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

Sponsor

Neuroscience Trials Australia (Other)

Overall Status

Completed

CT.gov ID

NCT03340493

Collaborator

The Florey Institute of Neuroscience and Mental Health (Other)

300

Enrollment

Locations

Arms

25.9

Actual Duration (Months)

10.7

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Ischemic Stroke	Drug: Tenecteplase	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

300 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

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).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 (Outcomes Assessor)

Masking Description:

Blinded core laboratory adjudication of the primary outcome. NIHSS and mRS (secondary outcomes) performed by blinded assessor.

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Dec 6, 2017

Actual Primary Completion Date :

Jul 23, 2019

Actual Study Completion Date :

Feb 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Assigned Interventions Patients will receive intravenous tenecteplase (0.25mg/kg, maximum 25mg, administered as a bolus over ~10 seconds).	Drug: Tenecteplase Tenecteplase 0.25mg/kg and 0.4mg/kg are being used Other Names: TNK
Experimental: Tenecteplase Patients will receive intravenous tenecteplase (0.4mg/kg, maximum 40mg, administered as a bolus over ~10 seconds).	Drug: Tenecteplase Tenecteplase 0.25mg/kg and 0.4mg/kg are being used Other Names: TNK

Arm

Intervention/Treatment

Active Comparator: Assigned Interventions

Patients will receive intravenous tenecteplase (0.25mg/kg, maximum 25mg, administered as a bolus over ~10 seconds).

Drug: Tenecteplase

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

Other Names:

TNK

Experimental: Tenecteplase

Patients will receive intravenous tenecteplase (0.4mg/kg, maximum 40mg, administered as a bolus over ~10 seconds).

Drug: Tenecteplase

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

Other Names:

TNK

Outcome Measures

Primary Outcome Measures

mTICI [Initial angiogram (day 0)]
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.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Albury Hospital	Albury	New South Wales	Australia	2640
2	Bankstown-Lidcombe Hospital	Bankstown	New South Wales	Australia	2200
3	Campbelltown Hospital	Campbelltown	New South Wales	Australia	2560
4	Royal Prince Alfred Hospital	Camperdown	New South Wales	Australia	2050
5	Gosford Hospital	Gosford	New South Wales	Australia	2250
6	Liverpool Hospital	Liverpool	New South Wales	Australia	2170
7	John Hunter Hospital	Newcastle	New South Wales	Australia
8	Royal North Shore Hospital	St Leonards	New South Wales	Australia	2605
9	Westmead Hospital	Westmead	New South Wales	Australia	2145
10	Royal Brisbane & Women's Hospital	Brisbane	Queensland	Australia
11	Gold Coast University Hospital	Gold Coast	Queensland	Australia
12	Sunshine Coast University Hospital	Nambour	Queensland	Australia	4560
13	Princess Alexandra Hospital	Woolloongabba	Queensland	Australia	4102
14	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
15	Lyell McEwin Hospital	Elizabeth Vale	South Australia	Australia	5112
16	Ballarat Health Services	Ballarat	Victoria	Australia	3353
17	Box Hill Hospital	Box Hill	Victoria	Australia	3128
18	Monash Medical Centre	Clayton	Victoria	Australia	3168
19	Austin Hospital	Heidelberg	Victoria	Australia
20	Alfred Hospital	Melbourne	Victoria	Australia	3004
21	Royal Melbourne Hospital	Melbourne	Victoria	Australia	3050
22	Goulburn Valley Health	Shepparton	Victoria	Australia	3630
23	Western Heath	St Albans	Victoria	Australia	3021
24	Latrobe Regional Hospital	Traralgon	Victoria	Australia	3844
25	North East Health Wangaratta	Wangaratta	Victoria	Australia	3677
26	South West Healthcare	Warrnambool	Victoria	Australia	3280
27	Auckland Hospital	Grafton	Auckland	New Zealand	1001
28	Christchurch Hospital	Christchurch		New Zealand	8011