Post-thrombectomy Intra-arterial Tenecteplase for Acute manaGement of Non-retrievable Thrombus and No-reflow in Emergent Stroke

Post-thrombectomy Intra-arterial Tenecteplase for Acute manaGement of Non-retrievable Thrombus and No-reflow in Emergent Stroke (EXTEND-AGNES TNK)

Multicentre, prospective, Multi-arm Multi-stage (MAMS) seamless phase 2b/3 interventional randomized placebo-controlled double-blinded parallel-assignment (2 arms with 1:1 randomization) efficacy and safety trial to test intra-arterial tenecteplase at the completion of thrombectomy versus best practice in participants with anterior circulation LVO receiving mechanical thrombectomy within 24 hours of symptoms onset.

Study Overview

• Status: Not yet recruiting
• Conditions: Cerebrovascular Disorders; Central Nervous System Diseases; Ischemic Stroke, Acute; Brain Disorder
• Intervention / Treatment: Drug: Placebo; Drug: Intra-arterial tenecteplase injection at the completion of thrombectomy

• Study Type: Interventional
• Enrollment (Estimated): 462
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Felix Ng; Phone Number: +03 9342 7000; Email: ng.f@unimelb.edu.au

Study Locations

• Australia
  • Adelaide, Australia
    • Royal Adelaide Hospital
    • Contact: Roy Drew
    • Principal Investigator: Timothy Kleinig
  • Brisbane, Australia
    • Princess Alexandra Hospital
    • Contact: Michael Devlin
    • Principal Investigator: Michael Devlin
  • Brisbane, Australia
    • Royal Brisbane and Women's Hospital
    • Contact: Andrew Wong
    • Principal Investigator: Andrew Wong
  • Canberra, Australia
    • Canberra Hospital
    • Contact: Peter Mews
    • Principal Investigator: Peter Mews
  • Melbourne, Australia
    • Alfred Hospital
    • Contact: Pamela Galindo
    • Principal Investigator: Geoff Cloud
  • Melbourne, Australia
    • Monash Medical Centre
    • Contact: Henry Ma
    • Principal Investigator: Henry Ma
  • Melbourne, Australia
    • Austin Hospital
    • Contact: Vincent Thijs
    • Principal Investigator: Vincent Thijs
  • Melbourne, Australia
    • Royal Melbourne Hospital
    • Contact: David Jackson
    • Principal Investigator: Felix Ng
  • Newcastle, Australia
    • John Hunter Hospital
    • Principal Investigator: Carlos Garcia-Esperon
    • Contact: Linda Belevski
  • Perth, Australia
    • Fiona Stanley Hospital
    • Contact: Darshan Ghia
    • Principal Investigator: Darshan Ghia
  • Sydney, Australia
    • Royal North Shore Hospital
    • Contact: Alice Ma
    • Principal Investigator: Alice Ma
  • Sydney, Australia
    • Liverpool Hospital
    • Contact: Dennis Cordato
    • Principal Investigator: Dennis Cordato
    • Principal Investigator: Mark Parsons

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult participants (age≥18 years) presenting with ischemic stroke with arterial LVO on CT/MR Angiogram of the intracranial internal carotid or middle cerebral artery (MCA) first segment (M1) or proximal second segment (M2) committed to thrombectomy using standard criteria within 24 hours of onset:
• For 0-6 hours of symptom onset: Presence of arterial occlusion as defined above and ASPECTS≥3 on NCCT
• For 6-24 hours of symptom onset: Additional imaging criteria on CTP or MRI perfusion of core volume <100ml.
• Qualifying CT/MR within 4hrs of randomisation (repeat CT for transferred participants required if >4hr)
• Pre-stroke Modified Rankin Scale (mRS) score of ≤2 (mild pre-existing disability permitted)
• Local legal requirements for consent have been satisfied.

Exclusion Criteria:

• Intracranial hemorrhage identified by CT or MRI
• ASPECTS 0-2 on NCCT
• CTP or MRI perfusion ischemic core volume >100ml if presenting within 6-24 hours from symptoms onset
• Anticipated endovascular stenting required for intracranial or extracranial atherosclerotic stenosis/occlusion.
• More than six retrieval attempts in the same vessel
• Alteplase being infused within 30 minutes (~5x half-life) of anticipated trial drug administration
• Contraindication to imaging with contrast agents
• Any condition (eg.mid-arterial phase early venous filling) that in the judgment of investigators could impose hazards if study therapy is initiated
• Pregnant women.
• Current participation in another intervention research study that includes experimental interventions beyond standard-of-care.
• Anticoagulation. INR ≤1.7 if on warfarin, and dabigatran reversal by idarucizumab are permitted.
• Other standard contraindications to thrombolysis apart from time window.
• Known terminal illness such that the participants would not be expected to survive a year.
• Planned withdrawal of care or comfort care measures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Intra-arterial bolus of placebo (0.9% Sodium Chloride solution) representing standard of care (no intra-arterial thrombolytic treatment).	Drug: Placebo; intra-arterial bolus of 0.9% Sodium Chloride solution
Experimental: Intra-arterial tenecteplase injection at the completion of thrombectomy; intra-arterial tenecteplase (0.062mg/kg, maximum 6.25mg) administered as a bolus at the completion of thrombectomy through a microcatheter at the site of the initial-but-now-retrieved intracranial occlusion or in direct contact with the residual thrombus	Drug: Intra-arterial tenecteplase injection at the completion of thrombectomy; Intra-arterial tenecteplase (0.062mg/kg, maximum 6.25mg) administered as a bolus at the completion of thrombectomy through a microcatheter at the site of the initial-but-now-retrieved intracranial occlusion, or in direct contact with the residual thrombus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early Neurological Improvement (Phase 2b)	Proportion of participants with Early Neurological Improvement (ENI) defined as NIHSS reduction>4	24-36 hours from time of randomisation
Functional independence (Phase 3)	Proportion of participants with Modified Rankin Scale (mRS) 0-2 (functional independence)	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Infarct growth	Infarct growth volume on follow-up MRI or CT	24 hours
No-reflow	Proportion of participants with radiological no-reflow on MR perfusion or CTP	24 hours
Symptomatic Intracerebral Hemorrhage	Proportion of participants with sICH defined as parenchymal haematoma type 2 (PH2) or SAH/IVH within 36 hours combined with neurological deterioration leading to an increase of NIHSS ≥4 from baseline or leading to death	36 hours
All cause mortality	Proportion of participants with death due to any cause	3 months
Functional improvement	Reduction of ≥ 1 mRS category (ordinal analysis merging mRS categories 5-6)	3 months
Quality of life assessment on EQ-5D	EQ-5D score	3 months

Collaborators and Investigators

• Sponsor: University of Melbourne

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2023
• Primary Completion (Estimated): August 30, 2027
• Study Completion (Estimated): November 30, 2027

Study Registration Dates

• First Submitted: May 26, 2023
• First Submitted That Met QC Criteria: May 26, 2023
• First Posted (Actual): June 7, 2023

Study Record Updates

• Last Update Posted (Estimated): June 16, 2023
• Last Update Submitted That Met QC Criteria: June 13, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Thrombectomy; No-reflow; Tenecteplase; Fibrinolytic agents
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Stroke; Ischemic Stroke; Nervous System Diseases; Brain Diseases; Cerebrovascular Disorders; Central Nervous System Diseases; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tenecteplase
• Other Study ID Numbers: CT26024

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
• product manufactured in and exported from the U.S.: No