Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke (EXTEND-IA TNK)

• ClinicalTrials.gov Identifier: NCT02388061
• Recruitment Status: Completed
• First Posted: March 13, 2015
• Last Update Posted: March 30, 2018
• Sponsor: Neuroscience Trials Australia
• Collaborator: The Florey Institute of Neuroscience and Mental Health
• Information provided by (Responsible Party): Neuroscience Trials Australia

Tracking Information

• First Submitted Date: March 9, 2015
• First Posted Date: March 13, 2015
• Last Update Posted Date: March 30, 2018
• Actual Study Start Date: March 23, 2015
• Actual Primary Completion Date: October 16, 2017 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: June 19, 2017): 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. [ Time Frame: Initial angiogram (day 0) ]
• Original Primary Outcome Measures (submitted: March 9, 2015): Proportion of patients with substantial angiographic reperfusion (assessed as a modified Treatment In Cerebral Ischemia (mTICI) score of 2b/3 (restoration of blood flow to >50% of the affected arterial territory) at initial angiogram. [ Time Frame: Initial angiogram (day 0) ]

Current Secondary Outcome Measures (submitted: June 19, 2017)

• 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. [ Time Frame: Initial angiogram (day 0) ]
• Modified Rankin Scale (mRS) at 3 months [ Time Frame: 3 months post stroke ]
  ordinal analysis
• mRS 0-1 or no change from baseline at 3 months [ Time Frame: 3 months post stroke ]
• mRS 0-2 or no change from baseline at 3 months [ Time Frame: 3 months post stroke ]
• Symptomatic intracranial hemorrhage (SICH) [ Time Frame: within 36 hours post treatment ]
• Death due to any cause [ Time Frame: Up to 3 months post stroke ]
• Proportion of patients with angiographic reperfusion adjusted for hyperdense clot length on non-contrast CT and time from thrombolysis to initial angiogram [ Time Frame: Up to 24 hours post treatment ]

Original Secondary Outcome Measures (submitted: March 9, 2015)

• Proportion of patients with complete angiographic reperfusion (mTICI 3) at initial angiogram. [ Time Frame: Initial angiogram (day 0) ]
• Median percentage reperfusion at 24 hrs post stroke, adjusted for site of occlusion (CT or MR perfusion imaging). [ Time Frame: 24 hours post stroke onset ]
• Favourable clinical response at 3 days [ Time Frame: 3 days post stroke ]
  National Institutes of Health Stroke Score (NIHSS) reduction >/= 8 points or reaching 0-1 at 3 days adjusted for baseline NIHSS and age
• Modified Rankin Scale (mRS) at 3 months [ Time Frame: 3 months post stroke ]
  ordinal analysis
• mRS 0-1 or no change from baseline at 3 months [ Time Frame: 3 months post stroke ]
• mRS 0-2 or no change from baseline at 3 months [ Time Frame: 3 months post stroke ]
• Symptomatic intracranial hemorrhage (SICH) assessed as a large parenchymal hematoma on CT or MR within 36hr of treatment combined with a clinical deterioration of >/= 4 points on the National Institutes of Health Stroke Scale Score (NIHSS) [ Time Frame: within 36 hours post treatment ]
• Death due to any cause [ Time Frame: 3 months post stroke ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke
• Official Title: Extending the Time for Thrombolysis in Emergency Neurological Deficits - Intra-Arterial Using Intravenous Tenecteplase
• Brief Summary: Patients presenting to the emergency department with acute ischemic stroke, who are are eligible for standard intravenous tPA therapy 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 intravenous alteplase or tenecteplase before all participants undergo intra-arterial clot retrieval. The trial is prospective, randomised, open-label, blinded endpoint (PROBE) design.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Ischemic Stroke

Intervention

• Drug: Tenecteplase
  Other Name: TNK
• Drug: Tissue Plasminogen Activator
  Other Names:

  • Alteplase
  • tPA

Study Arms

• Experimental: Intravenous tenecteplase (TNK)
  Patients will receive intravenous tenecteplase (0.25mg/kg, maximum 25mg, administered as a bolus over ~10 seconds).
  Intervention: Drug: Tenecteplase
• Active Comparator: Intravenous tissue plasminogen activator (tPA)
  Patients will receive intravenous t-PA 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.
  Intervention: Drug: Tissue Plasminogen Activator

