Renal Failure as defined by a serum creatinine > 2.5 mg/dl (or 220μmol/l) or glomerular Filtration Rate [GFR] < 30ml/min; Patient who requires hemodialysis or peritoneal dialysis, or who has a contraindication to angiogram for whatever reason; Suspicion of aortic dissection; Parenchymal organ surgery and biopsy were performed in the past one month; Any active bleeding or recent bleeding (gastrointestinal bleeding, urinary bleeding, etc.) in the past 1 month; History of life-threatening allergy (more than rash) to contrast medium; SBP >185 mmHg or DBP >110 mmHg refractory to treatment; Serious, advanced, terminal illness with anticipated life expectancy < 6 months; Participation in another randomized clinical trial that could confound the evaluation of the study; Other circumstances that the investigator considers inappropriate for participation or may pose a significant risk to patients (e.g. inability to understand and/or comply with study procedures and/or follow-up due to mental disorders, cognitive or mood disorders). Specific Neuroimaging Exclusion Criteria Midline shift or herniation, mass effect with effacement of the ventricles Evidence of acute intracranial hemorrhage on CT/MRI Acute bilateral strokes or multiple intracranial vessel occlusions Isolated extracranial ICA occlusion or tandem carotid / MCA occlusion Dissection of occluded artery on DSA after thrombectomy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TNK group<br>Patients of this group will receive IA rhTNK-tPA plus Best Medical Management (BMM) after successful mechanical thrombectomy (MT) recanalization | Drug: Recombinant Human tenecteplase Tissue-type Plasminogen Activator (rhTNK-tPA)<br>* The administration of rhTNK-tPA will be infused constant and slowly over 15min (0.125 mg/kg, Max 12.5mg) through a microcatheter.<br>* Other names: IA rhTNK-tPA;Other: Best Medical Management<br>* Best Medical Management<br>|
| Active Comparator: control group<br>Patients of this group will receive Best Medical Management (BMM) alone after successful mechanical thrombectomy (MT) recanalization | Other: Best Medical Management<br>* Best Medical Management<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of excellent outcome | Rate of 90 (±7) day modified Rankin scale (mRS) 0-1 | 90±7 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of sICH (Heidelberg Bleeding Classification) | Rate of sICH (Heidelberg Bleeding Classification) | within 48 hours after randomization | 
| Volume of Tmax>6s |  | 24 hours (±12 hours) after randomization | 
| Infarct core volume change from baseline | Infarct core volume change from baseline, assessed with NCCT at 7 days (±1 day) after randomization/at discharge or with MRI at 36 hours (±12 hours) | 7 days (±1 day) after randomization/at discharge or at 36 hours (±12 hours) after randomization | 
| mRS (shift analysis) | mRS (shift analysis) | 90 days (±7 days) after randomization | 
| Rate of good outcome | Rate of mRS 0-2 | 90 days (±7 days) after randomization | 
| Rate of mRS 0-3 | Rate of mRS 0-3 | 90 days (±7 days) after randomization | 
| NIHSS 0-1 or decrease ≥10 from baseline NIHSS | NIHSS 0-1 or decrease ≥10 from baseline NIHSS | 36 hours (±12hours) after randomization | 
| EQ-5D-5L score | EQ-5D-5L score | 90 days (±7 days) after randomization | 
| All-caused mortality | All-caused mortality | 90 days (±7 days) after randomization | 
| Rate of any intracranial hemorrhage (Heidelberg Bleeding Classification) | Rate of any intracranial hemorrhage (Heidelberg Bleeding Classification) | within 48 hours after randomization |