Teneteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events-III

Study Overview
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Brief Summary
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The trial is a multicenter, prospective, block randomized, open label, blinded-endpoint (PROBE) controlled design. Patients with acute ischemic stroke due to large vessel occlusion within 4.5-24 hours of symptom onset (including wake-up stroke and unwitnessed stroke) will be randomized 1:1 to 0.25mg/kg intravenous tenecteplase or standard medical treatment.

Detailed Description
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The study will be a multicenter, prospective, randomized, open label, blinded-endpoint (PROBE), controlled phase 3 trial (2 arms with 1:1 randomization) in ischemic stroke due to large vessel occlusion with perfusion mismatch up to 24 hours of symptom onset. The target mismatch profiles on CTP or MRI perfusion weighted imaging include ischemic core volume <70 mL, mismatch ratio≥1.8 and mismatch volume≥15 mL demonstrated by a certified automatic software. The sample size is 516 patients.

Official Title
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A Phase 3, Multicenter, Prospective, Randomized, Open Label, Blinded-endpoint (PROBE) Controlled Trial of Recombinant Human TNK Tissue-type Plasminogen Activator (rhTNK-tPA) for Injection Versus Standard Medical Treatment for Acute Ischemic Stroke Due to Large Vessel Occlusion With Perfusion Mismatch up to 24 Hours of Symptom Onset

Conditions
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Ischemic Stroke, Acute

Intervention / Treatment
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* Drug: rhTNK-tPA ( 0.25 mg/kg, Max 25 mg )
* Drug: standard medical treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years old; Acute ischemic stroke within 4.5 to 24 hours prior to enrolment; including wake-up stroke and no witness stroke patients, onset time refers to last-seen normal; Pre-stroke modified Rankin scale (mRS) score≤1; Baseline national institutes of health stroke scale (NIHSS) 6-25 ( both included ); Neuroimaging: Internal carotid artery, middle cerebral artery M1 or M2 occlusion confirmed by computed tomography angiography (CTA)/magnetic resonance angiography (MRA) ( carotid artery occlusion refers to the carotid artery or intracranial artery, with or without tandem occlusion ), with target mismatch profile on computed tomography perfusion (CTP) or magnetic resonance _diffusion weighted imaging and Perfusion weighted imaging (MR_DWI+PWI) including ischemic core volume <70 mL, mismatch ratio≥1.8 and mismatch volume≥15 mL demonstrated by a certified automatic evaluation software; written informed consent from patients or their legally authorized representatives. Exclusion Criteria: Intended to proceed to endovascular treatment; Allergy to rhTNK-tPA; Rapidly improving symptoms at the discretion of the investigator; NIHSS consciousness score 1a >2, or epileptic seizure, hemiplegia after seizures ( Todd's palsy ) or combined with other nervous/mental illness not able to cooperate or unwilling to cooperate; Persistent blood pressure elevation ( systolic ≥180 mmHg or diastolic ≥100 mmHg ), despite blood pressure lowering treatment; Blood glucose <2.8 or >22.2 mmol/L ( on random glucose testing is acceptable ); Active internal bleeding or at high risk of bleeding, e.g.: Major surgery, trauma or gastrointestinal or urinary tract haemorrhage within the previous 21 days, or arterial puncture at a non-compressible site within the previous 7 days; Any known impairment in coagulation due to comorbid disease or anticoagulant use. If on warfarin, then INR >1.7 or prothrombin time >15 seconds; if use of any direct thrombin inhibitors or direct factor Xa inhibitors during the last 48 hours unless reversal of effect can be achieved with a reversal agent; if on any full dose heparin/heparinoid during the last 24 hours or with an elevated APTT greater than the upper limit of normal; Known defect of platelet function or platelet count below 100,000/mm3 ( but patients on antiplatelet agents can be included ); Ischemic stroke or myocardial infarction in previous 3 months, previous intracranial haemorrhage, severe traumatic brain injury or intracranial or intraspinal operation in previous 3 months, or known intracranial neoplasm, arteriovenous malformation or giant aneurysm; Any terminal illness such that patient would not be expected to survive more than 1 year; Unable to perform CTP or PWI; Hypodensity in >1/3 MCA territory on non-contrast CT; Acute or past intracerebral hemorrhage ( ICH ) identified by CT or MRI; Multiple arterial occlusion ( bilateral MCA occlusion, MCA occlusion accompanied with basilar occlusion ); Pregnant women, nursing mothers, or reluctant to take effective contraceptive measures during the period of trial subjects; Unlikely to adhere to the trial protocol or follow-up; Any condition that, in the judgment of the investigator could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study; Participation in other interventional clinical trials within the previous 3 months.

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: rhTNK-tPA ( 0.25 mg/kg, Max 25 mg )<br>rhTNK-tPA ( 0.25 mg/kg ) is given as a single, intravenous bolus ( within 5-10 seconds ) immediately upon randomization. Maximum dose 25mg. | Drug: rhTNK-tPA ( 0.25 mg/kg, Max 25 mg )<br>* rhTNK-tPA (0.25 mg/kg) is being used.<br>* Other names: TNK-tPA;|
| Active Comparator: standard medical treatment<br>Aspirin combined with clopidogrel, aspirin alone, or clopidogrel alone after randomization at the discretion of local neurologists | Drug: standard medical treatment<br>* Aspirin combined with clopidogrel, aspirin alone, or clopidogrel alone are being used.<br>* Other names: Aspirin, Clopidogrel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Excellent functional outcome | Proportion of excellent functional outcome defined as an mRS score ≤ 1 at 90 days | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ordinal distribution of mRS | Ordinal distribution of mRS at 90 days. | 90 days | 
| Favorable functional outcome | Proportion of favorable functional outcome defined by an mRS score ≤ 2 point at 90 days | 90 days | 
| Clinical response rate at 72 hours | Clinical response rate at 72 hours defined by an improvement on NIHSS score ≥8 points compared with the initial deficit or a score ≤1. | 72 hours | 
| The rate of improvement on reperfusion | The rate of improvement on reperfusion at 24 hours (improved by 90% on Tmax>6s) | 24 hours | 
| NIHSS change from baseline | NIHSS change from baseline at 7 days | 7 days | 
| Symptomatic intracranial hemorrhage | Proportion of symptomatic intracranial hemorrhage (sICH) within 36 hours (as defined by The European Cooperative Acute Stroke Study III criteria [ECASSIII]) | 36 hours | 
| Mortality | Rate of death from any cause within 90 days | 90 days | 
| Systematic bleeding | Rate of systematic bleeding at 90 days ( as defined by The Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries [GUSTO]: moderate and severe bleeding) | 90 days | 
| Adverse events ( AEs ) / serious adverse events ( SAEs ) | Rate of adverse events ( AEs ) / serious adverse events ( SAEs ) within 90 days | 90 days | 

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