Clinical trial NCT03785678: Tenecteplase in Stroke Patients Between 4.5 and 24 Hours
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: THROMBOLYSIS
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2018-12-24
Enrollment: 458
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: Ordinal Modified Rankin Scale (mRS) Score at Day 90
timeFrame: Day 90
Secondary outcomes:
measure: Proportion of Patients With Functional Independence at Day 90
timeFrame: Day 90
measure: Proportion of Patients With Recanalization at 24 Hours Post-randomization
timeFrame: Day 2
measure: Proportion of Patients With Reperfusion at 24 Hours Post-randomization
timeFrame: Day 2
measure: Proportion of Patients With Angiographic Reperfusion at Completion of Angiographic Procedure
timeFrame: Day 1
measure: Median NIHSS Score at Day 90
timeFrame: Day 90
measure: Proportion of Patients With a Barthel Index (BI) Score ≥ 95 at Day 90
timeFrame: Day 90
measure: Proportion of Patients With Good Recovery Based on the Glasgow Outcome Scale (GOS) at Day 90
timeFrame: Day 90
measure: Incidence of Symptomatic Intracranial Hemorrhage (sICH) Within 36 Hours
timeFrame: Within 36 hours (Day 2) of treatment
measure: Mortality Rate up to Day 30 and Day 90
timeFrame: Day 30 and Day 90
measure: Proportion of Patients With Parenchymal Hematoma Type 2 (PH2) at the 72-96 Hour Visit
timeFrame: Day 3
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Mesa
country: United States
facility: Banner Desert Medical Center
state: Arizona
city: Anaheim
country: United States
facility: Kaiser Permanente - Anaheim (E. La Palma)
state: California
city: Burlingame
country: United States
facility: Mills-Peninsula Medical Center
state: California
city: Concord
country: United States
facility: John Muir Health, Concord Medical Center
state: California
city: Davis
country: United States
facility: Sutter Davis Hospital
state: California
city: Fontana
country: United States
facility: Kaiser Permanente - Fontana
state: California
city: Glendale
country: United States
facility: Adventist Health Glendale
state: California
city: Harbor City
country: United States
facility: Kaiser Permanente South Bay Medical Center
state: California
city: La Jolla
country: United States
facility: UCSD Medical Center - La Jolla
state: California
city: Los Angeles
country: United States
facility: Kaiser Permanente Los Angeles
state: California
city: Los Angeles
country: United States
facility: University of Southern California Medical Center
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Marina Del Rey
country: United States
facility: Cedars-Sinai Marina Del Rey Hospital
state: California
city: Ontario
country: United States
facility: Kaiser Permanente - Ontario
state: California
city: Palo Alto
country: United States
facility: Stanford University Medical Center
state: California
city: Roseville
country: United States
facility: Sutter Roseville Medical Center
state: California
city: Sacramento
country: United States
facility: Sutter Medical Group, Neurology
state: California
city: San Diego
country: United States
facility: UCSD - Hillcrest; Hillcrest Medical Center
state: California
city: San Francisco
country: United States
facility: CPMC - Van Ness Campus
state: California
city: San Francisco
country: United States
facility: CPMC - Davies Campus
state: California
city: Torrance
country: United States
facility: Torrance Memorial Medical Center
state: California
city: Walnut Creek
country: United States
facility: John Muir Medical Center-Walnut Creek
state: California
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida Health at Shands
state: Florida
city: Jacksonville
country: United States
facility: Baptist Medical Center - Jacksonville
state: Florida
city: Jacksonville
country: United States
facility: Baptist Medical Center-South
state: Florida
city: Miami
country: United States
facility: Jackson Memorial Hospital
state: Florida
city: Honolulu
country: United States
facility: The Queen's Medical Center
state: Hawaii
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Oak Lawn
country: United States
facility: Advocate Christ Medical Center
state: Illinois
city: Park Ridge
country: United States
facility: Advocate Lutheran General Hospital
state: Illinois
city: East Chicago
country: United States
facility: St. Catherine Hospital
state: Indiana
city: Hobart
country: United States
facility: St. Mary Medical Center
state: Indiana
city: Munster
country: United States
facility: Community Hospital
state: Indiana
city: Kansas City
country: United States
facility: Uni of Kansas Medical Center
