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

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ClinicalTrials.gov Identifier: NCT03340493
Recruitment Status : Active, not recruiting
First Posted : November 13, 2017
Last Update Posted : August 22, 2019
Sponsor:
Collaborator:
The Florey Institute of Neuroscience and Mental Health
Information provided by (Responsible Party):
Neuroscience Trials Australia

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Ischemic Stroke Drug: Tenecteplase Phase 2

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 188 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Outcomes Assessor)
Masking Description: Blinded core laboratory adjudication of the primary outcome. NIHSS and mRS (secondary outcomes) performed by blinded assessor.
Primary Purpose: Treatment
Official Title: EXTEND-IA TNK: Extending the Time for Thrombolysis in Emergency Neurological Deficits - Intra-Arterial Using Intravenous Tenecteplase Part 2
Actual Study Start Date : December 6, 2017
Actual Primary Completion Date : July 23, 2019
Estimated Study Completion Date : March 1, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Assigned Interventions
Patients will receive intravenous tenecteplase (0.25mg/kg, maximum 25mg, administered as a bolus over ~10 seconds).
Drug: Tenecteplase
Tenecteplase 0.25mg/kg and 0.4mg/kg are being used
Other Name: TNK

Experimental: Tenecteplase
Patients will receive intravenous tenecteplase (0.4mg/kg, maximum 40mg, administered as a bolus over ~10 seconds).
Drug: Tenecteplase
Tenecteplase 0.25mg/kg and 0.4mg/kg are being used
Other Name: TNK




Primary Outcome Measures :
  1. mTICI [ Time Frame: Initial angiogram (day 0) ]
    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.


Secondary Outcome Measures :
  1. Modified Rankin Scale (mRS) [ Time Frame: at 3 months post stroke ]
    mRS ordinal analysis. mRS 0-1 or no change from baseline and mRS 0-2 or no change from baseline.

  2. National Institutes of Health Stroke Scale (NIHSS) [ Time Frame: Initial angiogram (day 0) ]
    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

  3. Symptomatic intracranial haemorrhage (SICH) [ Time Frame: Within 36 hours post treatment ]
    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"

  4. Death [ Time Frame: Up to 3 months post stroke ]
    Death due to any cause

  5. Angiographic reperfusion [ Time Frame: Up to 24 hours post treatment ]
    Proportion of patients with angiographic reperfusion adjusted for hyperdense clot length on non-contrast CT and time from thrombolysis to initial angiogram



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03340493


Locations
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Australia, New South Wales
Albury Hospital
Albury, New South Wales, Australia, 2640
Bankstown-Lidcombe Hospital
Bankstown, New South Wales, Australia, 2200
Campbelltown Hospital
Campbelltown, New South Wales, Australia, 2560
Royal Prince Alfred Hospital
Camperdown, New South Wales, Australia, 2050
Gosford Hospital
Gosford, New South Wales, Australia, 2250
Liverpool Hospital
Liverpool, New South Wales, Australia, 2170
John Hunter Hospital
Newcastle, New South Wales, Australia
Royal North Shore Hospital
St Leonards, New South Wales, Australia, 2605
Westmead Hospital
Westmead, New South Wales, Australia, 2145
Australia, Queensland
Royal Brisbane & Women's Hospital
Brisbane, Queensland, Australia
Gold Coast University Hospital
Gold Coast, Queensland, Australia
Sunshine Coast University Hospital
Nambour, Queensland, Australia, 4560
Princess Alexandra Hospital
Woolloongabba, Queensland, Australia, 4102
Australia, South Australia
Royal Adelaide Hospital
Adelaide, South Australia, Australia, 5000
Lyell McEwin Hospital
Elizabeth Vale, South Australia, Australia, 5112
Australia, Victoria
Ballarat Health Services
Ballarat, Victoria, Australia, 3353
Box Hill Hospital
Box Hill, Victoria, Australia, 3128
Monash Medical Centre
Clayton, Victoria, Australia, 3168
Austin Hospital
Heidelberg, Victoria, Australia
Alfred Hospital
Melbourne, Victoria, Australia, 3004
Royal Melbourne Hospital
Melbourne, Victoria, Australia, 3050
Goulburn Valley Health
Shepparton, Victoria, Australia, 3630
Western Heath
St Albans, Victoria, Australia, 3021
Latrobe Regional Hospital
Traralgon, Victoria, Australia, 3844
North East Health Wangaratta
Wangaratta, Victoria, Australia, 3677
South West Healthcare
Warrnambool, Victoria, Australia, 3280
New Zealand
Auckland Hospital
Grafton, Auckland, New Zealand, 1001
Christchurch Hospital
Christchurch, New Zealand, 8011
Sponsors and Collaborators
Neuroscience Trials Australia
The Florey Institute of Neuroscience and Mental Health

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Responsible Party: Neuroscience Trials Australia
ClinicalTrials.gov Identifier: NCT03340493     History of Changes
Other Study ID Numbers: NTA1401a
First Posted: November 13, 2017    Key Record Dates
Last Update Posted: August 22, 2019
Last Verified: August 2019

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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
Keywords provided by Neuroscience Trials Australia:
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
Additional relevant MeSH terms:
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Stroke
Ischemia
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Plasminogen
Tenecteplase
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action