Thrombolysis Treated With TNK-tPA in Acute Ischemic Stroke Patients （3T Stroke-II）

Study Overview
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Brief Summary
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The trial is prospective, block randomized, open-label, blinded endpoint (PROBE) design. Patients with acute ischemic stroke, who are eligible for standard intravenous thrombolysis within 4.5 hours of stroke onset will be randomized 1:1:1 to 0.25mg/kg or 0.40mg/kg intravenous tenecteplase or 0.9 mg/kg alteplase before all participants undergo endovascular thrombectomy.

Detailed Description
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The study will be a multi-center, prospective, randomized, open- label, blinded endpoint (PROBE), controlled phase 2 trial (3 arm with 1:1:1 randomization) in ischemic stroke patients. Imagine is performed with CT or MRI acutely with imaging follow-up at 24-30 hours. The sample size is 225.

Official Title
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Thrombolysis Treated With TNK-tPA in Acute Ischemic Stroke Patients: a Multi-center, Block Randomized, Positive Drug Parallel Controlled Phase II Trial

Conditions
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Acute Ischemic Stroke

Intervention / Treatment
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* Drug: Alteplase
* Drug: Tenecteplase
* Drug: Tenecteplase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years old; The clinical diagnosis was Acute ischemic stroke The time from onset to treatment was < 4.5h; The time at which symptoms begin is defined as the time at which they finally appear normal; mRS before onset was ≤1 points; Baseline NIHSS (at the time of randomization) should be > 5 and ≤25 points; Informed consent from the patient or surrogate. Exclusion Criteria: Intracranial hemorrhage identified by CT or MRI (CMBs detected by SWI is not counted); Massive anterior cerebral infarction identified by CT or MRI (ASPECT < 6 or lesions larger than one third of the territory of the middle cerebral artery or with a volume larger than 70mL) A history of severe CNS damage (such as aneurysm or arteriovenous malformation, craniocerebral trauma, intracranial or spinal cord surgery) Onset with seizures, and the paralysis was suspected to be related to Todd paralysis. Administration of heparin within 48 hours preceding the onset of stroke with a baseline APTT exceeding the upper limit of the normal range. Oral anticoagulant (such as warfarin) treatment with baseline INR>1.7 or PT>15 s; Administration of thrombin inhibitors or factor Xa inhibitors within 48 hours preceding the onset of stroke with abnormal coagulation parameters or platelet count; BP couldn't be controlled with aggressive treatment. Uncontrolled hypertension was defined as systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg, measured for three times every 10 minutes. Platelet count of less than 100×109/ L; Blood glucose <50 mg/dl (<2.8 mmol/L) or >400 mg/dl (22.22 mmol/L); History of intracranial hemorrhage or active hemorrhagic disease. (Such as gastrointestinal, urinary tract or retinal bleeding) Tumors with an increased risk of bleeding. Prolonged or traumatic cardiopulmonary resuscitation (>2 min), delivery within the last 10 days or recent puncture of non-compression vessels such as subclavian vein or jugular vein Acute pancreatitis or severe liver disease, including liver failure, cirrhosis, portal hypertension, esophageal varicose veins, and active hepatitis; Aortic arch dissection; Major surgery or severe trauma in the past 2 weeks; Subjects had serious, fatal, or disabling disease with an expected survival of less than 3 months; Unable to complete neurological assessment and follow-up visits because of dementia or mental illness; Pregnant women, lactating women, or have positive pregnancy test; Allergy to tenecteplase or alteplase or their components; Participation in other clinical trials within 3 months prior to screening; Unsuitable to involve in this study or would result in increased risk, as judged by the investigators.

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 |
| --- | --- |
| Active Comparator: Alteplase<br>Patients will receive intravenous Alteplase at the standard licensed dose of 0.9 mg/kg up to a maximum of 90mg, 10% as bolus and the remainder over 1 hour. | Drug: Alteplase<br>* Alteplase 0.9mg/kg are being used.<br>* Other names: rt-PA;|
| Experimental: Tenecteplase 0.25mg/kg<br>Patients will receive intravenous Tenecteplase, 0.25mg/kg, maximum 25mg, administered as a bolus over 5 10 seconds | Drug: Tenecteplase<br>* Tenecteplase 0.25mg/kg are being used.<br>* Other names: TNK-tPA;|
| Experimental: Tenecteplase 0.4mg/kg<br>Patients will receive intravenous Tenecteplase, 0.4mg/kg, maximum 40mg, administered as a bolus over 5 10 seconds | Drug: Tenecteplase<br>* Tenecteplase 0.4mg/kg are being used.<br>* Other names: TNK-tPA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Rankin Scale(mRS) | Proportion of subjects with mRS scores of (0-1) at 90±7 days.(Comments:The minimum and maximum values are from 0 to 6,and higher scores mean a worse outcome.) | 90±7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| National Institutes of Health Stroke Scale (NIHSS) | NIHSS score at 24±2 hours.(Comments:The minimum and maximum values are from 0 to 40, and higher scores mean a worse outcome.) | 24±2 hours | 
| National Institutes of Health Stroke Scale (NIHSS) | Proportion of subjects with ≥ 4 point reduction in NIHSS or reaching 0-1 at 7 ± 2 days or before discharge (whichever occurs first).(Comments:The minimum and maximum values are from 0 to 40, and higher scores mean a worse outcome.) | 7±2days or discharge | 
| Modified Rankin Scale(mRS) | Proportion of subjects with mRS scores of (0-2) at 90±7 days.(Comments:The minimum and maximum values are from 0 to 6,and higher scores mean a worse outcome.) | 90±7 days | 
| Modified Rankin Scale(mRS) | mRS scores at 90±7 days.(Comments:The minimum and maximum values are from 0 to 6,and higher scores mean a worse outcome.) | 90±7 days | 
| The new vascular events | Incidence of the new vascular events, ischemic stroke, hemorrhagic stroke, myocardial infarction and cardio-cerebral revascularization at 90±7 days. (including: carotid endarterectomy, intracranial and extracranial artery interventional therapy, intracranial and extracranial artery bypass surgery, coronary interventional or bypass therapy) | 90±7 days | 
| Deaths | Vascular mortality at 90±7 days (mainly due to stroke, myocardial infarction or pulmonary embolism) | 90±7 days | 
| EQ-5D | EQ-5D scores at 90±7 days.(Comments:The minimum and maximum values are from 0 to 100,and higher scores mean a better outcome.) | 90±7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TNK-tPA, rt-PA, Acute stroke, phase II trial