Extending the Time Window for Tenecteplase by Recanalization of Basilar Artery Occlusion in Posterior Circulation Stroke

Official title

Extending the Time Window for Tenecteplase by Effective RecanalizatioN of bAsilar Artery occLusion in Patients With POSTerior Circulation Stroke (POST-ETERNAL)

Overview

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).

Detailed description

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.

Interventions

• Drug Tenecteplase
  Genetically modified tissue plasminogen activator at a dose of 0.25mg/kg given as an intravenous bolus over 5-10 seconds.
• Drug Standard Care (which may include intravenous Alteplase)
  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.

Primary outcome measures

• Modified Rankin Scale (mRS) 0-1 or return to baseline mRS at 90 days [Time frame: 90 days]

Secondary outcome measures (9)

• 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 [Time frame: 90 days]
• Ordinal analysis of the mRS at 90 days [Time frame: 90 days]
• Early clinical improvement [Time frame: 72 hours]
• Substantial reperfusion 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 [Time frame: 90 days and 12 months]
• Symptomatic intracerebral hemorrhage (sICH) [Time frame: 36 hours]
• All-cause mortality within 90 days [Time frame: 90 days]
• Modified Rankin Scale (mRS) 5-6 at 90 days [Time frame: 90 days]

Eligibility criteria

Inclusion criteria

• Patients presenting with posterior circulation ischemic stroke symptoms due to partial or complete basilar artery occlusion within 24 hours from symptom onset (or clinical deterioration/coma) or the time the patient was last known to be well.
• Patient's age is ≥18 years
• Presence of basilar artery occlusion, proven by CT Angiography or MR Angiography. Basilar artery occlusion is defined as 'potentially retrievable' occlusion at the basilar artery. This can be a partial or complete occlusion.
• Premorbid mRS ≤3 (independent function or requiring only minor domestic assistance and able to manage alone for at least 1 week).
• Local legal requirements for consent have been satisfied.

Exclusion criteria

• Intracerebral hemorrhage (ICH) or other diagnosis (e.g. tumour) identified by baseline imaging.
• Posterior circulation Acute Stroke Prognosis Early CT score (pc-ASPECTS) <7 on non-contrast CT, CT Angiography source images or DWI MRI.
• Significant cerebellar mass effect or acute hydrocephalus.
• Established frank hypodensity on non-contrast CT indicating subacute infarction.
• Bilateral extensive brainstem ischemia.
• Strong suspicion of underlying intracranial atherosclerotic disease (e.g diffuse arterial calcifications, basilar stenosis) or dissection which may require immediate neuro-interventional procedure with intracranial stenting and not benefit from intravenous thrombolysis at investigator's discretion.
• Pre-stroke mRS of ≥4 (indicating moderate to severe previous disability).
• Other standard contraindications to intravenous thrombolysis.
• Contraindication to imaging with contrast agents.
• Clinically evident pregnant women.
• Current participation in another research drug treatment protocol.
• Known terminal illness such that the patients would not be expected to survive a year.
• Planned withdrawal of care or comfort care measures.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Australia · 15 centers

• Bankstown-Lidcombe Hospital — Bankstown
• John Hunter Hospital — Newcastle
• Liverpool Hospital — Sydney
• Gold Coast Hospital — Gold Coast
• Princess Alexandra Hospital — Woolloongabba
• Royal Adelaide Hospital — Adelaide
• Alfred Health — Melbourne
• Austin Hospital — Melbourne
• … and 7 more centers

Brazil · 1 center

• Hospital Geral de Fortaleza — Fortaleza

France · 1 center

• Tours University Hospital — Tours

Identifiers

NCT: NCT05105633 · CT21028

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