Tenecteplase in Stroke Patients Between 4.5 and 24 Hours (TIMELESS)

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)

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.

Study Overview

• Status: Completed
• Conditions: THROMBOLYSIS
• Intervention / Treatment: Biological: Tenecteplase; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 458
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2G3
      • Uni of Alberta
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Hamilton General Hospital; Pharmacy
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Inst; Clinical Research Unit
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-3300
      • University of Alabama at Birmingham
  • Arizona
    • Mesa, Arizona, United States, 85202
      • Banner Desert Medical Center
  • California
    • Anaheim, California, United States, 92806
      • Kaiser Permanente - Anaheim (E. La Palma)
    • Burlingame, California, United States, 94010
      • Mills-Peninsula Medical Center
    • Concord, California, United States, 94520
      • John Muir Health, Concord Medical Center
    • Davis, California, United States, 95616
      • Sutter Davis Hospital
    • Fontana, California, United States, 92335
      • Kaiser Permanente - Fontana
    • Glendale, California, United States, 91206
      • Adventist Health Glendale
    • Harbor City, California, United States, 90710
      • Kaiser Permanente South Bay Medical center
    • La Jolla, California, United States, 92037
      • UCSD Medical Center - La Jolla
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Los Angeles, California, United States, 90033
      • University of Southern California Medical Center
    • Los Angeles, California, United States, 90027
      • Kaiser Permanente Los Angeles
    • Marina Del Rey, California, United States, 90292
      • Cedars-Sinai Marina Del Rey Hospital
    • Ontario, California, United States, 91761
      • Kaiser Permanente - Ontario
    • Palo Alto, California, United States, 94304
      • Stanford University Medical Center
    • Roseville, California, United States, 95661
      • Sutter Roseville Medical Center
    • Sacramento, California, United States, 95816
      • Sutter Medical Group, Neurology
    • San Diego, California, United States, 92103
      • UCSD - Hillcrest; Hillcrest Medical Center
    • San Francisco, California, United States, 94109
      • CPMC - Van Ness Campus
    • San Francisco, California, United States, 94114
      • CPMC - Davies Campus
    • Torrance, California, United States, 90505
      • Torrance Memorial Medical Center
    • Walnut Creek, California, United States, 94598
      • John Muir Medical Center-Walnut Creek
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Hartford Hospital
  • Florida
    • Gainesville, Florida, United States, 32608
      • University of Florida Health at Shands
    • Jacksonville, Florida, United States, 32207-8202
      • Baptist Medical Center - Jacksonville
    • Jacksonville, Florida, United States, 32258
      • Baptist Medical Center-South
    • Miami, Florida, United States, 33136
      • Jackson Memorial Hospital
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • The Queen's Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Oak Lawn, Illinois, United States, 60453
      • Advocate Christ Medical Center
    • Park Ridge, Illinois, United States, 60068
      • Advocate Lutheran General Hospital
  • Indiana
    • East Chicago, Indiana, United States, 46312
      • St. Catherine Hospital
    • Hobart, Indiana, United States, 46432
      • St. Mary Medical Center
    • Munster, Indiana, United States, 46321
      • Community Hospital
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Uni of Kansas Medical Center
  • Kentucky
    • Corbin, Kentucky, United States, 40701
      • Baptist Health Corbin
    • Lexington, Kentucky, United States, 40503
      • Baptist Health Lexington
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Sinai Hospital of Baltimore
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0718
      • Univ of Michigan Medical Ctr
    • Clinton Township, Michigan, United States, 48038
      • Henry Ford Macomb Hospital - Clinton Township
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Flint, Michigan, United States, 48532
      • McLaren Flint
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health Hospitals
    • Monroe, Michigan, United States, 48162
      • ProMedica Monroe Regional Hospital
  • Minnesota
    • Burnsville, Minnesota, United States, 55337
      • Fairview Ridges Hospital
    • Edina, Minnesota, United States, 55435
      • Fairview Southdale
    • Minneapolis, Minnesota, United States, 55455
      • U of Minnesota MedCtr Fairview
    • Worthington, Minnesota, United States, 56187
      • Sanford Worthington Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63128
      • Washington University
  • New Jersey
    • Edison, New Jersey, United States, 08820
      • JFK Neuroscience Institute
    • Summit, New Jersey, United States, 07901
      • Atlantic Health System - Overlook Medical Center
    • Trenton, New Jersey, United States, 08638
      • Capital Health Regional Medical Center
  • New York
    • Buffalo, New York, United States, 14203
      • Buffalo General Medical Center
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • North Carolina
    • Asheville, North Carolina, United States, 28803
      • Mission Hospitals Inc
    • Greensboro, North Carolina, United States, 27405
      • Guilford Neurologic Research
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Univ of Cincinnati
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43228
      • Doctors Hospital
    • Columbus, Ohio, United States, 43215
      • Grant Medical Center
    • Columbus, Ohio, United States, 43214-1419
      • Riverside Methodist Hospital; Cancer Services
    • Toledo, Ohio, United States, 43606
      • ProMedica Toledo Hospital
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74104
      • Ascension St. John
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center
    • Portland, Oregon, United States, 97225
      • Providence Saint Vincent's Medical Center
    • Portland, Oregon, United States, 97216
      • Adventist Health Portland
  • Pennsylvania
    • Monroeville, Pennsylvania, United States, 15146
      • UPMC East Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Presbyterian Medical Center
    • Philadelphia, Pennsylvania, United States, 19107
      • Pennsylvania Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • Uni of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
    • Pittsburgh, Pennsylvania, United States, 15219
      • UPMC Mercy
    • Pittsburgh, Pennsylvania, United States, 15237
      • UPMC Passavant Hospital
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57104
      • Sanford Neurology Clinic
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Chattanooga Center for Neurologic Research
    • Murfreesboro, Tennessee, United States, 37129
      • Saint Thomas Rutherford Hospital
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University
    • Nashville, Tennessee, United States, 37205
      • Saint Thomas Health
    • Nashville, Tennessee, United States, 37232
      • Saint Thomas Midtown Hospital
  • Texas
    • Austin, Texas, United States, 78705
      • Seton Medical Center Austin
    • Austin, Texas, United States, 78701
      • Dell Seton Medical Center at The University of Texas
    • Brownsville, Texas, United States, 78520
      • Valley Baptist Medical Center-Brownsville
    • Dallas, Texas, United States, 75231
      • Baylor University Medical Center
    • Harlingen, Texas, United States, 78550
      • Valley Baptist Medical Center
    • Houston, Texas, United States, 77030
      • University of Texas at Houston; Neurology
    • Kyle, Texas, United States, 78640
      • Ascension Seton Hays
    • Round Rock, Texas, United States, 78665
      • Ascension Seton Williamson
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio
  • Virginia
    • Charlottesville, Virginia, United States, 22906
      • University of Virginia