Publications *

• 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.
• 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.
• 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.
• 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.
• Gao L, Moodie M, Mitchell PJ, Churilov L, Kleinig TJ, Yassi N, Yan B, Parsons MW, Donnan GA, Davis SM, Campbell BCV; EXTEND-IA TNK Investigators. Cost-Effectiveness of Tenecteplase Before Thrombectomy for Ischemic Stroke. Stroke. 2020 Dec;51(12):3681-3689. doi: 10.1161/STROKEAHA.120.029666. Epub 2020 Oct 7.
• Campbell BCV, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Dowling RJ, Yan B, Bush SJ, Dewey HM, Thijs V, Scroop R, Simpson M, Brooks M, Asadi H, Wu TY, Shah DG, Wijeratne T, Ang T, Miteff F, Levi CR, Rodrigues E, Zhao H, Salvaris P, Garcia-Esperon C, Bailey P, Rice H, de Villiers L, Brown H, Redmond K, Leggett D, Fink JN, Collecutt W, Wong AA, Muller C, Coulthard A, Mitchell K, Clouston J, Mahady K, Field D, Ma H, Phan TG, Chong W, Chandra RV, Slater LA, Krause M, Harrington TJ, Faulder KC, Steinfort BS, Bladin CF, Sharma G, Desmond PM, Parsons MW, Donnan GA, Davis SM; EXTEND-IA TNK Investigators. Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. N Engl J Med. 2018 Apr 26;378(17):1573-1582. doi: 10.1056/NEJMoa1716405.
• Campbell BC, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Yan B, Dowling RJ, Bush SJ, Dewey HM, Thijs V, Simpson M, Brooks M, Asadi H, Wu TY, Shah DG, Wijeratne T, Ang T, Miteff F, Levi C, Krause M, Harrington TJ, Faulder KC, Steinfort BS, Bailey P, Rice H, de Villiers L, Scroop R, Collecutt W, Wong AA, Coulthard A, Barber PA, McGuinness B, Field D, Ma H, Chong W, Chandra RV, Bladin CF, Brown H, Redmond K, Leggett D, Cloud G, Madan A, Mahant N, O'Brien B, Worthington J, Parker G, Desmond PM, Parsons MW, Donnan GA, Davis SM; EXTEND-IA TNK Investigators. Tenecteplase versus alteplase before endovascular thrombectomy (EXTEND-IA TNK): A multicenter, randomized, controlled study. Int J Stroke. 2018 Apr;13(3):328-334. doi: 10.1177/1747493017733935. Epub 2017 Sep 27.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 19, 2017): 202
• Original Estimated Enrollment (submitted: March 9, 2015): 64
• Actual Study Completion Date: February 2018
• Actual Primary Completion Date: October 16, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Patients presenting with acute ischemic stroke eligible using standard criteria to receive IV thrombolysis within 4.5 hours of stroke onset
2. Patient's age is ≥18 years
3. Intra-arterial clot retrieval treatment can commence (arterial puncture) within 6 hours of stroke onset.
4. Arterial occlusion on CTA or MRA of the ICA, M1, M2 or basilar artery.

Exclusion Criteria:

1. Intracranial hemorrhage (ICH) identified by CT or MRI
2. Rapidly improving symptoms at the discretion of the investigator
3. Pre-stroke mRS score of ≥ 4 (indicating previous disability)
4. Hypodensity in >1/3 MCA territory or equivalent proportion of basilar artery territory on non-contrast CT
5. Contra indication to imaging with contrast agents
6. Any terminal illness such that patient would not be expected to survive more than 1 year
7. 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.
8. Pregnant women

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, New Zealand

Administrative Information

• NCT Number: NCT02388061
• Other Study ID Numbers: NTA1401
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Neuroscience Trials Australia
• Original Responsible Party: National Stroke Research Institute, Australia
• Current Study Sponsor: Neuroscience Trials Australia
• Original Study Sponsor: National Stroke Research Institute, Australia
• Collaborators: The Florey Institute of Neuroscience and Mental Health
• Investigators: Not Provided
• PRS Account: Neuroscience Trials Australia
• Verification Date: March 2018