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

Sponsor

University of Melbourne (Other)

Overall Status

Recruiting

CT.gov ID

NCT05105633

Collaborator

(none)

688

Enrollment

Locations

Arms

60.1

Anticipated Duration (Months)

62.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Basilar Artery Occlusion	Drug: Tenecteplase Drug: Standard Care (which may include intravenous Alteplase)	Phase 2/Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

688 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Patients will receive either intravenous tenecteplase (0.25mg/kg, maximum 25mg, administered as a bolus over 5-10 seconds) or standard of care (alteplase 0.9mg/kg or no lysis) +/- mechanical thrombectomyPatients will receive either intravenous tenecteplase (0.25mg/kg, maximum 25mg, administered as a bolus over 5-10 seconds) or standard of care (alteplase 0.9mg/kg or no lysis) +/- mechanical thrombectomy

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Nov 29, 2021

Anticipated Primary Completion Date :

Aug 1, 2026

Anticipated Study Completion Date :

Dec 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Intravenous tenecteplase (TNK) Patients will receive intravenous tenecteplase (0.25mg/kg, maximum 25mg, administered as a bolus over 5-10 seconds).	Drug: Tenecteplase Genetically modified tissue plasminogen activator at a dose of 0.25mg/kg given as an intravenous bolus over 5-10 seconds.
Active Comparator: Standard Care (which may include intravenous Alteplase) Patients will receive standard of care (no intravenous thrombolytic treatment or intravenous alteplase 0.9mg/kg 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).	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.

Arm

Intervention/Treatment

Experimental: Intravenous tenecteplase (TNK)

Patients will receive intravenous tenecteplase (0.25mg/kg, maximum 25mg, administered as a bolus over 5-10 seconds).

Drug: Tenecteplase

Genetically modified tissue plasminogen activator at a dose of 0.25mg/kg given as an intravenous bolus over 5-10 seconds.

Active Comparator: Standard Care (which may include intravenous Alteplase)

Patients will receive standard of care (no intravenous thrombolytic treatment or intravenous alteplase 0.9mg/kg 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).

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.

Outcome Measures

Primary Outcome Measures

Modified Rankin Scale (mRS) 0-1 or return to baseline mRS at 90 days [90 days]
Modified Rankin Scale (mRS) 0-1 (no disability) or return to baseline mRS (if baseline premorbid mRS 2-3) at 90 days

Secondary Outcome Measures

Modified Rankin Scale 0-2 or return to baseline mRS at 90 days [90 days]
Proportion of patients with Modified Rankin Scale 0-2 or return to baseline mRS at 90 days
Modified Rankin Scale 0-3 or return to baseline mRS at 90 days [90 days]
Proportion of patients with Modified Rankin Scale 0-3 or return to baseline mRS at 90 days
Ordinal analysis of the mRS at 90 days [90 days]
Ordinal analysis of the mRS, merging category 5-6, at 90 days
Early clinical improvement [72 hours]
Proportion of patients achieving early clinical improvement (reduction in acute - 72 hour NIHSS score of ≥8 or 72 hour NIHSS 0-1).
Substantial reperfusion on initial digital subtraction angiography run prior to thrombectomy [Initial angiogram (day 0)]
Proportion of patients with complete occlusion at baseline who achieve eTICI 2b/3 on initial digital subtraction angiography run prior to thrombectomy.
Quality of Life assessment (EQ-5D) - at 90 days and 12 months [90 days and 12 months]
Quality of Life assessment (EQ-5D) - at 90 days and 12 months
Symptomatic intracerebral hemorrhage (sICH) [36 hours]
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.
All-cause mortality within 90 days [90 days]
All-cause mortality within 90 days
Modified Rankin Scale (mRS) 5-6 at 90 days [90 days]
Proportion of patients with Modified Rankin Scale (mRS) 5-6 at 90 days (severe disability or death)

Other Outcome Measures

Intermediate outcome (Stage 1): Partial or complete recanalization of the basilar artery without sICH [Initial angiogram (day 0)]
Proportion of patients achieving partial or complete recanalization of the basilar artery on initial digital subtraction angiography (DSA) prior to thrombectomy or repeat CT Angiography (if DSA not performed) without symptomatic intracerebral hemorrhage (sICH). Partial or complete recanalization is defined as reperfusion of ≥50% of the affected territory or absence of retrievable thrombus.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country
1	Bankstown-Lidcombe Hospital	Bankstown	New South Wales	Australia
2	John Hunter Hospital	Newcastle	New South Wales	Australia
3	Liverpool Hospital	Sydney	New South Wales	Australia
4	Gold Coast Hospital	Gold Coast	Queensland	Australia
5	Royal Adelaide Hospital	Adelaide	South Australia	Australia
6	Alfred Health	Melbourne	Victoria	Australia
7	Austin Hospital	Melbourne	Victoria	Australia
8	Box Hill Hospital	Melbourne	Victoria	Australia
9	Monash Health	Melbourne	Victoria	Australia
10	Royal Melbourne Hospital	Melbourne	Victoria	Australia
11	Western Health	Melbourne	Victoria	Australia