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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT03785678
Other study ID # ML40787
Secondary ID
Status Completed
Phase Phase 3
First received
Last updated
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
Health authority
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

Study Design


Related Conditions & MeSH terms


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
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