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

Key Findings

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.

At-a-glance

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
SECONDARY
Return of functional independence (mRS 0-2)	59%	56%
	aRR 1.08 P=0.40
Early neurological improvement	68%	62%
	aRR 1.08 P=0.39
Death	17%	15%
aRR 1.27 P=0.35

Results: no difference between the two TNK doses for pre-thrombectomy reperfusion

Impression:

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.

Screen capture of Bruce Campbell, MBBS (Hons), BMedSc, PhD and another gentleman conversing

Results

Results:

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.

Primary Endpoint:

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.

Secondary Endpoints:

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

Safety Endpoints:

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:

Background

Trial Design:

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

Trial Population:

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.

Interventions:

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.

Primary Endpoints:

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.

Secondary Endpoints:

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.

Safety Endpoints:

Death due to any cause, adjusted for baseline NIHSS and age
Symptomatic intracranial haemorrhage (SICH)
Parenchymal hematoma

Tertiary Endpoints:

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

References

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.

Key Words

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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