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

PHASE2PHASE3RECRUITING

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).

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

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.
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    Eligibility

    Age eligible for study : 18 and older

    Healthy volunteers accepted : No

    Gender eligible for study: All

    Things to know

    Study dates

    Study start: 2021-11-29

    Primary completion: 2026-08-01

    Study completion finish: 2026-12-01

    study type

    Study type

    TREATMENT

    phase

    Phase

      PHASE2

      PHASE3

    trial

    Trial ID

    NCT05105633

    Intervention or treatment

    DRUG: Tenecteplase

    DRUG: Standard Care (which may include intravenous Alteplase)

    Conditions

    • Basilar Artery Occlusion

    Find a site

    Closest Location:

    John Hunter Hospital

    Research sites nearby

    Select from list below to view details:

    • John Hunter Hospital

      Newcastle, New South Wales, Australia

    • Liverpool Hospital

      Sydney, New South Wales, Australia

    • Princess Alexandra Hospital

      Woolloongabba, Queensland, Australia

    • Royal Adelaide Hospital

      Adelaide, South Australia, Australia

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    Study Plan

    This section provides details of the study plan, including how the study is designed and what the study is measuring.

    How is the study designed?

    Participant Group/ArmIntervention/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.

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    Modified Rankin Scale (mRS) 0-1 or return to baseline mRS at 90 daysModified Rankin Scale (mRS) 0-1 (no disability) or return to baseline mRS (if baseline premorbid mRS 2-3) at 90 days90 days

    Secondary outcome

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    Modified Rankin Scale 0-2 or return to baseline mRS at 90 daysProportion of patients with Modified Rankin Scale 0-2 or return to baseline mRS at 90 days90 days
    Modified Rankin Scale 0-3 or return to baseline mRS at 90 daysProportion of patients with Modified Rankin Scale 0-3 or return to baseline mRS at 90 days90 days
    Ordinal analysis of the mRS at 90 daysOrdinal analysis of the mRS, merging category 5-6, at 90 days90 days
    Early clinical improvementProportion of patients achieving early clinical improvement (reduction in acute - 72 hour NIHSS score of ≥8 or 72 hour NIHSS 0-1).72 hours
    Substantial reperfusion on initial digital subtraction angiography run prior to thrombectomyProportion of patients with complete occlusion at baseline who achieve eTICI 2b/3 on initial digital subtraction angiography run prior to thrombectomy.Initial angiogram (day 0)
    Quality of Life assessment (EQ-5D) - at 90 days and 12 monthsQuality of Life assessment (EQ-5D) - at 90 days and 12 months90 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.36 hours
    All-cause mortality within 90 daysAll-cause mortality within 90 days90 days
    Modified Rankin Scale (mRS) 5-6 at 90 daysProportion of patients with Modified Rankin Scale (mRS) 5-6 at 90 days (severe disability or death)90 days

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    References

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

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