AcT: Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke

Sponsor

University of Calgary (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03889249

Collaborator

(none)

1,600

Enrollment

Locations

Arms

36.7

Anticipated Duration (Months)

72.7

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Stroke, Acute Thromboses, Intracranial	Drug: Tenecteplase Drug: Alteplase	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

1600 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention 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.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 (Outcomes Assessor)

Masking Description:

90 day outcomes are assessed in a blinded manner

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Dec 10, 2019

Anticipated Primary Completion Date :

Apr 26, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Tenecteplase (tNK-TPA) 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 Stroke Thrombolytic Other Names: tNK
Active Comparator: Alteplase ( tPA) 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 Stroke Thrombolytic Other Names: tPA

Arm

Intervention/Treatment

Active Comparator: Tenecteplase (tNK-TPA)

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

Stroke Thrombolytic

Other Names:

tNK

Active Comparator: Alteplase ( tPA)

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

Stroke Thrombolytic

Other Names:

tPA

Outcome Measures

Primary Outcome Measures

Modified Rankin Scale (mRS) 0-1 (freedom from disability) [By telephone Follow-up between 90-120 days]
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

Secondary Outcome Measures

Discharge Destination [90-120 days after randomization]
Location where the patient is living at 90-120 days from randomization. Locations include home, early supported discharge, rehabilitation facility, long term care, death.
Home Time [90-120 days after randomization]
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.
Door to needle time [Baseline-Day 1]
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.
Door-in-door-out (DIDO) times at Primary Stroke Centres [Baseline - Day 1]
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.
Recanalization [Baseline- After Randomization- Day 1-]
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.
Proportion of patients administered EVT [After IV thrombolysis -within the first hour after randomization - baseline-Day 1]
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.
Door-to-groin puncture time in patients undergoing EVT [During EVT administration-Baseline- after randomization]
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.
CT-to-puncture time in patients undergoing EVT [Before EVT administration- baseline- after Randomization- Day 1]
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.
% patients returning to baseline level of functioning [By telephone Follow-up between 90-120 days]
Patient or surrogate reported return to baseline level of functioning

Other Outcome Measures

Death within 90 days [From Baseline- (Randomization) until Day 90]
Collect if the patient died while in the trial and the cause of death.
Number of Patients Diagnosed with a Symptomatic ICH post-acute stroke treatment by CT/MRI [24 hours days from Baseline- (Randomization)]
Assess any symptomatic ICH related to the tNK or tPA post treatment. AcT defines symptomatic ICH as intracerebral hemorrhage that in the opinion of the investigator is temporally related to and directly responsible for worsening of the neurological condition. While other factors may contribute to neurological worsening, the hemorrhage should, in the investigator's opinion, be the most important factor if there are multiple factors. Thus, the neurological worsening should not be explained better by any other patient condition such as evolution of infarct, hemodynamic alteration, hypoxia etc.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Calgary	Calgary	Alberta	Canada	T2N2T9
2	Grey Nuns Hospital	Edmonton	Alberta	Canada
3	University of Alberta	Edmonton	Alberta	Canada
4	Medicine Hat Regional Hospital	Medicine Hat	Alberta	Canada
5	Red Deer Regional Hospital	Red Deer	Alberta	Canada
6	Kelowna General Hospital	Kelowna	B.C.	Canada
7	Royal Columbian Hospital	New Westminster	British Columbia	Canada
8	Vancouver General Hospital	Vancouver	British Columbia	Canada
9	University of Manitoba	Winnipeg	Manitoba	Canada
10	Halifax Infirmary Queen Elizabeth II	Halifax	Nova Scotia	Canada
11	Hamilton Health Sciences General Hospital	Hamilton	Ontario	Canada
12	Kingston Health Science Centre	Kingston	Ontario	Canada
13	London Health Sciences	London	Ontario	Canada
14	Ottawa Civic Hospital	Ottawa	Ontario	Canada
15	St. Michaels Hospital	Toronto	Ontario	Canada
16	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada
17	Toronto Western Hospital	Toronto	Ontario	Canada
18	Queen Elizabeth Hospital	Charlottetown	PEI	Canada
19	CHUM -Centre Hospitalier de l'Universite de Montreal	Montréal	Quebec	Canada
20	Univerisite Laval-Hopital de l'Enfant-Jesus	Québec	Quebec	Canada
21	Universite de Sherbrooke	Sherbrooke	Quebec	Canada
22	Royal University Hospital	Saskatoon	Saskatchewan	Canada