- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03785678
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
Conditions
Intervention / Treatment
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Contact
- Name: Reference Study ID Number: ML40787 https://forpatients.roche.com/
- Phone Number: 888-662-6728 (U.S. and Canada)
- Email: global-roche-genentech-trials@gene.com
Study Locations
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Alberta
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Edmonton, Alberta, Canada, T6G 2G3
- Uni of Alberta
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Ontario
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Hamilton, Ontario, Canada, L8L 2X2
- Hamilton General Hospital; Pharmacy
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Quebec
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Montreal, Quebec, Canada, H3A 2B4
- Montreal Neurological Inst; Clinical Research Unit
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Alabama
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Birmingham, Alabama, United States, 35294-3300
- University of Alabama at Birmingham
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Arizona
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Mesa, Arizona, United States, 85202
- Banner Desert Medical Center
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California
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Anaheim, California, United States, 92806
- Kaiser Permanente - Anaheim (E. La Palma)
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Burlingame, California, United States, 94010
- Mills-Peninsula Medical Center
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Concord, California, United States, 94520
- John Muir Health, Concord Medical Center
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Davis, California, United States, 95616
- Sutter Davis Hospital
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Fontana, California, United States, 92335
- Kaiser Permanente - Fontana
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Glendale, California, United States, 91206
- Adventist Health Glendale
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Harbor City, California, United States, 90710
- Kaiser Permanente South Bay Medical Center
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La Jolla, California, United States, 92037
- UCSD Medical Center - La Jolla
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Los Angeles, California, United States, 90048
- Cedars-Sinai Medical Center
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Los Angeles, California, United States, 90033
- University of Southern California Medical Center
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Los Angeles, California, United States, 90027
- Kaiser Permanente Los Angeles
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Marina Del Rey, California, United States, 90292
- Cedars-Sinai Marina Del Rey Hospital
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Ontario, California, United States, 91761
- Kaiser Permanente - Ontario
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Palo Alto, California, United States, 94304
- Stanford University Medical Center
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Roseville, California, United States, 95661
- Sutter Roseville Medical Center
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Sacramento, California, United States, 95816
- Sutter Medical Group, Neurology
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San Diego, California, United States, 92103
- UCSD - Hillcrest; Hillcrest Medical Center
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San Francisco, California, United States, 94109
- CPMC - Van Ness Campus
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San Francisco, California, United States, 94114
- CPMC - Davies Campus
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Torrance, California, United States, 90505
- Torrance Memorial Medical Center
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Walnut Creek, California, United States, 94598
- John Muir Medical Center-Walnut Creek
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Connecticut
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Hartford, Connecticut, United States, 06102
- Hartford Hospital
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Florida
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Gainesville, Florida, United States, 32608
- University of Florida Health at Shands
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Jacksonville, Florida, United States, 32207-8202
- Baptist Medical Center - Jacksonville
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Jacksonville, Florida, United States, 32258
- Baptist Medical Center-South
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Miami, Florida, United States, 33136
- Jackson Memorial Hospital
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Hawaii
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Honolulu, Hawaii, United States, 96813
- The Queen's Medical Center
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Illinois
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Chicago, Illinois, United States, 60611
- Northwestern University
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Oak Lawn, Illinois, United States, 60453
- Advocate Christ Medical Center
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Park Ridge, Illinois, United States, 60068
- Advocate Lutheran General Hospital
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Indiana
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East Chicago, Indiana, United States, 46312
- St. Catherine Hospital
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Hobart, Indiana, United States, 46432
- St. Mary Medical Center
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Munster, Indiana, United States, 46321
- Community Hospital
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Kansas
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Kansas City, Kansas, United States, 66160
- Uni of Kansas Medical Center
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Kentucky
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Corbin, Kentucky, United States, 40701
- Baptist Health Corbin
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Lexington, Kentucky, United States, 40503
- Baptist Health Lexington
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Maryland
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Baltimore, Maryland, United States, 21215
- Sinai Hospital of Baltimore
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Baltimore, Maryland, United States, 21287
- Johns Hopkins
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Massachusetts
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Boston, Massachusetts, United States, 02114
- Massachusetts General Hospital
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Michigan
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Ann Arbor, Michigan, United States, 48109-0718
- Univ of Michigan Medical Ctr
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Clinton Township, Michigan, United States, 48038
- Henry Ford Macomb Hospital - Clinton Township
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Detroit, Michigan, United States, 48202
- Henry Ford Hospital
