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ACT-GLOBAL THROMBOLYSIS (ACT-WHEN-001) Domain Within the ACT-GLOBAL Adaptive Platform Trial-NCT06352632 (ACT-WHEN)

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ClinicalTrials.gov Identifier: NCT06320431
Recruitment Status : Not yet recruiting
First Posted : March 20, 2024
Last Update Posted : May 17, 2024
Sponsor:
Collaborator:
The George Institute for Global Health, Australia
Information provided by (Responsible Party):
Dr. Bijoy Menon, University of Calgary

Brief Summary:

This domain has a prospective, randomized, controlled, open-label, parallel group with blinded endpoint assessment (PROBE) design. Up to 4,000 patients with presumed acute ischemic stroke (AIS) will be followed for 90 days (or until death, if prior to 90 days). The end of the trial is defined as the date that all participants have completed their Day 90 assessment.

This domain aim is to efficiently, reliably, and simultaneously, determine the comparative effectiveness of intravenous thrombolysis (IVT) using standard-dose intravenous tenecteplase (0.25 mg/kg body weight), vs. low-dose intravenous tenecteplase (0.18 mg/kg body weight) in all patients who present to hospital with acute ischemic stroke and are considered for intravenous thrombolysis. In addition, this domain also seeks to study standard-dose intravenous tenecteplase (0.25 mg/kg body weight), vs. low-dose intravenous tenecteplase (0.18 mg/kg body weight) vs. no TNK upfront with rescue IA TNK if necessary (in those eligible for emergency EVT) and no TNK upfront in those who have taken DOACs during the preceding 24 hours. This domain therefore seeks to generate more robust randomized evidence to guide clinicians in their decisions over the balance of risks and treatment with intravenous thrombolysis with tenecteplase wherever such evidence is currently insufficient.

This domain will currently evaluate four research questions in relation to the use of IVT with tenecteplase:

  1. In patients with recent (24 hours) intake of a standard-dose direct oral anticoagulant (DOAC), how should IVT be used? - Use standard-dose (0.25 mg/kg body weight) or low-dose tenecteplase (0.18 mg/kg) or not at all.
  2. In patients planned to be treated with endovascular thrombectomy, how should tenecteplase be used? -Treat with IV tenecteplase (standard- or low-dose) or not at all.
  3. In any patient receiving IVT, what is the optimal dose of tenecteplase? - use standard-dose (0.25 mg/kg body weight) or low-dose tenecteplase (0.18 mg/kg).
  4. To what extent is the treatment effect of standard- vs. low-dose tenecteplase modified by key patient characteristics, such as diabetes, prior antiplatelet therapy, renal failure, or frailty, old age or having a heavy burden of cerebral small vessel disease on brain imaging.

Condition or disease Intervention/treatment Phase
Acute Ischemic Stroke AIS Stroke Acute Stroke, Acute, Stroke Ischemic Drug: Tenecteplase Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 4000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Randomization will be stratified by: (1) planned emergency endovascular thrombectomy (EVT) and (2) known use or history to suggest use of a standard-dose direct oral anticoagulant (DOAC) within the last 24 hours. Randomization will be centralized, secure and concealed, using a web-based server and permuted blocks of varying sizes will be used.

This will result in four pre-defined strata: (i) EVT+ / DOAC+ (ii) EVT+ / DOAC- (iii) EVT- / DOAC+ and (iv) EVT- / DOAC-.

Patients in strata 1, 2 and 3 will be randomized to standard-dose IV tenecteplase (0.25 mg/kg body weight) vs. Low-dose tenecteplase (0.18 mg/kg body weight) or no IV thrombolysis (1:1:1 randomization). Patients in strata 4 will be randomized to standard-dose intravenous (IV) tenecteplase (0.25 mg/kg body weight) vs. Low-dose IV tenecteplase (0.18 mg/kg body weight) only (1:1 randomization).

Emergency EVT is defined as anticipated arterial puncture time in the enrolling hospital ≤ 60 minutes from randomization.

Masking: Single (Outcomes Assessor)
Masking Description:

The trial will have allocation concealment and blinded endpoint assessment, but open-label treatment. Given the time sensitive nature of acute stroke treatment, blinding the enrolling personnel to treatment assignment is not practical. Clinical site staff, including the Principal Investigator (PI), sub-investigators, clinic site staff, and the Sponsor will not be blinded to treatment allocated or received. In the event of an emergency the PI will be already unblinded.

The trial will have blinded endpoint assessment on Day 90, with central blinded assessors contacting the participants.

Primary Purpose: Treatment
Official Title: A Multicentre, Prospective, Randomized, Open Label, Blinded-endpoint Trial to Optimize the Use of Intravenous Tenecteplase in Participants With Acute Ischemic Stroke (ACT-GLOBAL THROMBOLYSIS (ACT WHEN-001) Within A Multi-faCtorial, mulTi-arm, Multi-staGe, Randomised, gLOBal Adaptive pLatform Trial for Stroke (ACT-GLOBAL) NCT06352632
Estimated Study Start Date : June 15, 2024
Estimated Primary Completion Date : September 30, 2030
Estimated Study Completion Date : December 31, 2030

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Ischemic Stroke

Arm Intervention/treatment
No Intervention: Standard-dose intravenous tenecteplase (0.25 mg/kg body weight)
The intervention group will receive intravenous tenecteplase as a single bolus as per the standard manufacturers' instructions for use. The dose administered will be 0.25 mg/kg body weight (maximum dose 25 mg) over 10-20 seconds as soon as possible after randomization.
Active Comparator: 2) IVT with tenecteplase at low-dose: 0.18 mg/kg
The intervention group will receive intravenous tenecteplase as a single bolus as per the standard manufacturers' instructions for use. The dose administered will be 0.18 mg/kg body weight (maximum dose 18 mg) over 10-20 seconds as soon as possible after randomization.
Drug: Tenecteplase
Thrombolytic
Other Names:
  • TNKase
  • Metalyse

Active Comparator: 3) No IV thrombolysis [(only in those undergoing EVT or those on DOACs)
No intravenous tenecteplase only applied to subjects on DOACs over the last 24 hours or those planned for emergency EVT
Drug: Tenecteplase
Thrombolytic
Other Names:
  • TNKase
  • Metalyse




Primary Outcome Measures :
  1. A reduction of functional dependence analyzed across the whole distribution of outcomes assessed on the modified Rankin Scale (mRS), [ Time Frame: From enrollment to the Day 90 assessment - Day 90 outcomes are assessed in a blinded manner ]
    Modified Rankin Scale (mRS) -which scores of 0 to 1 indicate a favourable outcome without or with symptoms but no disability, scores of 2 to 5 indicate increasing levels of disability (and dependency), and a score of 6 indicates death.


Secondary Outcome Measures :
  1. 90-day mortality [ Time Frame: From enrollment to the Day 90 assessment. ]
    Date and cause of death are collected from randomization until End of Study.

  2. Proportion of participants with a Modified Rankin Scale (mRS) of 0-1 at Day 90. [ Time Frame: Completed by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner) ]
    Modified Rankin Scale (mRS) -which scores of 0 to 1 indicate a favourable outcome without or with symptoms but no disability, scores of 2 to 5 indicate increasing levels of disability (and dependency), and a score of 6 indicates death.

  3. Proportion of participants with a Modified Rankin Scale (mRS) of 0-2 at Day 90. [ Time Frame: Completed by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner) ]
    Modified Rankin Scale (mRS) -which scores of 0 to 1 indicate a favourable outcome without or with symptoms but no disability, scores of 2 to 5 indicate increasing levels of disability (and dependency), and a score of 6 indicates death.

  4. Health-related quality of life, as measured by the EQ-5D-5L at Day 90. [ Time Frame: Completed by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner) ]
    The EQ-5D-5L is a generic instrument for describing and valuing health. It is based on a descriptive system that defines health in terms of five dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension has five response categories corresponding to: no problems, slight, moderate, severe and extreme problems. The version of the instrument selected for the trial is interviewer administered either in-person, or by telemedicine or by telephone. The respondents will also rate their overall health on the day of the interview on a 0-100 visual analogue scale (EQ-VAS).

  5. The frequencies of Serious Adverse Events (SAEs) from enrollment up to Day 4 [ Time Frame: From enrollment ( randomization) to the Day 4 ]
    Serious Adverse events include the following events :results in death, life threatening,Requires inpatient hospitalization or prolongation of existing hospitalization,Results in persistent disability/incapacity,Is a congenital anomaly/birth defect, an important medical event that may not result in death, be life-threatening, or require hospitalization, but may jeopardize the participant and may require medical or surgical intervention to prevent an outcome listed in the SAE selection.

  6. Symptomatic intracranial hemorrhage [ Time Frame: Up to 36 hours from randomization ]
    Any new intracranial hemorrhage detected by brain imaging associated with neuroligical worsening or deterioration of symptoms.

  7. Large parenchymal hemorrhage (PH-2) [ Time Frame: up to 36 hours from randomization ]
    PH-2:( hemorrhage grading scale) homogeneous hyperdensity occupying over 30% of the infarct zone, with significant mass effect

  8. Ordinal shift of 7 levels of mRS at 90 days [ Time Frame: Done by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner) ]
    Modified Rankin Scale (mRS) -which scores of 0 to 1 indicate a favourable outcome without or with symptoms but no disability, scores of 2 to 5 indicate increasing levels of disability (and dependency), and a score of 6 indicates death.

  9. Proportion of participants achieving first pass (eTICI 2c or higher) reperfusion (when treated with EVT). [ Time Frame: Assessed and evaluated after the EVT procedure by the Central Imaging Core lab by blinded radiologists/stroke neurologists-the imaging reading will be done over the course of the trial through study completion. ]
    The thrombolysis in cerebral infarction (TICI) grading system was described in 2003 by Higashida et al. as a tool for determining the response of thrombolytic therapy for ischemic stroke. In neurointerventional radiology it is commonly used for patients post endovascular revascularization.

  10. Proportion of participants achieving successful recanalization (revised arterial occlusive lesion [rAOL] score of 2b-3) at first angiographic acquisition (when treated with EVT). [ Time Frame: Assessed and evaluated after the EVT procedure by the Central Imaging Core lab by blinded radiologists/stroke neurologists. These imaging readings will be done over the course of the trial through study completion. ]
    The thrombolysis in cerebral infarction (TICI) grading system was described in 2003 by Higashida et al. as a tool for determining the response of thrombolytic therapy for ischemic stroke. In neurointerventional radiology it is commonly used for patients post endovascular revascularization.

  11. Ambulatory status at discharge [ Time Frame: Completed the day the patient is discharged from hospital. ]
    Assessing mobility of the patient at discharge

  12. Place of residence at 90 days [ Time Frame: Completed at the Day 90 follow-up visit ]
    Assessing the patient's residence at the Day 90 follow up. ( example: home,rehabilitation, long term care, remains hospitalized)

  13. Imaging assessment (e.g., infarct size and edema volume) [ Time Frame: Assessed and evaluated by the Central Imaging Core lab by blinded radiologists/stroke neurologists. These imaging readings will be performed over the course of the trial through study completion. ]
    The total absolute infarct volume is the sum of infarct volumes calculated for each slice.

  14. Summative total length of hospital stay in the first 90-days after stroke onset [ Time Frame: Completed at the Day 90 follow-up visit. ]
    Calculating the total number of days the patient was hospitalized since their hospital admission.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. All patients with disabling AIS presenting within 4.5 hours of symptom onset or last known well who may benefit from intravenous thrombolysis (IVT) with tenecteplase. Patients potentially eligible for IVT with conditions described as relative contraindications in national guidelines where physician discretion is recommended are eligible. Patients who received a DOAC, and those planned for emergency EVT are eligible.
  2. Consent process completed as per national laws and regulation and the applicable ethics committee requirements.

Exclusion Criteria:

  1. Any absolute contraindication for IV thrombolysis per current national guidelines. Examples include those who are actively bleeding, had recent intracranial surgery, head trauma, intracranial or subarachnoid hemorrhage, or a bleeding diathesis.
  2. Minor stroke patients with non-disabling symptoms.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT06320431


Contacts
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Contact: Bijoy K Menon, MD 4039448107 bkmmenon@ucalgary.ca
Contact: Craig Anderson, MD 4039448107 canderson@georgeinstitute.org.au

Locations
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Australia, Barangaroo
The George Institute for Global Health
Sydney, Barangaroo, Australia, NSW 2000
Contact: Xiaoying Chen, PHD       xchen@georgeinstitute.org.au   
Principal Investigator: Craig Anderson, MD         
Canada, Alberta
University of Calgary
Calgary, Alberta, Canada, T2N 1N4
Contact: Carol C Kenney, RN    4039444286    ckenney@ucalgary.ca   
Contact: Michael D Hill, MD       michael.hill@ucalgary.ca   
Principal Investigator: Michael D Hill, MD         
Sponsors and Collaborators
University of Calgary
The George Institute for Global Health, Australia
Investigators
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Principal Investigator: Bijoy K Menon, MD University of Calgary
Principal Investigator: Craig Anderson, MD The George Institute
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Responsible Party: Dr. Bijoy Menon, MD, University of Calgary
ClinicalTrials.gov Identifier: NCT06320431    
Other Study ID Numbers: ACT-WHEN-001
First Posted: March 20, 2024    Key Record Dates
Last Update Posted: May 17, 2024
Last Verified: May 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Domain information and tabular trial results will be posted on the National Institutes of Health's website www.clinicaltrials.gov within one year of domain completion.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Dr. Bijoy Menon, University of Calgary:
Stroke
Thrombolysis
Platform
Tenecteplase
Endovascular thrombectomy
EVT
Domain
Additional relevant MeSH terms:
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Stroke
Ischemic Stroke
Ischemia
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Tenecteplase
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action