Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke (AcT)

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

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.

Study Overview

• Status: Completed
• Conditions: Stroke, Acute; Thromboses, Intracranial
• Intervention / Treatment: Drug: Tenecteplase; Drug: Alteplase

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 Type: Interventional
• Enrollment (Actual): 1600
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N2T9
      • University of Calgary
    • Edmonton, Alberta, Canada
      • University of Alberta
    • Edmonton, Alberta, Canada
      • Grey Nuns Hospital
    • Medicine Hat, Alberta, Canada
      • Medicine Hat Regional Hospital
    • Red Deer, Alberta, Canada
      • Red Deer Regional Hospital
  • B.C.
    • Kelowna, B.C., Canada
      • Kelowna General Hospital
  • British Columbia
    • New Westminster, British Columbia, Canada
      • Royal Columbian Hospital
    • Vancouver, British Columbia, Canada
      • Vancouver General Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada
      • University of Manitoba
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
      • Halifax Infirmary Queen Elizabeth II
  • Ontario
    • Hamilton, Ontario, Canada
      • Hamilton Health Sciences General Hospital
    • Kingston, Ontario, Canada
      • Kingston Health Science Centre
    • London, Ontario, Canada
      • London Health Sciences
    • Ottawa, Ontario, Canada
      • Ottawa Civic Hospital
    • Toronto, Ontario, Canada
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada
      • Toronto Western Hospital
    • Toronto, Ontario, Canada
      • St. Michaels Hospital
  • PEI
    • Charlottetown, PEI, Canada
      • Queen Elizabeth Hospital
  • Quebec
    • Montréal, Quebec, Canada
      • CHUM -Centre Hospitalier de l'Universite de Montreal
    • Québec, Quebec, Canada
      • Univerisite Laval-Hopital de l'Enfant-Jesus
    • Sherbrooke, Quebec, Canada
      • Université de Sherbrooke
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada
      • Royal University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death within 90 days	Collect if the patient died while in the trial and the cause of death.	From Baseline- (Randomization) until Day 90
Number of Patients Diagnosed with a Symptomatic ICH post-acute stroke treatment by CT/MRI	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.	24 hours days from Baseline- (Randomization)

Collaborators and Investigators

• Sponsor: University of Calgary
• Investigators: Principal Investigator: Bijoy K Menon, MD, University of Calgary

Publications and helpful links

General Publications

• Menon BK, Buck BH, Singh N, Deschaintre Y, Almekhlafi MA, Coutts SB, Thirunavukkarasu S, Khosravani H, Appireddy R, Moreau F, Gubitz G, Tkach A, Catanese L, Dowlatshahi D, Medvedev G, Mandzia J, Pikula A, Shankar J, Williams H, Field TS, Manosalva A, Siddiqui M, Zafar A, Imoukhuede O, Hunter G, Demchuk AM, Mishra S, Gioia LC, Jalini S, Cayer C, Phillips S, Elamin E, Shoamanesh A, Subramaniam S, Kate M, Jacquin G, Camden MC, Benali F, Alhabli I, Bala F, Horn M, Stotts G, Hill MD, Gladstone DJ, Poppe A, Sehgal A, Zhang Q, Lethebe BC, Doram C, Ademola A, Shamy M, Kenney C, Sajobi TT, Swartz RH; AcT Trial Investigators. Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial. Lancet. 2022 Jul 16;400(10347):161-169. doi: 10.1016/S0140-6736(22)01054-6. Epub 2022 Jun 29.

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2019
• Primary Completion (Actual): April 26, 2022
• Study Completion (Actual): April 30, 2023

Study Registration Dates

• First Submitted: March 20, 2019
• First Submitted That Met QC Criteria: March 21, 2019
• First Posted (Actual): March 26, 2019

Study Record Updates

• Last Update Posted (Actual): May 12, 2023
• Last Update Submitted That Met QC Criteria: May 11, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Embolism and Thrombosis; Intracranial Embolism and Thrombosis; Thromboembolism; Stroke; Ischemic Stroke; Thrombosis; Intracranial Thrombosis; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tissue Plasminogen Activator; Tenecteplase
• Other Study ID Numbers: Version 2.0 (Sponsor assigned)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No