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Flint, Michigan, United States, 48532
- McLaren Flint
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Grand Rapids, Michigan, United States, 49503
- Spectrum Health Hospitals
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Monroe, Michigan, United States, 48162
- ProMedica Monroe Regional Hospital
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Minnesota
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Burnsville, Minnesota, United States, 55337
- Fairview Ridges Hospital
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Edina, Minnesota, United States, 55435
- Fairview Southdale
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Minneapolis, Minnesota, United States, 55455
- U of Minnesota MedCtr Fairview
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Worthington, Minnesota, United States, 56187
- Sanford Worthington Medical Center
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Missouri
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Saint Louis, Missouri, United States, 63128
- Washington University
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New Jersey
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Edison, New Jersey, United States, 08820
- JFK Neuroscience Institute
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Summit, New Jersey, United States, 07901
- Atlantic Health System - Overlook Medical Center
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Trenton, New Jersey, United States, 08638
- Capital Health Regional Medical Center
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New York
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Buffalo, New York, United States, 14203
- Buffalo General Medical Center
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New York, New York, United States, 10032
- Columbia University Medical Center
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North Carolina
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Asheville, North Carolina, United States, 28803
- Mission Hospitals Inc
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Greensboro, North Carolina, United States, 27405
- Guilford Neurologic Research
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Ohio
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Cincinnati, Ohio, United States, 45219
- Univ of Cincinnati
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Cleveland, Ohio, United States, 44195
- Cleveland Clinic
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Columbus, Ohio, United States, 43228
- Doctors Hospital
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Columbus, Ohio, United States, 43215
- Grant Medical Center
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Columbus, Ohio, United States, 43214-1419
- Riverside Methodist Hospital; Cancer Services
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Toledo, Ohio, United States, 43606
- ProMedica Toledo Hospital
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Oklahoma
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Tulsa, Oklahoma, United States, 74104
- Ascension St. John
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Oregon
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Portland, Oregon, United States, 97239
- Oregon Health and Science University
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Portland, Oregon, United States, 97213
- Providence Portland Medical Center
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Portland, Oregon, United States, 97225
- Providence Saint Vincent's Medical Center
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Portland, Oregon, United States, 97216
- Adventist Health Portland
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Pennsylvania
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Monroeville, Pennsylvania, United States, 15146
- UPMC East Hospital
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Philadelphia, Pennsylvania, United States, 19104
- Penn Presbyterian Medical Center
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Philadelphia, Pennsylvania, United States, 19107
- Pennsylvania Hospital
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Philadelphia, Pennsylvania, United States, 19104
- Uni of Pennsylvania
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Pittsburgh, Pennsylvania, United States, 15213
- University of Pittsburgh Medical Center
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Pittsburgh, Pennsylvania, United States, 15219
- UPMC Mercy
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Pittsburgh, Pennsylvania, United States, 15237
- UPMC Passavant Hospital
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Rhode Island
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Providence, Rhode Island, United States, 02903
- Rhode Island Hospital
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South Dakota
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Sioux Falls, South Dakota, United States, 57104
- Sanford Neurology Clinic
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Tennessee
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Chattanooga, Tennessee, United States, 37404
- Chattanooga Center for Neurologic Research
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Murfreesboro, Tennessee, United States, 37129
- Saint Thomas Rutherford Hospital
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Nashville, Tennessee, United States, 37232
- Vanderbilt University
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Nashville, Tennessee, United States, 37205
- Saint Thomas Health
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Nashville, Tennessee, United States, 37232
- Saint Thomas Midtown Hospital
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Texas
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Austin, Texas, United States, 78705
- Seton Medical Center Austin
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Austin, Texas, United States, 78701
- Dell Seton Medical Center at The University of Texas
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Brownsville, Texas, United States, 78520
- Valley Baptist Medical Center-Brownsville
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Dallas, Texas, United States, 75231
- Baylor University Medical Center
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Harlingen, Texas, United States, 78550
- Valley Baptist Medical Center
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Houston, Texas, United States, 77030
- University of Texas at Houston; Neurology
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Kyle, Texas, United States, 78640
- Ascension Seton Hays
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Round Rock, Texas, United States, 78665
- Ascension Seton Williamson
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San Antonio, Texas, United States, 78229
- University of Texas Health Science Center at San Antonio
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Virginia
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Charlottesville, Virginia, United States, 22906
- University of Virginia
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
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
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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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.
