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Ischemic StrokePhase 2NCT03340493

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

A Phase 2 study testing Tenecteplase in people with Ischemic Stroke, run by Neuroscience Trials Australia at 28 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Ischemic Stroke
What is being tested?
Tenecteplase
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
300 participants
Where
28 sitesin 2 countries
Study dates
6 Dec 2017to 1 Feb 2020
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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

Trial locations and contacts

28 sites in 2 countries.

28 sites in 2 countries

Australia26 sites

  • Royal Adelaide Hospital

    Adelaide, South Australia, 5000

  • Albury Hospital

    Albury, New South Wales, 2640

  • Ballarat Health Services

    Ballarat, Victoria, 3353

  • Bankstown-Lidcombe Hospital

    Bankstown, New South Wales, 2200

  • Box Hill Hospital

    Box Hill, Victoria, 3128

  • Royal Brisbane & Women's Hospital

    Brisbane, Queensland

  • Campbelltown Hospital

    Campbelltown, New South Wales, 2560

  • Royal Prince Alfred Hospital

    Camperdown, New South Wales, 2050

  • Monash Medical Centre

    Clayton, Victoria, 3168

  • Lyell McEwin Hospital

    Elizabeth Vale, South Australia, 5112

  • Gold Coast University Hospital

    Gold Coast, Queensland

  • Gosford Hospital

    Gosford, New South Wales, 2250

  • Austin Hospital

    Heidelberg, Victoria

  • Liverpool Hospital

    Liverpool, New South Wales, 2170

  • Alfred Hospital

    Melbourne, Victoria, 3004

  • Royal Melbourne Hospital

    Melbourne, Victoria, 3050

  • Sunshine Coast University Hospital

    Nambour, Queensland, 4560

  • John Hunter Hospital

    Newcastle, New South Wales

  • Goulburn Valley Health

    Shepparton, Victoria, 3630

  • Western Heath

    St Albans, Victoria, 3021

  • Royal North Shore Hospital

    St Leonards, New South Wales, 2605

  • Latrobe Regional Hospital

    Traralgon, Victoria, 3844

  • North East Health Wangaratta

    Wangaratta, Victoria, 3677

  • South West Healthcare

    Warrnambool, Victoria, 3280

  • Westmead Hospital

    Westmead, New South Wales, 2145

  • Princess Alexandra Hospital

    Woolloongabba, Queensland, 4102

Other trials in Australia

New Zealand2 sites

  • Christchurch Hospital

    Christchurch, 8011

  • Auckland Hospital

    Grafton, Auckland, 1001

Other trials in New Zealand

About this study

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

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.

Read the 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.

Conditions
Ischemic Stroke
Being tested
Tenecteplase
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
Medical subject headings
Ischemic Stroke, Stroke, Ischemia, Cerebral Infarction, Cerebrovascular Disorders, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TenecteplaseDrug

    Also called TNK

    Tenecteplase 0.25mg/kg and 0.4mg/kg are being used

Study groups in NCT03340493
Study groupRoleWhat they receive
Assigned InterventionsActive comparatorPatients will receive intravenous tenecteplase (0.25mg/kg, maximum 25mg, administered as a bolus over ~10 seconds).
Receives: Drug: Tenecteplase
TenecteplaseExperimentalPatients will receive intravenous tenecteplase (0.4mg/kg, maximum 40mg, administered as a bolus over ~10 seconds).
Receives: Drug: Tenecteplase

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Initial angiogram (day 0)

Secondary outcomes (5)

  1. Modified Rankin Scale (mRS)

    mRS ordinal analysis. mRS 0-1 or no change from baseline and mRS 0-2 or no change from baseline.

