Clinical trial NCT03889249: Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke
Official title: Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke: QuICR & OPTIMISE Registry Based Pragmatic Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Stroke, Acute
Thromboses, Intracranial
Lead sponsor: University of Calgary
Sponsor class: OTHER
First posted: 2019-03-26
Enrollment: 1600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Modified Rankin Scale (mRS) 0-1 (freedom from disability)
timeFrame: By telephone Follow-up between 90-120 days
Secondary outcomes:
measure: Discharge Destination
timeFrame: 90-120 days after randomization
measure: Home Time
timeFrame: 90-120 days after randomization
measure: Door to needle time
timeFrame: Baseline-Day 1
measure: Door-in-door-out (DIDO) times at Primary Stroke Centres
timeFrame: Baseline - Day 1
measure: Recanalization
timeFrame: Baseline- After Randomization- Day 1-
measure: Proportion of patients administered EVT
timeFrame: After IV thrombolysis -within the first hour after randomization - baseline-Day 1
measure: Door-to-groin puncture time in patients undergoing EVT
timeFrame: During EVT administration-Baseline- after randomization
measure: CT-to-puncture time in patients undergoing EVT
timeFrame: Before EVT administration- baseline- after Randomization- Day 1
measure: % patients returning to baseline level of functioning
timeFrame: By telephone Follow-up between 90-120 days
Other outcomes:
measure: Death within 90 days
timeFrame: From Baseline- (Randomization) until Day 90
measure: Number of Patients Diagnosed with a Symptomatic ICH post-acute stroke treatment by CT/MRI
timeFrame: 24 hours days from Baseline- (Randomization)
Locations:
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: Grey Nuns Hospital
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Medicine Hat
country: Canada
facility: Medicine Hat Regional Hospital
state: Alberta
city: Red Deer
country: Canada
facility: Red Deer Regional Hospital
state: Alberta
city: Kelowna
country: Canada
facility: Kelowna General Hospital
state: B.C.
city: New Westminster
country: Canada
facility: Royal Columbian Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: University of Manitoba
state: Manitoba
city: Halifax
country: Canada
facility: Halifax Infirmary Queen Elizabeth II
state: Nova Scotia
city: Hamilton
country: Canada
facility: Hamilton Health Sciences General Hospital
state: Ontario
city: Kingston
country: Canada
facility: Kingston Health Science Centre
state: Ontario
city: London
country: Canada
facility: London Health Sciences
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Civic Hospital
state: Ontario
city: Toronto
country: Canada
facility: St. Michaels Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Toronto Western Hospital
state: Ontario
city: Charlottetown
country: Canada
facility: Queen Elizabeth Hospital
state: PEI
city: Montréal
country: Canada
facility: CHUM -Centre Hospitalier de l'Universite de Montreal
state: Quebec
city: Québec
country: Canada
facility: Univerisite Laval-Hopital de l'Enfant-Jesus
state: Quebec
city: Sherbrooke
country: Canada
facility: Universite de Sherbrooke
state: Quebec
city: Saskatoon
country: Canada
facility: Royal University Hospital
state: Saskatchewan
Study officials:
affiliation: University of Calgary
name: Bijoy K Menon, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.