Determining the Optimal Dose of Tenecteplase Before Endovascular Therapy for Ischaemic Stroke (EXTEND-IA TNK Part 2)

Study Overview
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Brief Summary
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Patients presenting to the emergency department with acute ischemic stroke, who are eligible for standard intravenous thrombolysis within 4.5 hours of stroke onset will be assessed for major vessel occlusion to determine their eligibility for randomization into the trial. If the patient gives informed consent they will be randomised 50:50 using central computerised allocation to either 0.4mg/kg or 0.25mg/kg intravenous tenecteplase before all participants undergo endovascular thrombectomy. The trial is prospective, randomised, open-label, blinded endpoint (PROBE) design.

Detailed Description
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The study will be a multicentre, prospective, randomized, open- label, blinded endpoint (PROBE), controlled phase 2 trial (2 arm with 1:1 randomization) in ischemic stroke patients. Randomized patients will first be stratified by both the setting of treatment: metropolitan hospital vs regional hospital (>1 hour transfer to endovascular centre) vs mobile stroke unit; and by site of baseline arterial occlusion: Intracranial internal carotid artery (ICA) and Basilar artery versus Middle cerebral artery (MCA - M1 and M2); overall resulting in six strata. Imaging is performed with CT or MR (magnetic resonance) acutely as part of standard care with imaging follow-up at 18-30 hours. The sequences and the parameters used follow the STIR (Stroke Imaging Research) roadmap guidelines, but imaging takes place acutely and at 18- 30hrs only, as previously validated. The sample size estimation was based on the proportion of pre-endovascular reperfusion observed in the 0.25mg/kg group from Part 1 of EXTEND-IA TNK (22%). An estimated total sample size of 188 patients (with 94 patients in each of treatment and control arms) yielded 80% power to detect a significant difference of 20% in strata-weighted angiographic reperfusion (mTICI 2b/3) at initial angiogram (22% in 0.25mg/kg vs 42% in 0.4mg/kg arm) at two-sided statistical significance threshold of p=0.05 for superiority. Adaptive increase in sample size will be performed if the result of interim analysis using data from the first 150 patients is promising, as per the methodology of Mehta and Pocock. During the trial, blinded analysis of operational characteristics revealed a 20% reduction in the time from thrombolysis to arterial access versus part 1 due to improved workflow (In the first 150 patients in part 2 median 37min [IQR 19-54] versus 46min [IQR 28-63] in part 1). This directly impacts the time for thrombolysis to have an effect. A 20% reduction in the hypothesized rate of reperfusion at initial angiogram (18% vs 33%) would require 145 patients per group. Allowing for potential further improvements in workflow the sample size re-estimation was postponed from 150 to 240 patients with a revised minimum sample of 300 patients. Adaptive increase in sample size will be performed if the result of interim analysis using data from the first 240 patients is promising, as per the methodology of Mehta and Pocock. The maximum sample size is capped at 656 patients.

Official Title
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EXTEND-IA TNK: Extending the Time for Thrombolysis in Emergency Neurological Deficits - Intra-Arterial Using Intravenous Tenecteplase Part 2

Conditions
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Ischemic Stroke

Intervention / Treatment
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* Drug: Tenecteplase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients presenting with acute ischemic stroke eligible using standard criteria to receive IV thrombolysis within 4.5 hours of stroke onset Patient's age is ≥18 years Arterial occlusion on CTA (computed tomography angiography) or MRA (Magnetic Resonance Angiography) of the ICA, M1, M2 or basilar artery. Exclusion Criteria: Intracranial hemorrhage (ICH) identified by CT or MRI Rapidly improving symptoms at the discretion of the investigator Pre-stroke mRS score of ≥ 4 (indicating previous disability) Hypodensity in >1/3 MCA territory or equivalent proportion of basilar artery territory on non-contrast CT Contra indication to imaging with contrast agents 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

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
Interventional Model Description: Patients will receive either intravenous tenecteplase (0.4mg/kg, maximum 40mg, administered as a bolus over  10 seconds) or intravenous tenecteplase (0.25mg/kg, maximum 25mg, administered as a bolus over  10 seconds).
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Assigned Interventions<br>Patients will receive intravenous tenecteplase (0.25mg/kg, maximum 25mg, administered as a bolus over  10 seconds). | Drug: Tenecteplase<br>* Tenecteplase 0.25mg/kg and 0.4mg/kg are being used<br>* Other names: TNK;|
| Experimental: Tenecteplase<br>Patients will receive intravenous tenecteplase (0.4mg/kg, maximum 40mg, administered as a bolus over  10 seconds). | Drug: Tenecteplase<br>* Tenecteplase 0.25mg/kg and 0.4mg/kg are being used<br>* Other names: TNK;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| mTICI | Proportion of patients with substantial angiographic reperfusion (mTICI) score of 2b/3 (restoration of blood flow to >50% of the affected arterial territory) or absence of retrievable thrombus at initial angiogram. | Initial angiogram (day 0) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Rankin Scale (mRS) | mRS ordinal analysis. mRS 0-1 or no change from baseline and mRS 0-2 or no change from baseline. | at 3 months post stroke | 
| National Institutes of Health Stroke Scale (NIHSS) | Proportion of patients with ≥8 point reduction in NIHSS or reaching 0-1 at 3 days (favourable clinical response) adjusted for baseline NIHSS and age | Initial angiogram (day 0) | 
| Symptomatic intracranial haemorrhage (SICH) | SICH is defined as Intracerebral hemorrhage (parenchymal hematoma type 2 - PH2 within 36 hours of treatment) combined with neurological deterioration leading to an increase of ≥4 points on the NIHSS | Within 36 hours post treatment | 
| Death | Death due to any cause | Up to 3 months post stroke | 
| Angiographic reperfusion | Proportion of patients with angiographic reperfusion adjusted for hyperdense clot length on non-contrast CT and time from thrombolysis to initial angiogram | Up to 24 hours post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stroke, Ischemia, Cerebral Infarction, Cerebrovascular Disorders, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases, Vascular Diseases, Cardiovascular Diseases, Pathologic Processes, Brain Infarction, Brain Ischemia, Tenecteplase, Fibrinolytic agents, Fibrin Modulating agents, Molecular Mechanisms of Pharmacological Action, Plasminogen, Tissue Plasminogen Activator