Clinical trial NCT01282242: A Study of Intravenous Thrombolysis With Alteplase in MRI-Selected Patients
Official title: MR WITNESS: A Phase IIa Safety Study of Intravenous Thrombolysis With Alteplase in MRI-Selected Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Stroke
Keywords: acute stroke, IV rt-PA, Activase, Alteplase
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Genentech, Inc.
First posted: 2011-01-24
Enrollment: 88
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study was jointly developed and is jointly led by investigators at Massachusetts General Hospital and the intramural division of NINDS. We are doing this research study to find out if Activase ® (also called alteplase or rt-PA) can safely be given to people with an acute ischemic stroke when their stroke onset was not witnessed making them ineligible for standard thrombolytic (clot busting) therapy. We also want to find out if rt-PA can help people recover better from their stroke.

The purpose of this study is to: 1) see if it is safe to give intravenous (IV) rt-PA to people with unwitnessed stroke but with MRI evidence of early ischemic stroke, 2) see if rt-PA is effective if given to people who are selected for treatment based on MRI evidence of an early stroke, and 3) get information about this new MRI diagnostic methods for guiding stroke treatment.

Detailed description: This study was jointly developed and is jointly led by Massachusetts General Hospital and the NINDS. This is a multi-center, open-label, Phase IIa safety study in adult acute ischemic stroke patients to determine if it is safe to extend intravenous thrombolytic treatment to subjects who are evaluated within 24 hours from last known well ("stroke onset") and eligible to receive thrombolytic treatment within 4.5 hours from symptom discovery with the assistance of an MRI-based "witness" when no human witness of stroke onset is available. The study is designed to investigate the safety in using standard diagnostic MRI in selecting patients for thrombolytic therapy when the last known well time places the patient beyond the current IV thrombolytic time-window.

Eligibility criteria: Inclusion Criteria:

* Age, 18 to 85 years inclusive
* Brain MRI findings consistent with early stroke onset
* Clinical diagnosis of acute ischemic stroke with disabling neurological deficit
* Stroke symptoms present for at least 30 minutes with no significant improvement before treatment
* Be last known well (without stroke symptoms) within 24 hours of triage
* Be able to receive IV rt-PA within 4.5 hours from the time the symptoms were discovered.
* MRI diagnostic of acute ischemic stroke and consistent with clinical syndrome
* Time between completion of qualifying MRI studies to treatment initiation ≤ 1 hour

Exclusion Criteria:

* History of intracranial hemorrhage
* Symptoms rapidly improving or only minor before start of study drug.
* Severe stroke as assessed clinically (e.g., NIHSS score \>25) or by appropriate imaging techniques (lesion volume \> one-third of MCA by visual inspection or \>100 cm3 using the ellipsoid estimation formula of ABC/2)
* Stroke or serious head trauma within the previous 3 months
* Administration of heparin within the 48 hours preceding the onset of stroke, with an activated partial-thromboplastin time at presentation exceeding the upper limit of the normal range
* Platelet count of less than 100,000 per cubic millimeter
* Uncontrolled hypertension defined as systolic blood pressure \> 185 mm Hg or diastolic blood pressure \> 110 mm Hg that cannot be controlled except with continuous parenteral antihypertensive medication
* Blood glucose less than 50 mg per deciliter or greater than 400 mg per deciliter
* Symptoms suggestive of subarachnoid hemorrhage, even if CT/MRI scan was normal
* Oral anticoagulant treatment, regardless of INR.
* Major surgery or severe trauma within the previous 3 months
* Other major disorders associated with an increased risk of bleeding
* Eligible for rt-PA therapy per institutional protocol as part of routine clinical practice
* Non-ischemic etiology demonstrated by neuroimaging
* Neuroimaging (CT or gradient echo MRI) evidence of acute or chronic ICH (non-microbleed)
* Presence of 10 or more microbleeds on GRE (suggestive of amyloid angiopathy)
* Any contraindication for MRI, e.g. presence of a pacemaker, ferromagnetic aneurysm clip, etc, pre-menopausal women with a positive pregnancy blood test, or severe claustrophobia.
* Poor quality MRI- images are not interpretable
* In the opinion of the investigator, the patient is not an appropriate candidate for IV rt-PA
* Women known to be pregnant, lactating or having a positive or indeterminate pregnancy test.

Primary outcomes:
measure: Number of Subjects With Symptomatic Intracerebral Hemorrhage
timeFrame: Within 7 days from tPA administration.
Secondary outcomes:
measure: Number of Subjects With Symptomatic Cerebral Edema
timeFrame: Within 96 hours of tPA administration
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Bethesda
country: United States
facility: NIH/ NINDS, Washington Hospital, Suburban Hospital
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine/Barnes Jewish Hospital
state: Missouri
city: Memphis
country: United States
facility: University of Tennessee Health Science Center
state: Tennessee
city: Austin
country: United States
facility: Seton/UT Southwestern Medical Center
state: Texas
city: Murray
country: United States
facility: Intermountain Healthcare
state: Utah
Study officials:
affiliation: Massachusetts General Hospital
name: Lee Schwamm, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NINDS/Seton/UT Southwestern Clinical Research Institute of Austin
name: Steven Warach, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital
name: Ona Wu, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: NIH Intramural Stroke Program/Suburban Hospital/Washington Hospital Center
name: Lawrence Latour, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schwamm LH, Wu O, Song SS, Latour LL, Ford AL, Hsia AW, Muzikansky A, Betensky RA, Yoo AJ, Lev MH, Boulouis G, Lauer A, Cougo P, Copen WA, Harris GJ, Warach S; MR WITNESS Investigators. Intravenous thrombolysis in unwitnessed stroke onset: MR WITNESS trial results. Ann Neurol. 2018 May;83(5):980-993. doi: 10.1002/ana.25235. Epub 2018 Apr 27.
citation: Ali SF, Siddiqui K, Ay H, Silverman S, Singhal A, Viswanathan A, Rost N, Lev M, Schwamm LH. Baseline Predictors of Poor Outcome in Patients Too Good to Treat With Intravenous Thrombolysis. Stroke. 2016 Dec;47(12):2986-2992. doi: 10.1161/STROKEAHA.116.014871. