Tenecteplase in Stroke Patients Between 4.5 and 24 Hours
NCT ID: NCT03785678
Last Updated: 2024-05-22
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
458 participants
INTERVENTIONAL
2019-03-02
2023-02-28
Brief Summary
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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.
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Tenecteplase
Patients in this arm will receive Tenecteplase (0.25 mg/kg, maximum 25 mg) administered as a single bolus injection over 5 seconds.
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
Patients in this arm will receive placebo administered as a single bolus injection over 5 seconds.
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.
Interventions
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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
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.
Eligibility Criteria
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Inclusion Criteria
* 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
* 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
18 Years
ALL
No
Sponsors
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Genentech, Inc.
INDUSTRY
Responsible Party
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Locations
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University of Alabama at Birmingham
Birmingham, Alabama, United States
Banner Desert Medical Center
Mesa, Arizona, United States
Kaiser Permanente - Anaheim (E. La Palma)
Anaheim, California, United States
Mills-Peninsula Medical Center
Burlingame, California, United States
John Muir Health, Concord Medical Center
Concord, California, United States
Sutter Davis Hospital
Davis, California, United States
Kaiser Permanente - Fontana
Fontana, California, United States
Adventist Health Glendale
Glendale, California, United States
Kaiser Permanente South Bay Medical Center
Harbor City, California, United States
UCSD Medical Center - La Jolla
La Jolla, 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 Medical Center
Los Angeles, California, United States
Cedars-Sinai Marina Del Rey Hospital
Marina del Rey, California, United States
Kaiser Permanente - Ontario
Ontario, California, United States
Stanford University Medical Center
Palo Alto, California, United States
Sutter Roseville Medical Center
Roseville, California, United States
Sutter Medical Group, Neurology
Sacramento, California, United States
UCSD - Hillcrest; Hillcrest Medical Center
San Diego, California, United States
CPMC - Van Ness Campus
San Francisco, California, United States
CPMC - Davies Campus
San Francisco, California, United States
Torrance Memorial Medical Center
Torrance, California, United States
John Muir Medical Center-Walnut Creek
Walnut Creek, California, United States
Hartford Hospital
Hartford, Connecticut, United States
University of Florida Health at Shands
Gainesville, Florida, United States
Baptist Medical Center - Jacksonville
Jacksonville, Florida, United States
Baptist Medical Center-South
Jacksonville, Florida, United States
Jackson Memorial Hospital
Miami, Florida, United States
The Queen's Medical Center
Honolulu, Hawaii, United States
Northwestern University
Chicago, Illinois, United States
Advocate Christ Medical Center
Oak Lawn, Illinois, United States
Advocate Lutheran General Hospital
Park Ridge, Illinois, United States
St. Catherine Hospital
East Chicago, Indiana, United States
St. Mary Medical Center
Hobart, Indiana, United States
Community Hospital
Munster, Indiana, United States
Uni of Kansas Medical Center
Kansas City, Kansas, United States
Baptist Health Corbin
Corbin, Kentucky, United States
Baptist Health Lexington
Lexington, Kentucky, United States
Sinai Hospital of Baltimore
Baltimore, Maryland, United States
Johns Hopkins
Baltimore, Maryland, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Univ of Michigan Medical Ctr
Ann Arbor, Michigan, United States
Henry Ford Macomb Hospital - Clinton Township
Clinton Township, Michigan, United States
Henry Ford Hospital
Detroit, Michigan, United States
McLaren Flint
Flint, Michigan, United States
Spectrum Health Hospitals
Grand Rapids, Michigan, United States
ProMedica Monroe Regional Hospital
Monroe, Michigan, United States
Fairview Ridges Hospital
Burnsville, Minnesota, United States
Fairview Southdale
Edina, Minnesota, United States
U of Minnesota MedCtr Fairview
Minneapolis, Minnesota, United States
Sanford Worthington Medical Center
Worthington, Minnesota, United States
Washington University
St Louis, Missouri, United States
JFK Neuroscience Institute
Edison, New Jersey, United States
Atlantic Health System - Overlook Medical Center
Summit, New Jersey, United States
Capital Health Regional Medical Center
Trenton, New Jersey, United States
Buffalo General Medical Center
Buffalo, New York, United States
Columbia University Medical Center
New York, New York, United States
Mission Hospitals Inc
Asheville, North Carolina, United States
Guilford Neurologic Research
Greensboro, North Carolina, United States
Univ of Cincinnati
Cincinnati, Ohio, United States
Cleveland Clinic
Cleveland, Ohio, United States
Riverside Methodist Hospital; Cancer Services
Columbus, Ohio, United States
Grant Medical Center
Columbus, Ohio, United States
Doctors Hospital
Columbus, Ohio, United States
ProMedica Toledo Hospital
Toledo, Ohio, United States
Ascension St. John
Tulsa, Oklahoma, United States
Providence Portland Medical Center
Portland, Oregon, United States
Adventist Health Portland
Portland, Oregon, United States
Providence Saint Vincent's Medical Center
Portland, Oregon, United States
Oregon Health and Science University
Portland, Oregon, United States
UPMC East Hospital
Monroeville, Pennsylvania, United States
Penn Presbyterian Medical Center
Philadelphia, Pennsylvania, United States
Uni of Pennsylvania
Philadelphia, Pennsylvania, United States
Pennsylvania Hospital
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
Rhode Island Hospital
Providence, Rhode Island, United States
Sanford Neurology Clinic
Sioux Falls, South Dakota, United States
Chattanooga Center for Neurologic Research
Chattanooga, Tennessee, 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
Dell Seton Medical center at the University of Texas
Austin, Texas, United States
Seton Medical Center Austin
Austin, Texas, United States
Valley Baptist Medical Center-Brownsville
Brownsville, Texas, United States
Baylor University Medical Center
Dallas, Texas, United States
Valley Baptist Medical Center
Harlingen, Texas, United States
University of Texas at Houston; Neurology
Houston, Texas, United States
Ascension Seton Hays
Kyle, Texas, United States
Ascension Seton Williamson
Round Rock, Texas, United States
University of Texas Health Science Center at San Antonio
San Antonio, Texas, United States
University of Virginia
Charlottesville, Virginia, United States
Uni of Alberta
Edmonton, Alberta, Canada
Hamilton General Hospital; Pharmacy
Hamilton, Ontario, Canada
Montreal Neurological Inst; Clinical Research Unit
Montreal, Quebec, Canada
Countries
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References
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Albers GW, Jumaa M, Purdon B, Zaidi SF, Streib C, Shuaib A, Sangha N, Kim M, Froehler MT, Schwartz NE, Clark WM, Kircher CE, Yang M, Massaro L, Lu XY, Rippon GA, Broderick JP, Butcher K, Lansberg MG, Liebeskind DS, Nouh A, Schwamm LH, Campbell BCV; TIMELESS Investigators. Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection. N Engl J Med. 2024 Feb 22;390(8):701-711. doi: 10.1056/NEJMoa2310392. Epub 2024 Feb 8.
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.
Albers GW, Campbell BC, Lansberg MG, Broderick J, Butcher K, Froehler MT, Schwamm LH, Nouh AM, Liebeskind DS, Toy F, Yang M, Massaro L, Schoeffler M, Purdon B. 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): Rationale and design. Int J Stroke. 2023 Feb;18(2):237-241. doi: 10.1177/17474930221088400. Epub 2022 Apr 1.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Other Identifiers
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ML40787
Identifier Type: -
Identifier Source: org_study_id
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