Extending the Time Window for Tenecteplase by Effective Reperfusion in Patients With Large Vessel Occlusion

Study Overview
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Brief Summary
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Patients presenting to the emergency department with an acute ischemic stroke due to a large vessel occlusion eligible for thrombectomy and target mismatch on computed tomography perfusion imaging within 24 hours of onset will be assessed determine their eligibility for randomization into the trial. If the patient gives informed consent they will be randomised using a central computerised allocation process to either standard of care (no intravenous thrombolytic treatment or intravenous alteplase 0.9mg/kg) or tenecteplase before undergoing intra-arterial clot retrieval. The trial is prospective, randomised, open-label, blinded endpoint (PROBE) design.

Official Title
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Extending the Time Window for Tenecteplase by Effective Reperfusion of peNumbrAL Tissue in Patients With Large Vessel Occlusion

Conditions
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Ischemic Stroke

Intervention / Treatment
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* Drug: Tenecteplase
* Drug: Standard Care (which may include intravenous Alteplase)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients presenting with acute hemispheric ischemic stroke with onset (or the time they last known to be well) within 24 hours. Patient's age is ≥18 years. Premorbid mRS <3, with a concurrent assessment of whether the patient was able, immediately prior to the stroke, to: 1) Drive, or (if never drives) perform own Domestic duties, and 2) Shop for themselves, and 3) Bank/do their own finances (i.e. Drive/Domestic, Bank, Shop = DBS +ve). Need to be DBS +ve to be study eligible. Presence of a vessel occlusion on CTA or MRA. LVO will be defined as 'potentially retrievable' thrombus at one or more of the following sites: intracranial internal carotid (ICA), middle cerebral artery (MCA) first segment (M1), proximal middle cerebral artery second segment (M2) or isolated/tandem occlusion of the extracranial ICA. Patients with an extracranial ICA stenosis and occlusion are also eligible. Presence of 'target mismatch' on automated perfusion CT (CTP) or diffusion-perfusion MRI software defined as an ischemic core of <70mL, penumbra of >20mL and an ischemic core to perfusion lesion ratio of >1.8 Exclusion Criteria: Intracranial hemorrhage (ICH) or other diagnosis (e.g. tumor). Basilar Artery occlusion. Extensive early ischemic change (hypodensity on NCCT or high signal on DWI-MRI) or early ischemic change outside the perfusion lesion that invalidates mismatch criteria. Pre-stroke mRS score of > 2 (indicating significant previous disability) or DBS -ve. Any terminal illness such that patient would not be expected to survive more than 1 year 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. Pregnant women. Other standard contraindications to thrombolysis. Minor stroke symptoms, or major stroke symptoms rapidly improving Clinical presentation suggesting subarachnoid haemorrhage Known bleeding diasthesis and/or platelet count <100,000 or taking warfarin with INR > 1.7. Patients who have received heparin within 48 hours must have normal aPTT. Major surgery or serious trauma within 14 days, serious head trauma within 3 months. GI or urinary tract haemorrhage within last 21 days Arterial puncture at a non-compressible site or lumbar puncture within 7 days Systolic BP > 185, diastolic BP > 110mmHg Clinical stroke within 3 months or history of ICH Unable to gain consent from patient or person responsible Known severe renal impairment (GFR < 15mls/min)

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous tenecteplase (TNK)<br>Patients will receive intravenous tenecteplase (0.25mg/kg, maximum 25mg, administered as a bolus over 5-10 seconds). | Drug: Tenecteplase<br>* Genetically modified tissue plasminogen activator at a dose of 0.25mg/kg given as intravenous bolus over 5-10 seconds<br>|
| Active Comparator: Intravenous tissue plasminogen activator (tPA)<br>Patients will receive standard of care (no intravenous thrombolytic treatment or intravenous alteplase 0.9mg/kg 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: Standard Care (which may include intravenous Alteplase)<br>* Patients will receive standard care which may include 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Rankin Scale (mRS) 0-1 (no disability) or return to baseline mRS | Modified Rankin Scale (mRS) 0-1 (no disability) or return to baseline mRS (if baseline premorbid mRS =2) at 90 days | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early clinical improvement | Reduction in National Institutes of Health Stroke Scale (NIHSS) score of ≥8 points at 24 hours or reaching NIHSS 0-1 | 24 hours | 
| Modified Rankin Scale (mRS) 0-2 (functional independence) | Modified Rankin Scale (mRS) 0-2 (functional independence) at 90 days | 90 days | 
| Substantial reperfusion at initial angiographic assessment | Proportion of patients with >50% reperfusion of the affected vascular territory (mTICI 3b/3) on initial digital subtraction angiography prior to thrombectomy | initial angiography within 24 hours of stroke onset | 
| Symptomatic intracerebral hemorrhage (sICH) | sICH defined as parenchymal hematoma type 2 (PH2) - blood clot occupying >30% of the infarcted territory with substantial mass effect | 24 hours post-randomization | 
| Death due to any cause |  | 90 days | 
| Modified Rankin Scale (mRS) 5-6 | Poor functional outcome of death or requirement for fulltime nursing care | 90 days | 
| Successful reperfusion at 24 hours | Reperfusion (defined as >90% and >50% reduction in perfusion lesion volume) | 24 hours | 
| Infarct growth | Increase in the volume of irreversibly injured brain between pre-treatment and 24 hour imaging | 24 hours | 
| Recanalization | Change in vessel patency between pre-treatment and 24h imaging (CT or MR angiography) | 24 hours |