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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.
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Placebo Comparator: Placebo
Patients in this arm will receive placebo administered as a single bolus injection over 5 seconds.
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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.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Ordinal modified Rankin scale (mRS) score
Time Frame: Day 90
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The Efficacy of Tenecteplase compared to placebo is evaluated in terms of Ordinal mRS score at day 90.
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Day 90
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Proportion of patients with functional independence
Time Frame: Day 90
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The efficacy of Tenecteplase is evaluated in terms of proportion of patients with functional independence, defined as an mRS of 0-2, at Day 90
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Day 90
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Proportion of patients with angiographic reperfusion
Time Frame: Day 1
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The efficacy of Tenecteplase is evaluated in terms of proportion of patients with angiographic reperfusion at completion of angiographic procedure (endovascular patients only).
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Day 1
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Median NIHSS score
Time Frame: Day 90
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The efficacy of Tenecteplase is evaluted in terms of Median NIHSS score at Day 90.
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Day 90
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Proportion of patients with a Barthel Index (BI) score >=95
Time Frame: Day 90
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The efficacy of Tenecteplase is evaluated in terms of Proportion of patients with a BI score >=95 at Day 90.
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Day 90
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Proportion of patients with good recovery based on the Glasgow Outcome Scale (GOS) at Day 90
Time Frame: Day 90
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The efficacy of Tenecteplase is evaluated in terms of the proportion of patients with good recovery based on the GOS at Day 90.
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Day 90
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Proportion of patients with reperfusion at 24 hours post-randomization
Time Frame: Day 2
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The efficacy of Tenecteplase is evaluated in terms of proportion of patients with reperfusion at 24 hours post-randomization, defined as >90% reduction in Tmax>6s lesion volume
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Day 2
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Proportion of patients with recanalization at 24 hours post-randomization
Time Frame: Day 2
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The efficacy of Tenecteplase is evaluated in terms of proportion of patients with recanalization at 24 hours post-randomization, defined as complete or partial recanalization on CT angiography (CTA)/magnetic resonance angiography (MRA).
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Day 2
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Number of patients with symptomatic intracranial hemorrhage (sICH a)
Time Frame: Day 2
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The safety profile of Tenecteplase is evaluated in terms of number of patients with sICH within 36 hours
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Day 2
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Incidence and severity of adverse events
Time Frame: From baseline up to day 90
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The safety profile of Tenecteplase is evaluated in terms of incidence and severity of adverse events.
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From baseline up to day 90
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Mortality rate up to Day 30 and Day 90
Time Frame: Day 30 and Day 90
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The safety profile of Tenecteplase is evaluated in terms of mortality rate up to Day 30 and Day 90
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Day 30 and Day 90
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Proportion of patients with parenchymal hematoma type 2 (PH2) at the 72-96 hour visit
Time Frame: Day 3
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The safety profile of Tenecteplase is evaluated in terms of proportion of patients with PH2 at the 72-96 hour visit
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Day 3
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Collaborators and Investigators
Sponsor
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- ML40787
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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