EXTEND-IA TNK Part 2 Clinical Trial Details
Clinical Trial Details
EXTEND-IA TNK: Extending the Time for Thrombolysis in Emergency Neurological Deficits - Intra-Arterial Using Intravenous Tenecteplase Part 2
The purpose of the trial is to test the hypothesis that 0.40 mg/kg tenecteplase is superior to 0.25 mg/kg tenecteplase in achieving reperfusion at initial angiogram, when administered within 4.5 h of ischemic stroke onset in patients planned to undergo endovascular therapy.
Trial summarized by: Irene L. Llorente, PhD
Content reviewed by: Joe Broderick, MD
TNK 0.4mg/kg did not significantly improve reperfusion or clinical outcomes compared to 0.25mg/kg. Safety also did not differ significantly. The optimal TNK dose for ischemic stroke patients appears to be 0.25mg/kg.
Purpose: To learn if angiogram reperfusion before endovascular thrombectomy for large vessel occlusion ischemic stroke was improved using tenecteplase (TNK) TNK 0.4mg/kg (max 40mg) or 0.25mg/kg (max 25mg).?
Trial Design: phase 2, prospective, multicenter, open-label, randomized 1:1, controlled trial with a blinded endpoint. N= 300. Patients with onset of large vessel ischemic stroke symptoms 0-4.5 hours, randomized before thrombectomy to IV TNK 0.4mg/kg or 0.25mg/kg.
Primary Endpoints: Proportion of patients with an angiographic reperfusion score (mTICI) of 2b/3 (restoration of blood flow to >50% of the affected arterial territory).
|IV TNK Dose||0.4mg/kg (max 40mg)||0.25mg/kg (max 25mg)|
|mTICI pre-thrombectomy (reperfusion)||Both Groups: 19.3%, (29/150), aRR 1.03, P=0.89|
|Return of functional independence (mRS 0-2)||59%||56%|
|aRR 1.08 P=0.40|
|Early neurological improvement
|aRR 1.08 P=0.39
|aRR 1.27 P=0.35|
Results: no difference between the two TNK doses for pre-thrombectomy reperfusion
An improved incidence of pre-endovascular reperfusion would reduce the overall need for endovascular treatment, and reduced time to reperfusion would likely improve patient outcomes.
EXTEND IA TNK Part 2
Bruce Ovbiagele, MD, the immediate past chair for ISC, interviews Bruce Campbell, principal investigator of the EXTEND-IA TNK Part 2 trial, about the results and what they suggest for optimizing acute stroke care.
- TNK 0.4mg/kg did not significantly improve reperfusion or clinical outcomes compared to 0.25mg/kg. Safety also did not differ significantly. The optimal TNK dose for ischemic stroke patients appears to be 0.25mg/kg.
- The number of participants with greater than 50% reperfusion of the previously occluded vascular territory was 29 of 150 (19.3%) in the 0.40mg/kg group vs 29 of 150 (19.3%) in the 0.25mg/kg group (unadjusted risk difference, 0.0%[95%CI, −8.9%to −8.9%]; adjusted risk ratio, 1.03 [95%CI, 0.66-1.61]; P = .89.
- mRS score at 90 days, median (IQR) 2 (0 to 4) 2 (0 to 4) NA Adjusted generalized OR, 0.96 (0.74 to 1.24) .73
- Functional independence (mRS score of 0-2 or no change) 88/150 (59) 84/150 (56) 2.7 (−8.5 to 13.9) Adjusted RR, 1.08 (0.90 to 1.29) .40
- Freedom from disability (mRS score of 0-1 or no change) 74/150 (49) 74/150 (49) 0.0 (−11.3 to 11.3) Adjusted RR, 1.04 (0.84 to 1.29) .69
- Substantial early neurological deficit improvement 102/150 (68) 93/150 (62) 6.0 (−4.8 to 16.8) Adjusted RR, 1.08 (0.91 to 1.27) .39
- Death 26/150 (17) 22/150 (15) 2.7 (−5.6 to 11.0) Adjusted RR, 1.27 (0.77 to 2.11) .35
- Symptomatic intracranial hemorrhage 7/150 (4.7) 2/150 (1.3) 3.3 (−0.5 to 7.2) RR, 3.50 (0.74 to 16.62) .12
- Parenchymal hematoma 4/150 (2.7) 6/150 (4.0) −1.3 (−5.4, 2.7) RR, 0.67 (0.19 to 2.32) .52
Recommended and supporting content:
- Bruce C. Campbell's presentation slides (PDF) from ISC 2020
- Bruce C. Campbell's abstract from ISC 2020
- Article in JAMA: 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
- clinicaltrials.gov: NCT03340493
- Phase 2
- Allocation: Randomized 1:1
- Intervention Model: Parallel Assignment
- Intervention Model Description: Patients will receive either intravenous tenecteplase (0.4mg/kg, maximum 40mg, administered as a bolus over ~5 seconds) or intravenous tenecteplase (0.25mg/kg, maximum 25mg, administered as a bolus over ~5 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
- 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:
- Severe premorbid disability (mRS≥4)
- Contra-indication to imaging with contrast agents
- Rapid neurological recovery (investigator’s discretion) prior to randomization.
- Patients receive either intravenous TNK (Active comparator-0.40 mg/kg, maximum 40 mg or Experimental-0.25 mg/kg, maximum 25 mg) administered as a bolus over ∼5 s.
- 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 intra-cranial thrombus at initial angiogram, adjusted for site of vessel occlusion.
- mRS at three months – ordinal full scale analysis, adjusted for baseline NIHSS and age
- mRS 0–1 at three months or no change from baseline, adjusted for baseline NIHSS and age
- mRS 0–2 at three months or no change from baseline, adjusted for baseline NIHSS and age
- Proportion of patients with ≥8-point reduction in NIHSS or reaching 0–1 at 24 h and three days (early neurological improvement) adjusted for baseline NIHSS and age.
- Death due to any cause, adjusted for baseline NIHSS and age
- Symptomatic intracranial haemorrhage (SICH)
- Parenchymal hematoma
- Proportion of patients with angiographic reperfusion adjusted for hyperdense clot length on non-contrast CT and time from thrombolysis to initial angiogram
- Proportion of patients with excellent angiographic reperfusion (mTICI 2 c/3) at final angiogram, adjusted for site of vessel occlusion.
- Time from thrombolysis initiation to TICI 2 c/3
- Reperfusion at 24 h post-stroke without SICH, adjusted for site of vessel occlusion
- Recanalization at 24 h post stroke, adjusted for site of vessel occlusion
- Ischemic core volume at 24 h, adjusted for baseline core volume
- Median percentage reperfusion at 24 h post stroke, adjusted for site of occlusion.
- Median reduction in stroke severity (NIHSS) at 24 h and day 3
- Home time (number of days spent at home up to day 90)
Sponsors and collaborators— Neuroscience Trials Australia, The Florey Institute of Neuroscience and Mental Health
- Campbell, BCV, Mitchell, PJ, Churilov, L, et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. N Engl J Med 2018; 378: 1573–1582.
- Logallo, N, Novotny, V, Assmus, J, et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial. Lancet Neurol 2017; 16: 781–788.
- Haley, EC, Thompson, JL, Grotta, JC, et al. Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial. Stroke 2010; 41: 707–711.
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.
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