Determining the Optimal Dose of Tenecteplase Before Endovascular Therapy for Ischaemic Stroke (EXTEND-IA TNK Part 2)
- Registration Number
- NCT03340493
- Lead Sponsor
- Neuroscience Trials Australia
- 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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 300
- 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.
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Assigned Interventions Tenecteplase Patients will receive intravenous tenecteplase (0.25mg/kg, maximum 25mg, administered as a bolus over \~10 seconds). Tenecteplase Tenecteplase Patients will receive intravenous tenecteplase (0.4mg/kg, maximum 40mg, administered as a bolus over \~10 seconds).
- Primary Outcome Measures
Name Time Method 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
Name Time Method 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
Death Up to 3 months post stroke Death due to any cause
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"
Trial Locations
- Locations (28)
Ballarat Health Services
🇦🇺Ballarat, Victoria, Australia
Austin Hospital
🇦🇺Heidelberg, Victoria, Australia
Albury Hospital
🇦🇺Albury, New South Wales, Australia
Latrobe Regional Hospital
🇦🇺Traralgon, Victoria, Australia
Gosford Hospital
🇦🇺Gosford, New South Wales, Australia
Campbelltown Hospital
🇦🇺Campbelltown, New South Wales, Australia
Royal Prince Alfred Hospital
🇦🇺Camperdown, New South Wales, Australia
Liverpool Hospital
🇦🇺Liverpool, New South Wales, Australia
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
Princess Alexandra Hospital
🇦🇺Woolloongabba, Queensland, Australia
Bankstown-Lidcombe Hospital
🇦🇺Bankstown, New South Wales, Australia
John Hunter Hospital
🇦🇺Newcastle, New South Wales, Australia
Royal North Shore Hospital
🇦🇺St Leonards, New South Wales, Australia
Lyell McEwin Hospital
🇦🇺Elizabeth Vale, South Australia, Australia
Gold Coast University Hospital
🇦🇺Gold Coast, Queensland, Australia
Sunshine Coast University Hospital
🇦🇺Nambour, Queensland, Australia
Box Hill Hospital
🇦🇺Box Hill, Victoria, Australia
Monash Medical Centre
🇦🇺Clayton, Victoria, Australia
Alfred Hospital
🇦🇺Melbourne, Victoria, Australia
Royal Melbourne Hospital
🇦🇺Melbourne, Victoria, Australia
Goulburn Valley Health
🇦🇺Shepparton, Victoria, Australia
North East Health Wangaratta
🇦🇺Wangaratta, Victoria, Australia
Western Heath
🇦🇺St Albans, Victoria, Australia
South West Healthcare
🇦🇺Warrnambool, Victoria, Australia
Auckland Hospital
🇳🇿Grafton, Auckland, New Zealand
Christchurch Hospital
🇳🇿Christchurch, New Zealand
Westmead Hospital
🇦🇺Westmead, New South Wales, Australia
Royal Brisbane & Women's Hospital
🇦🇺Brisbane, Queensland, Australia