Patients presenting to the emergency department with an acute ischemic stroke due to basilar artery occlusion within 24 hours of stroke onset will be assessed to determine their eligibility for randomization into the trial. If the patient gives informed consent they will be randomised 50:50 using a central computerised allocation process to either standard of care (no intravenous thrombolytic treatment or intravenous alteplase 0.9mg/kg) or tenecteplase 0.25mg/kg before undergoing mechanical thrombectomy as required at treating clinician's discretion. The trial is Multi-arm, Multi-stage, prospective, randomised, open-label, blinded endpoint (PROBE) design with seamless phase 2b/3 transition if the intermediate endpoint (recanalization without symptomatic intracerebral hemorrhage) is met in analysis of the first 202 patients. Adaptive sample size re-estimation (Mehta and Pocock) will be performed when 240 patients have completed 3 month follow-up (minimum sample size 320, maximum sample size 688).
The study is a Multi-Arm Multi-Stage (MAMS), multiregional, multicentre, prospective, randomised, open-label, blinded endpoint (PROBE), controlled seamless phase 2b/3 trial (2 arm with 1:1 randomisation) with adaptive sample size recalculation in patients with stroke due to basilar artery occlusion. Stage 1 will use the surrogate outcome of recanalization without symptomatic intracerebral hemorrhage (sICH) to establish whether proceeding to Stage 2 is warranted. If results in the first n= 202 patients meet success criteria, the trial will seamlessly convert to a phase 3 design using modified Rankin scale 0-1 at 3 months as the primary outcome (minimum n=320 with interim sample size re-estimation at n=240, maximum sample n=688) using the Mehta and Pocock conditional power method. Each regionally-based stratum will be pooled in the final analysis and analysed as a stratification by geographic region. Randomisation of patients within each stratum will be stratified by the investigator's intention to treat with mechanical thrombectomy (or not) and the investigator's intention to treat with alteplase intravenous thrombolysis should the patient be randomised to the control group (or not). Covariate adjusted minimum sufficient balance randomisation will then be applied to control for age, NIHSS and time from onset-to-randomisation (dichotomized as 0-6 hours vs 6-24 hours). The primary objective of the study is to test the hypothesis that the thrombolytic tenecteplase (TNK, 0.25mg/kg) ± mechanical thrombectomy administered within 24 hours after symptoms onset, is superior to current best practice (alteplase, rtPA, 0.9mg/kg or standard care/no lysis ± mechanical thrombectomy) in achieving excellent functional outcome (mRS 0-1) or return to the premorbid modified Rankin Scale at 90 days in patients with acute ischemic stroke due to basilar artery occlusion. Estimated study duration is 5 years. Patients will participate in the trial for 12 months.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
688
Genetically modified tissue plasminogen activator at a dose of 0.25mg/kg given as an intravenous bolus over 5-10 seconds.
Patients will receive standard care which may include intravenous alteplase at the standard licensed dose of 0.9 mg/kg up to a maximum of 90mg, 10% as a bolus and the remainder as an infusion over 1 hour.
Bankstown-Lidcombe Hospital
Bankstown, New South Wales, Australia
NOT_YET_RECRUITINGJohn Hunter Hospital
Newcastle, New South Wales, Australia
NOT_YET_RECRUITINGLiverpool Hospital
Sydney, New South Wales, Australia
NOT_YET_RECRUITINGGold Coast Hospital
Gold Coast, Queensland, Australia
NOT_YET_RECRUITINGPrincess Alexandra Hospital
Woolloongabba, Queensland, Australia
RECRUITINGRoyal Adelaide Hospital
Adelaide, South Australia, Australia
RECRUITINGAlfred Health
Melbourne, Victoria, Australia
RECRUITINGAustin Hospital
Melbourne, Victoria, Australia
NOT_YET_RECRUITINGBox Hill Hospital
Melbourne, Victoria, Australia
RECRUITINGMonash Health
Melbourne, Victoria, Australia
NOT_YET_RECRUITING...and 3 more locations
Modified Rankin Scale (mRS) 0-1 or return to baseline mRS at 90 days
Modified Rankin Scale (mRS) 0-1 (no disability) or return to baseline mRS (if baseline premorbid mRS 2-3) at 90 days
Time frame: 90 days
Modified Rankin Scale 0-2 or return to baseline mRS at 90 days
Proportion of patients with Modified Rankin Scale 0-2 or return to baseline mRS at 90 days
Time frame: 90 days
Modified Rankin Scale 0-3 or return to baseline mRS at 90 days
Proportion of patients with Modified Rankin Scale 0-3 or return to baseline mRS at 90 days
Time frame: 90 days
Ordinal analysis of the mRS at 90 days
Ordinal analysis of the mRS, merging category 5-6, at 90 days
Time frame: 90 days
Early clinical improvement
Proportion of patients achieving early clinical improvement (reduction in acute - 72 hour NIHSS score of ≥8 or 72 hour NIHSS 0-1).
Time frame: 72 hours
Substantial reperfusion on initial digital subtraction angiography run prior to thrombectomy
Proportion of patients with complete occlusion at baseline who achieve eTICI 2b/3 on initial digital subtraction angiography run prior to thrombectomy.
Time frame: Initial angiogram (day 0)
Quality of Life assessment (EQ-5D) - at 90 days and 12 months
Quality of Life assessment (EQ-5D) - at 90 days and 12 months
Time frame: 90 days and 12 months
Symptomatic intracerebral hemorrhage (sICH)
Proportion of patients with sICH defined as parenchymal hemorrhage type 2 (PH2), subarachnoid hemorrhage, and/or intraventricular hemorrhage within 36 of treatment, combined with a neurological deterioration of ≥4 points on the NIHSS from baseline, or leading to death.
Time frame: 36 hours
All-cause mortality within 90 days
All-cause mortality within 90 days
Time frame: 90 days
Modified Rankin Scale (mRS) 5-6 at 90 days
Proportion of patients with Modified Rankin Scale (mRS) 5-6 at 90 days (severe disability or death)
Time frame: 90 days
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