Tenecteplase in Stroke Patients Between 4.5 and 24 Hours

THROMBOLYSIS Clinical Trial

— TIMELESS  

Official title:

A Phase III, Prospective, Double-blind, Randomized, Placebo-controlled Trial of Thrombolysis in Imaging-eligible, Late-window Patients to Assess the Efficacy and Safety of Tenecteplase (TIMELESS)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03785678
• Other study ID #: ML40787
• Status: Completed
• Phase: Phase 3
• Start date: March 2, 2019
• Est. completion date: February 28, 2023

Study information

• Verified date: May 2024
• Source: Genentech, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will evaluate the efficacy and safety of tenecteplase compared with placebo in participants with acute ischemic stroke (AIS).

All participants will receive standard-of-care therapy according to AmericanHeart Association/American Stroke Association clinical guidelines (2018). To determine eligibility for randomization, all participants will undergo multimodal CT or MRI at baseline. Only participants with a vessel occlusion (ICA or MCA M1/M2) and penumbral tissue will be randomized. The primary analysis is to compare the efficacy of tenecteplase versus placebo in all participants at Day 90.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 458
• Est. completion date: February 28, 2023
• Est. primary completion date: February 28, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patient/legally authorized representative has signed the Informed Consent Form

• Age >= 18 years

• AIS symptom onset within 4.5 to 24 hours Signs and symptoms consistent with the diagnosis of an acute anterior circulation ischemic stroke involving occlusion of the ICA, M1, or M2 vessels

• Functionally independent (mRS 0-2) prior to stroke onset

• Baseline NIHSS >=5 and that remains >=5 immediately prior to randomization

• Neuroimaging: ICA or M1, M2 occlusion (carotid occlusions can be cervical or intracranial, with or without tandem MCA lesions) by magnetic resonance angiography (MRA) or computed tomography angiography (CTA) AND target mismatch profile on CT perfusion or MR perfusion (ischemic core volume <70 mL, mismatch ratio is >=1.8 and mismatch volume is >= 15 mL)

• The mismatch volume is determined by FDA-approved imaging software in real time based on the difference between the ischemic core lesion volume and the Tmax>6s lesion volume. If both a CT perfusion and a multimodal MRI scan are performed prior to enrollment, the later of the 2 scans is assessed to determine eligibility. Only an intracranial MRA is required for patients screened with MRA; cervical MRA is not required. Cervical and intracranial CTA are typically obtained simultaneously in patients screened with CTA, but only the intracranial CTA is required for enrollment.

Alternative neuroimaging:

• If CTA (or MRA) is technically inadequate: Tmax>6s perfusion deficit consistent with an ICA or M1, M2 occlusion AND target mismatch profile (ischemic core volume <70 mL, mismatch ratio >= 1.8 and mismatch volume >= 15 mL as determined by RAPID software)

• If magnetic resonance perfusion (MRP) is technically inadequate: ICA or M1, M2 occlusion (carotid occlusions can be cervical or intracranial; with or without tandem MCA lesions) by MRA (or CTA, if MRA is technically inadequate and a CTA was performed within 60 minutes prior to the MRI) AND diffusion-weighted imaging (DWI) lesion volume <=25 mL for an M1 or ICA occlusion and =<15 mL for an M2 occlusion

• If CTP is technically inadequate: patient can be screened with MRI and randomized if neuroimaging criteria are met.

• Ability to comply with the study protocol, in the investigator's judgment

Exclusion Criteria:

General

• Current participation in another investigational drug or device study

• Active internal bleeding

• Known hypersensitivity or allergy to any ingredients of tenecteplase

• Known bleeding diathesis

• Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency; recent oral anticoagulant therapy with INR >1.7

• Use of one of the new oral anticoagulants within the last 48 hours (dabigatran, rivaroxaban, apixaban, edoxaban)

• Pregnant

• Intracranial neoplasm (except small meningioma), arteriovenous malformation, or aneurysm

• Seizures at stroke onset if it precludes obtaining an accurate baseline NIHSS

• Severe, uncontrolled hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure > 110 mmHg)

• For participants with suspected coagulopathy, platelet count must be checked prior to randomization and participant is excluded if baseline platelet count <100,000/microL

• Baseline blood glucose >400 mg/dL (22.20 mmol/L)

• Baseline blood glucose <50 mg/dL needs to be normalized prior to randomization

• Clot retrieval attempted using a neurothrombectomy device prior to randomization

• Intracranial or intraspinal surgery or trauma within 2 months

• Treatment with a thrombolytic within the last 3 months prior to randomization

• Other serious, advanced, or terminal illness (investigator judgment) with life expectancy less than 6 months

• Pre-existing medical, neurological, or psychiatric disease that would confound the neurological or functional evaluations

• History of cerebrovascular accident in the last 90 days

• Presumed septic embolus; suspicion of bacterial endocarditis

• Any other condition that, in the opinion of the investigator, precludes an endovascular procedure or poses a significant hazard to the patient if an endovascular procedure was to be performed

Imaging

• Unable to undergo a contrast brain perfusion scan with either MRI or CT

• Extensive early ischemic change (hypodensity) on non-contrast CT estimated to be >1/3 MCA territory, or significant hypodensity outside the Tmax>6s perfusion lesion that invalidates mismatch criteria (if patient is enrolled based on CT perfusion criteria)

• Significant mass effect

• Acute symptomatic arterial occlusions in more than one vascular territory confirmed on CTA/MRA (e.g., bilateral MCA occlusions, or an MCA and a basilar artery occlusion)

• Evidence of intracranial tumor (except small meningioma) acute intracranial hemorrhage, neoplasm, or arteriovenous malformation

Related Conditions & MeSH terms

• THROMBOLYSIS

Intervention

Biological:
• Tenecteplase
The investigational medicinal product (IMP) for this study is tenecteplase. The recommended total dose for this study is weight-based with 0.25 mg of tenecteplase per kg, not exceeding a maximum dose of 25 mg. A single bolus dose should be administered over 5 seconds based on patient weight.

Other:
• Placebo
Placebo is being used as the comparator since a thrombolytic is only FDA-approved in the United States for use out to 3 hours, and the standard of care guidelines support use out to 4.5 hours.

Locations

Country	Name	City	State
Canada	Uni of Alberta	Edmonton	Alberta
Canada	Hamilton General Hospital; Pharmacy	Hamilton	Ontario
Canada	Montreal Neurological Inst; Clinical Research Unit	Montreal	Quebec
United States	Kaiser Permanente - Anaheim (E. La Palma)	Anaheim	California
United States	Univ of Michigan Medical Ctr	Ann Arbor	Michigan
United States	Mission Hospitals Inc	Asheville	North Carolina
United States	Dell Seton Medical center at the University of Texas	Austin	Texas
United States	Seton Medical Center Austin	Austin	Texas
United States	Johns Hopkins	Baltimore	Maryland
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Valley Baptist Medical Center-Brownsville	Brownsville	Texas
United States	Buffalo General Medical Center	Buffalo	New York
United States	Mills-Peninsula Medical Center	Burlingame	California
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	University of Virginia	Charlottesville	Virginia
United States	Chattanooga Center for Neurologic Research	Chattanooga	Tennessee
United States	Northwestern University	Chicago	Illinois
United States	Univ of Cincinnati	Cincinnati	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	Henry Ford Macomb Hospital - Clinton Township	Clinton Township	Michigan
United States	Doctors Hospital	Columbus	Ohio
United States	Grant Medical Center	Columbus	Ohio
United States	Riverside Methodist Hospital; Cancer Services	Columbus	Ohio
United States	John Muir Health, Concord Medical Center	Concord	California
United States	Baptist Health Corbin	Corbin	Kentucky
United States	Baylor University Medical Center	Dallas	Texas
United States	Sutter Davis Hospital	Davis	California
United States	Henry Ford Hospital	Detroit	Michigan
United States	St. Catherine Hospital	East Chicago	Indiana
United States	Fairview Southdale	Edina	Minnesota
United States	JFK Neuroscience Institute	Edison	New Jersey
United States	McLaren Flint	Flint	Michigan
United States	Kaiser Permanente - Fontana	Fontana	California
United States	University of Florida Health at Shands	Gainesville	Florida
United States	Adventist Health Glendale	Glendale	California
United States	Spectrum Health Hospitals	Grand Rapids	Michigan
United States	Guilford Neurologic Research	Greensboro	North Carolina
United States	Kaiser Permanente South Bay Medical Center	Harbor City	California
United States	Valley Baptist Medical Center	Harlingen	Texas
United States	Hartford Hospital	Hartford	Connecticut
United States	St. Mary Medical Center	Hobart	Indiana
United States	The Queen's Medical Center	Honolulu	Hawaii
United States	University of Texas at Houston; Neurology	Houston	Texas
United States	Baptist Medical Center - Jacksonville	Jacksonville	Florida
United States	Baptist Medical Center-South	Jacksonville	Florida
United States	Uni of Kansas Medical Center	Kansas City	Kansas
United States	Ascension Seton Hays	Kyle	Texas
United States	UCSD Medical Center - La Jolla	La Jolla	California
United States	Baptist Health Lexington	Lexington	Kentucky
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Kaiser Permanente Los Angeles	Los Angeles	California
United States	University of Southern California Medical Center	Los Angeles	California
United States	Cedars-Sinai Marina Del Rey Hospital	Marina Del Rey	California
United States	Banner Desert Medical Center	Mesa	Arizona
United States	Jackson Memorial Hospital	Miami	Florida
United States	U of Minnesota MedCtr Fairview	Minneapolis	Minnesota
United States	ProMedica Monroe Regional Hospital	Monroe	Michigan
United States	UPMC East Hospital	Monroeville	Pennsylvania
United States	Community Hospital	Munster	Indiana
United States	Saint Thomas Rutherford Hospital	Murfreesboro	Tennessee
United States	Saint Thomas Health	Nashville	Tennessee
United States	Saint Thomas Midtown Hospital	Nashville	Tennessee
United States	Vanderbilt University	Nashville	Tennessee
United States	Columbia University Medical Center	New York	New York
United States	Advocate Christ Medical Center	Oak Lawn	Illinois
United States	Kaiser Permanente - Ontario	Ontario	California
United States	Stanford University Medical Center	Palo Alto	California
United States	Advocate Lutheran General Hospital	Park Ridge	Illinois
United States	Penn Presbyterian Medical Center	Philadelphia	Pennsylvania
United States	Pennsylvania Hospital	Philadelphia	Pennsylvania
United States	Uni of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	UPMC Mercy	Pittsburgh	Pennsylvania
United States	UPMC Passavant Hospital	Pittsburgh	Pennsylvania
United States	Adventist Health Portland	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent's Medical Center	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Sutter Roseville Medical Center	Roseville	California
United States	Ascension Seton Williamson	Round Rock	Texas
United States	Sutter Medical Group, Neurology	Sacramento	California
United States	Washington University	Saint Louis	Missouri
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	UCSD - Hillcrest; Hillcrest Medical Center	San Diego	California
United States	CPMC - Davies Campus	San Francisco	California
United States	CPMC - Van Ness Campus	San Francisco	California
United States	Sanford Neurology Clinic	Sioux Falls	South Dakota
United States	Atlantic Health System - Overlook Medical Center	Summit	New Jersey
United States	ProMedica Toledo Hospital	Toledo	Ohio
United States	Torrance Memorial Medical Center	Torrance	California
United States	Capital Health Regional Medical Center	Trenton	New Jersey
United States	Ascension St. John	Tulsa	Oklahoma
United States	John Muir Medical Center-Walnut Creek	Walnut Creek	California
United States	Sanford Worthington Medical Center	Worthington	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
Genentech, Inc.

