Clinical trial NCT05105633: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Basilar Artery Occlusion
Keywords: ischemic stroke
basilar artery occlusion
Stroke
Tenecteplase
Tissue Plasminogen Activator
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Lead sponsor: University of Melbourne
Sponsor class: OTHER
First posted: 2021-11-03
Enrollment: 688
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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 thrombectomy
Primary purpose: TREATMENT

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).

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.

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.

Primary outcomes:
measure: Modified Rankin Scale (mRS) 0-1 or return to baseline mRS at 90 days
timeFrame: 90 days
Secondary outcomes:
measure: Modified Rankin Scale 0-2 or return to baseline mRS at 90 days
timeFrame: 90 days
measure: Modified Rankin Scale 0-3 or return to baseline mRS at 90 days
timeFrame: 90 days
measure: Ordinal analysis of the mRS at 90 days
timeFrame: 90 days
measure: Early clinical improvement
timeFrame: 72 hours
measure: Substantial reperfusion on initial digital subtraction angiography run prior to thrombectomy
timeFrame: Initial angiogram (day 0)
measure: Quality of Life assessment (EQ-5D) - at 90 days and 12 months
timeFrame: 90 days and 12 months
measure: Symptomatic intracerebral hemorrhage (sICH)
timeFrame: 36 hours
measure: All-cause mortality within 90 days
timeFrame: 90 days
measure: Modified Rankin Scale (mRS) 5-6 at 90 days
timeFrame: 90 days
Other outcomes:
measure: Intermediate outcome (Stage 1): Partial or complete recanalization of the basilar artery without sICH
timeFrame: Initial angiogram (day 0)
Locations:
city: Bankstown
country: Australia
facility: Bankstown-Lidcombe Hospital
state: New South Wales
city: Newcastle
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Gold Coast
country: Australia
facility: Gold Coast Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Melbourne
country: Australia
facility: Alfred Health
state: Victoria
city: Melbourne
country: Australia
facility: Austin Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Monash Health
state: Victoria
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Western Health
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
Study officials:
affiliation: University of Melbourne
name: Bruce Campbell
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Melbourne
name: Fana Alemseged
role: PRINCIPAL_INVESTIGATOR
References: