Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke

Study Overview
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Brief Summary
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The proposed trial is a pragmatic, registry linked, prospective, randomized (1:1) controlled, open-label parallel group clinical trial with blinded endpoint assessment of 1600 patients to test if intravenous tenecteplase (0.25 mg/kg body weight, max dose 25 mg) is non-inferior to intravenous alteplase (0.9 mg/kg body weight) in patients with acute ischemic stroke otherwise eligible for intravenous thrombolysis as per standard care. All patients will have standard of care medical management on an acute stroke unit. There are no additional trial specific management recommendations. Patients will be followed for approximately 90-120 days.

Detailed Description
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There are two established therapies for acute ischemic stroke, namely intravenous alteplase and endovascular thrombectomy (EVT). The guiding principles behind these therapies are fast, effective and safe reperfusion of ischemic brain. Patients with acute ischemic stroke presenting within 4.5 hours from symptom onset are administered intravenous alteplase. If there is evidence of large vessel occlusion (LVO), these patients are transferred to the nearest comprehensive stroke center (CSC) for EVT.Physicians, hospitals and health systems are focused on implementing efficient triaging systems and workflow processes to improve speed and efficacy of administration of these life-saving therapies. Although efforts over the years with intravenous alteplase administration has resulted in improvement in efficiency metrics like door to needle time (DTN) and door-in-door-out (DIDO) time, these metrics are still not optimal, and the therapy is underutilized. Physicians continue to have concerns about low early reperfusion rates, increased risk of symptomatic intracerebral hemorrhage and challenges with drug administration (bolus + 60-minute infusion) with intravenous alteplase. Recent phase II trials have shown that intravenous tenecteplase is potentially safer and may achieve higher early reperfusion rates than alteplase in patients with acute ischemic stroke. Bolus administration makes tenecteplase easier to administer than alteplase (which requires infusion pumps). Transfer of patients from primary stroke centers (PSC) to comprehensive stroke centers (CSCs) is potentially easier without infusion pumps. Moreover, depending on the province, tenecteplase either costs the same, or even less, than alteplase. It is therefore possible that the use of intravenous tenecteplase in patients with acute ischemic stroke otherwise eligible for intravenous alteplase may result in faster administration of thrombolysis and more efficient transport to CSCs, thus saving time, reducing adverse events (intracranial hemorrhage) and potentially improving patient outcomes, while saving the health system costs. For these various reasons, robust evidence that tenecteplase is non-inferior to alteplase as an intravenous thrombolytic agent in patients with acute ischemic stroke will change current clinical practice as it did in patients with myocardial infarction. The proposed trial is therefore a pragmatic, registry linked, prospective, randomized (1:1) controlled, open-label parallel group clinical trial with blinded endpoint assessment of 1600 patients to generate real world evidence whether intravenous tenecteplase (0.25 mg/kg body weight, max dose 25 mg) is non-inferior to intravenous alteplase (0.9 mg/kg body weight) in patients with acute ischemic stroke otherwise eligible for intravenous thrombolysis as per current standard of care.

Official Title
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Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke: QuICR & OPTIMISE Registry Based Pragmatic Randomized Controlled Trial

Conditions
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Stroke, Acute, Thromboses, Intracranial

Intervention / Treatment
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* Drug: Tenecteplase
* Drug: Alteplase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion criteria is pragmatic and informed by Canadian Best Practices. All patients with acute ischemic stroke eligible to receive intravenous alteplase as per standard care will be eligible for enrolment in the proposed trial. Patients eligible for endovascular thrombectomy in addition to intravenous thrombolysis are eligible for enrolment. Exclusion Criteria: Contra-indications to intravenous thrombolysis as used by treating physicians as current standard of care apply. The benefits of thrombolysis with intravenous alteplase in the pediatric population is unknown. Any patient < 18 years of age may therefore not be enrolled. Women with pregnancy known to the investigator by history or examination, without requiring pregnancy testing, may only be enrolled in consultation with an expert stroke physician (either in person or through tele-stroke)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The proposed trial is a pragmatic, registry linked, prospective, randomized (1:1) controlled, open-label parallel group clinical trial with blinded endpoint assessment of 1600 patients to test if intravenous tenecteplase (0.25 mg/kg body weight, max dose 25 mg) is non-inferior to intravenous alteplase (0.9 mg/kg body weight) in patients with acute ischemic stroke otherwise eligible for intravenous thrombolysis as per standard care.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tenecteplase (tNK-TPA)<br>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. Tenecteplase has a longer half-life, is more fibrin specific, produces less systemic depletion of circulating fibrinogen, and is more resistant to plasminogen activator inhibitor than alteplase. | Drug: Tenecteplase<br>* Stroke Thrombolytic<br>* Other names: tNK;|
| Active Comparator: Alteplase ( tPA)<br>The control group will receive standard of care dosing of intravenous alteplase (0.9 mg/kg body weight, 10% bolus and 90% infusion as per standard care, maximum dose 90 mg). | Drug: Alteplase<br>* Stroke Thrombolytic<br>* Other names: tPA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Rankin Scale (mRS) 0-1 (freedom from disability) | The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The mRS is a range from 0-6. 0=No symptoms, 1=No significant disability. Able to carry out all usual activities, despite some symptoms 2=Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.3=Moderate disability. Requires some help, but able to walk unassisted4=Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.5=Severe disability. Requires constant nursing care and attention, bedridden, incontinent.6=Dead | By telephone Follow-up between 90-120 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Discharge Destination | Location where the patient is living at 90-120 days from randomization. Locations include home, early supported discharge, rehabilitation facility, long term care, death. | 90-120 days after randomization | 
| Home Time | Defined as number of days subject spends at home after index stroke event. The home time outcome will be determined through linkage with administrative data to calculate the total time in the first 90 days after index event that a stroke patient is not an inpatient. | 90-120 days after randomization | 
| Door to needle time | Time from when the patient enters the Emergency Room until treatment with either tNK or tPA. Secondary outcome measures described above are all available through the QuICR and OPTIMISE registries and will be collected from those data sources. | Baseline-Day 1 | 
| Door-in-door-out (DIDO) times at Primary Stroke Centres | The amount of time from when the patient enters the Emergency room to the time of discharge from the same hospital is collected. Secondary outcome measures described above are all available through the QuICR and OPTIMISE registries and will be collected from those data sources. | Baseline - Day 1 | 
| Recanalization | Recanalization status (mTICI score) at first angiographic acquisition in patients taken to the angio-suite for the purpose of administering EVT.Secondary outcome measures described above are all available through the QuICR and OPTIMISE registries and will be collected from those data sources. | Baseline- After Randomization- Day 1- | 
| Proportion of patients administered EVT | Patients receiving Endovascular Therapy after being treated with either tNK or tPA.Secondary outcome measures described above are all available through the QuICR and OPTIMISE registries and will be collected from those data sources. | After IV thrombolysis -within the first hour after randomization - baseline-Day 1 | 
| Door-to-groin puncture time in patients undergoing EVT | Patients receiving Endovascular Therapy after being treated with either tNK or tPA-treatment time. Secondary outcome measures described above are all available through the QuICR and OPTIMISE registries and will be collected from those data sources. | During EVT administration-Baseline- after randomization | 
| CT-to-puncture time in patients undergoing EVT | Patients receiving Endovascular Therapy after being treated with either tNK or tPA-treatment time. Secondary outcome measures described above are all available through the QuICR and OPTIMISE registries and will be collected from those data sources. | Before EVT administration- baseline- after Randomization- Day 1 | 
| % patients returning to baseline level of functioning | Patient or surrogate reported return to baseline level of functioning | By telephone Follow-up between 90-120 days |