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tenecteplase; Patients in this arm will receive Tenecteplase (0.25 mg/kg, maximum 25 mg) administered as a single bolus injection over 5 seconds.	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.
Placebo Comparator: Placebo; Patients in this arm will receive placebo administered as a single bolus injection over 5 seconds.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
Incidence of Symptomatic Intracranial Hemorrhage (sICH) Within 36 Hours		Within 36 hours (Day 2) of treatment
Mortality Rate up to Day 30 and Day 90		Day 30 and Day 90
Proportion of Patients With Parenchymal Hematoma Type 2 (PH2) at the 72-96 Hour Visit		Day 3

Collaborators and Investigators

• Sponsor: Genentech, Inc.

Publications and helpful links

General Publications

• Zachrison KS, Amati V, Schwamm LH, Yan Z, Nielsen V, Christie A, Reeves MJ, Sauser JP, Lomi A, Onnela JP. Influence of Hospital Characteristics on Hospital Transfer Destinations for Patients With Stroke. Circ Cardiovasc Qual Outcomes. 2022 May;15(5):e008269. doi: 10.1161/CIRCOUTCOMES.121.008269. Epub 2022 Apr 4.

Study record dates

Study Major Dates

• Study Start (Actual): March 2, 2019
• Primary Completion (Actual): February 28, 2023
• Study Completion (Actual): February 28, 2023

Study Registration Dates

• First Submitted: December 19, 2018
• First Submitted That Met QC Criteria: December 20, 2018
• First Posted (Actual): December 24, 2018

Study Record Updates

• Last Update Posted (Actual): May 22, 2024
• Last Update Submitted That Met QC Criteria: May 20, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tenecteplase
• Other Study ID Numbers: ML40787

Drug and device information, study documents

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