state: Kansas
city: Corbin
country: United States
facility: Baptist Health Corbin
state: Kentucky
city: Lexington
country: United States
facility: Baptist Health Lexington
state: Kentucky
city: Baltimore
country: United States
facility: Sinai Hospital of Baltimore
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: Univ of Michigan Medical Ctr
state: Michigan
city: Clinton Township
country: United States
facility: Henry Ford Macomb Hospital - Clinton Township
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Flint
country: United States
facility: McLaren Flint
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health Hospitals
state: Michigan
city: Monroe
country: United States
facility: ProMedica Monroe Regional Hospital
state: Michigan
city: Burnsville
country: United States
facility: Fairview Ridges Hospital
state: Minnesota
city: Edina
country: United States
facility: Fairview Southdale
state: Minnesota
city: Minneapolis
country: United States
facility: U of Minnesota MedCtr Fairview
state: Minnesota
city: Worthington
country: United States
facility: Sanford Worthington Medical Center
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Edison
country: United States
facility: JFK Neuroscience Institute
state: New Jersey
city: Summit
country: United States
facility: Atlantic Health System - Overlook Medical Center
state: New Jersey
city: Trenton
country: United States
facility: Capital Health Regional Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Buffalo General Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Asheville
country: United States
facility: Mission Hospitals Inc
state: North Carolina
city: Greensboro
country: United States
facility: Guilford Neurologic Research
state: North Carolina
city: Cincinnati
country: United States
facility: Univ of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Riverside Methodist Hospital; Cancer Services
state: Ohio
city: Columbus
country: United States
facility: Grant Medical Center
state: Ohio
city: Columbus
country: United States
facility: Doctors Hospital
state: Ohio
city: Toledo
country: United States
facility: ProMedica Toledo Hospital
state: Ohio
city: Tulsa
country: United States
facility: Ascension St. John
state: Oklahoma
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Portland
country: United States
facility: Adventist Health Portland
state: Oregon
city: Portland
country: United States
facility: Providence Saint Vincent's Medical Center
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Monroeville
country: United States
facility: UPMC East Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Penn Presbyterian Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Uni of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Pennsylvania Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Mercy
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Passavant Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Sioux Falls
country: United States
facility: Sanford Neurology Clinic
state: South Dakota
city: Chattanooga
country: United States
facility: Chattanooga Center for Neurologic Research
state: Tennessee
city: Murfreesboro
country: United States
facility: Saint Thomas Rutherford Hospital
state: Tennessee
city: Nashville
country: United States
facility: Saint Thomas Health
state: Tennessee
city: Nashville
country: United States
facility: Saint Thomas Midtown Hospital
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Austin
country: United States
facility: Dell Seton Medical center at the University of Texas
state: Texas
city: Austin
country: United States
facility: Seton Medical Center Austin
state: Texas
city: Brownsville
country: United States
facility: Valley Baptist Medical Center-Brownsville
state: Texas
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Harlingen
country: United States
facility: Valley Baptist Medical Center
state: Texas
city: Houston
country: United States
facility: University of Texas at Houston; Neurology
state: Texas
city: Kyle
country: United States
facility: Ascension Seton Hays
state: Texas
city: Round Rock
country: United States
facility: Ascension Seton Williamson
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Edmonton
country: Canada
facility: Uni of Alberta
state: Alberta
city: Hamilton
country: Canada
facility: Hamilton General Hospital; Pharmacy
state: Ontario
city: Montreal
country: Canada
facility: Montreal Neurological Inst; Clinical Research Unit
state: Quebec
Study officials:
References:
citation: 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.