    Measured: at 3 months post stroke

  2. 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

    Measured: Initial angiogram (day 0)

  3. 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"

    Measured: Within 36 hours post treatment

  4. Death

    Death due to any cause

    Measured: Up to 3 months post stroke

  5. Angiographic reperfusion

    Proportion of patients with angiographic reperfusion adjusted for hyperdense clot length on non-contrast CT and time from thrombolysis to initial angiogram

    Measured: Up to 24 hours post treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted13 Nov 2017
  2. Study start6 Dec 2017
  3. Primary completion23 Jul 2019
  4. Study completion1 Feb 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
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 blind
Who is masked
Outcomes assessor
Enrolment
300 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03340493
Sponsor's protocol ID
NTA1401a
Status last verified
Mar 2020
First submitted
8 Nov 2017
Last updated
4 Mar 2020
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Yogendrakumar V, Beharry J, Churilov L, Pesavento L, Alidin K, Ugalde M, Weir L, Mitchell PJ, Kleinig TJ, Yassi N, Thijs VN, Wu TY, Brown H, Dewey HM, Wijeratne T, Yan B, Sharma GJ, Desmond P, Parsons MW, Donnan GA, Davis SM, Campbell BCV; EXTEND-IA TNK and Royal Melbourne Stroke Registry Investigators. Association of Time to Thrombolysis With Early Reperfusion After Alteplase and Tenecteplase in Patients With Large Vessel Occlusion. Neurology. 2024 Apr 9;102(7):e209166. doi: 10.1212/WNL.0000000000209166. Epub 2024 Mar 19.

    PubMed 38502892

  • Yogendrakumar V, Churilov L, Mitchell PJ, Kleinig TJ, Yassi N, Thijs V, Wu T, Shah D, Bailey P, Dewey HM, Choi PMC, Ma A, Wijeratne T, Garcia-Esperon C, Cloud G, Chandra RV, Cordato DJ, Yan B, Sharma G, Desmond PM, Parsons MW, Donnan GA, Davis SM, Campbell BCV; EXTEND-IA TNK Investigators. Safety and Efficacy of Tenecteplase and Alteplase in Patients With Tandem Lesion Stroke: A Post Hoc Analysis of the EXTEND-IA TNK Trials. Neurology. 2023 May 2;100(18):e1900-e1911. doi: 10.1212/WNL.0000000000207138. Epub 2023 Mar 6.

    PubMed 36878701

  • Sarraj A, Albers GW, Mitchell PJ, Hassan AE, Abraham MG, Blackburn S, Sharma G, Yassi N, Kleinig TJ, Shah DG, Wu TY, Hussain MS, Tekle WG, Gutierrez SO, Aghaebrahim AN, Haussen DC, Toth G, Pujara D, Budzik RF, Hicks W, Vora N, Edgell RC, Slavin S, Lechtenberg CG, Maali L, Qureshi A, Rosterman L, Abdulrazzak MA, AlMaghrabi T, Shaker F, Mir O, Arora A, Martin-Schild S, Sitton CW, Churilov L, Gupta R, Lansberg MG, Nogueira RG, Grotta JC, Donnan GA, Davis SM, Campbell BCV; SELECT, EXTEND-IA, EXTEND-IA TNK, and EXTEND-IA TNK Part-II Investigators. Thrombectomy Outcomes With General vs Nongeneral Anesthesia: A Pooled Patient-Level Analysis From the EXTEND-IA Trials and SELECT Study. Neurology. 2023 Jan 17;100(3):e336-e347. doi: 10.1212/WNL.0000000000201384. Epub 2022 Oct 26.

    PubMed 36289001

  • 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.

    PubMed 35017305

  • 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.

    PubMed 34906976

  • 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.

    PubMed 33408145

  • 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.

    PubMed 32078683

  • 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.

    PubMed 31564231

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Tenecteplase in people with Ischemic Stroke, run by Neuroscience Trials Australia at 28 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 4 Mar 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 28 sites in Australia, New Zealand. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

mTICI (time frame: Initial angiogram (day 0)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03340493, which also lists 8 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Mar 2020.

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