Extending the Time Window for Tenecteplase by Effective Reperfusion in Patients With Large Vessel Occlusion (ETERNAL-LVO)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Ischemic Stroke
• Intervention / Treatment: Drug: Tenecteplase; Drug: Standard Care (which may include intravenous Alteplase)

• Study Type: Interventional
• Enrollment (Anticipated): 740
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Andrew Bivard, PHD; Phone Number: +6193424424; Email: abivard@unimelb.edu.au
• Study Contact Backup: Name: Amy McDonald, BN; Phone Number: +6193424424; Email: amym1@unimelb.edu.au

Study Locations

• Australia
  • New South Wales
    • Liverpool, New South Wales, Australia
      • Recruiting
      • Liverpool Hospital
      • Contact: Dennis Cordato
    • Newcastle, New South Wales, Australia
      • Recruiting
      • John Hunter Hospital
      • Contact: Michelle Russell
    • Randwick, New South Wales, Australia
      • Recruiting
      • Prince of Wales Hospital
      • Contact: Ken Butcher; Email: ken.butcher@unsw.edu.au
  • Queensland
    • Woolloongabba 4102, Queensland, Australia, 4102
      • Recruiting
      • Princess Alexandra Hospital
      • Contact: Helen Brown
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Recruiting
      • Royal Adelaide Hospital
      • Contact: Tim Kleinig; Email: tim.kleinig@sa.gov.au
  • Victoria
    • Melbourne, Victoria, Australia, 3050
      • Recruiting
      • Royal Melbourne Hospital
      • Contact: Amy McDonald
    • Melbourne, Victoria, Australia
      • Recruiting
      • Box Hill Hospital
      • Contact: Phillip Choi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intravenous tenecteplase (TNK); Patients will receive intravenous tenecteplase (0.25mg/kg, maximum 25mg, administered as a bolus over 5-10 seconds).	Drug: Tenecteplase; Genetically modified tissue plasminogen activator at a dose of 0.25mg/kg given as intravenous bolus over 5-10 seconds
Active Comparator: Intravenous tissue plasminogen activator (tPA); 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); 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Melbourne
• Collaborators: Professor Mark Parsons

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2020
• Primary Completion (Anticipated): June 1, 2025
• Study Completion (Anticipated): December 1, 2025

Study Registration Dates

• First Submitted: June 16, 2020
• First Submitted That Met QC Criteria: June 28, 2020
• First Posted (Actual): July 2, 2020

Study Record Updates

• Last Update Posted (Actual): June 22, 2021
• Last Update Submitted That Met QC Criteria: June 15, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tissue Plasminogen Activator; Tenecteplase
• Other Study ID Numbers: 2019.125

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No