Clinical trial NCT03340493: Determining the Optimal Dose of Tenecteplase Before Endovascular Therapy for Ischaemic Stroke (EXTEND-IA TNK Part 2)
Official title: EXTEND-IA TNK: Extending the Time for Thrombolysis in Emergency Neurological Deficits - Intra-Arterial Using Intravenous Tenecteplase Part 2
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ischemic Stroke
Keywords: 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
Lead sponsor: Neuroscience Trials Australia
Sponsor class: OTHER
Collaborators: name: The Florey Institute of Neuroscience and Mental Health
First posted: 2017-11-13
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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).
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: mTICI
timeFrame: Initial angiogram (day 0)
Secondary outcomes:
measure: Modified Rankin Scale (mRS)
timeFrame: at 3 months post stroke
measure: National Institutes of Health Stroke Scale (NIHSS)
timeFrame: Initial angiogram (day 0)
measure: Symptomatic intracranial haemorrhage (SICH)
timeFrame: Within 36 hours post treatment
measure: Death
timeFrame: Up to 3 months post stroke
measure: Angiographic reperfusion
timeFrame: Up to 24 hours post treatment
Other outcomes:
Locations:
city: Albury
country: Australia
facility: Albury Hospital
state: New South Wales
city: Bankstown
country: Australia
facility: Bankstown-Lidcombe Hospital
state: New South Wales
city: Campbelltown
country: Australia
facility: Campbelltown Hospital
state: New South Wales
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Gosford
country: Australia
facility: Gosford Hospital
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Newcastle
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane & Women's Hospital
state: Queensland
city: Gold Coast
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Nambour
country: Australia
facility: Sunshine Coast University Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Elizabeth Vale
country: Australia
facility: Lyell McEwin Hospital
state: South Australia
city: Ballarat
country: Australia
facility: Ballarat Health Services
state: Victoria
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Shepparton
country: Australia
facility: Goulburn Valley Health
state: Victoria
city: St Albans
country: Australia
facility: Western Heath
state: Victoria
city: Traralgon
country: Australia
facility: Latrobe Regional Hospital
state: Victoria
city: Wangaratta
country: Australia
facility: North East Health Wangaratta
state: Victoria
city: Warrnambool
country: Australia
facility: South West Healthcare
state: Victoria
city: Grafton
country: New Zealand
facility: Auckland Hospital
state: Auckland
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
Study officials:
References:
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citation: Yogendrakumar V, Churilov L, Mitchell PJ, Kleinig TJ, Yassi N, Thijs V, Wu TY, Shah DG, Ng FC, Dewey HM, Wijeratne T, Yan B, Desmond PM, Parsons MW, Donnan GA, Davis SM, Campbell BCV; EXTEND-IA TNK Investigators. Safety and Efficacy of Tenecteplase in Older Patients With Large Vessel Occlusion: A Pooled Analysis of the EXTEND-IA TNK Trials. Neurology. 2022 Mar 22;98(12):e1292-e1301. doi: 10.1212/WNL.0000000000013302. Epub 2022 Jan 11.
citation: Ng FC, Churilov L, Yassi N, Kleinig TJ, Thijs V, Wu T, Shah D, Dewey H, Sharma G, Desmond P, Yan B, Parsons M, Donnan G, Davis S, Mitchell P, Campbell B. Prevalence and Significance of Impaired Microvascular Tissue Reperfusion Despite Macrovascular Angiographic Reperfusion (No-Reflow). Neurology. 2022 Feb 22;98(8):e790-e801. doi: 10.1212/WNL.0000000000013210. Epub 2021 Dec 14.
citation: Alemseged F, Ng FC, Williams C, Puetz V, Boulouis G, Kleinig TJ, Rocco A, Wu TY, Shah D, Arba F, Kaiser D, Di Giuliano F, Morotti A, Sallustio F, Dewey HM, Bailey P, O'Brien B, Sharma G, Bush S, Dowling R, Diomedi M, Churilov L, Yan B, Parsons MW, Davis SM, Mitchell PJ, Yassi N, Campbell BCV; BATMAN study group and EXTEND IA TNK study group. Tenecteplase vs Alteplase Before Endovascular Therapy in Basilar Artery Occlusion. Neurology. 2021 Mar 2;96(9):e1272-e1277. doi: 10.1212/WNL.0000000000011520. Epub 2021 Jan 6.
citation: Campbell BCV, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Dowling RJ, Yan B, Bush SJ, Thijs V, Scroop R, Simpson M, Brooks M, Asadi H, Wu TY, Shah DG, Wijeratne T, Zhao H, Alemseged F, Ng F, Bailey P, Rice H, de Villiers L, Dewey HM, Choi PMC, Brown H, Redmond K, Leggett D, Fink JN, Collecutt W, Kraemer T, Krause M, Cordato D, Field D, Ma H, O'Brien B, Clissold B, Miteff F, Clissold A, Cloud GC, Bolitho LE, Bonavia L, Bhattacharya A, Wright A, Mamun A, O'Rourke F, Worthington J, Wong AA, Levi CR, Bladin CF, Sharma G, Desmond PM, Parsons MW, Donnan GA, Davis SM; EXTEND-IA TNK Part 2 investigators. Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke: The EXTEND-IA TNK Part 2 Randomized Clinical Trial. JAMA. 2020 Apr 7;323(13):1257-1265. doi: 10.1001/jama.2020.1511.
citation: Campbell BC, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Yan B, Thijs V, Desmond PM, Parsons MW, Donnan GA, Davis SM. Determining the optimal dose of tenecteplase before endovascular therapy for ischemic stroke (EXTEND-IA TNK Part 2): A multicenter, randomized, controlled study. Int J Stroke. 2020 Jul;15(5):567-572. doi: 10.1177/1747493019879652. Epub 2019 Sep 30.