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ordinal Modified Rankin Scale (mRS) Score at Day 90	The the modified Rankin score (mRS) is a 6-point scale commonly used to assess disability due to stroke, with higher values indicating worse outcomes.; 0 = No symptoms; = No significant disability; = Slight disability; = Moderate disability; = Moderately severe disability; = Severe disability; = Death	Day 90
Secondary	Proportion of Patients With Functional Independence at Day 90	Functional independence, was defined as an mRS of 0-2 (no symptoms to mild symptoms), at Day 90.	Day 90
Secondary	Proportion of Patients With Recanalization at 24 Hours Post-randomization	This endpoint measured complete or partial recanalization (restored blood flow) on CT angiography (CTA)/magnetic resonance angiography (MRA) post-randomization, defined as complete or partial recanalization on CT angiography (CTA)/magnetic resonance angiography (MRA).	Day 2
Secondary	Proportion of Patients With Reperfusion at 24 Hours Post-randomization	This endpoint was defined by the proportion of participants with reperfusion (the restoration of blood flow to an organ or tissue after having been blocked) at 24 hours post-randomization, defined as > 90% reduction in Tmax > 6s lesion volume.	Day 2
Secondary	Proportion of Patients With Angiographic Reperfusion at Completion of Angiographic Procedure	Angiographic reperfusion was evaluated using the modified Thrombolysis in Cerebral Infarction (TICI) Scale: 0: No perfusion or anterograde flow beyond site of occlusion.; Contrast passes the area of occlusion but fails to opacify the entire cerebral bed distal to the obstruction during angiographic run.; Partial perfusion wherein the contrast passes the occlusion and opacifies the distal arterial bed but rate of entry or clearance from the bed is slower than non-involved territories 2A: < 50% of territory visualized 2B: = 50% of territory is visualized 2C: Near complete perfusion except for slow flow in a few distal cortical vessels or presence of small distal cortical emboli; Complete reperfusion with normal filling.	Day 1
Secondary	Median NIHSS Score at Day 90	The National Institutes of Health Stroke Score (NIHSS) is a 15-item scale that measures neurological deficit in acute stroke patients. Each item is ranked using a 3-, 4-, or 5-point scale, including allowances for items that cannot be scored due to the patient's condition, with higher scores indicating more severe deficit. Total scores range from 0-42, with higher scores indicating more severe deficits.	Day 90
Secondary	Proportion of Patients With a Barthel Index (BI) Score = 95 at Day 90	The Barthel Index (BI) is a 10-item ordinal scale used to measure performance in activities of daily living (ADL) and mobility. The BI scoring range is from 0-100, with lower scores representing greater dependency.	Day 90
Secondary	Proportion of Patients With Good Recovery Based on the Glasgow Outcome Scale (GOS) at Day 90	The Glasgow Outcome Scale (GOS) is a scale used to assess recovery of participants with brain damage. The scale has 5 categories: = Death; = Persistent vegetative state; = Severe disability; = Moderate disability; = Good recovery; The GOS was re-scaled from observed data. For this measure, 1 = good recovery and 5 = death.	Day 90
Secondary	Incidence of Symptomatic Intracranial Hemorrhage (sICH) Within 36 Hours		Within 36 hours (Day 2) of treatment
Secondary	Mortality Rate up to Day 30 and Day 90		Day 30 and Day 90
Secondary	Proportion of Patients With Parenchymal Hematoma Type 2 (PH2) at the 72-96 Hour Visit		Day 3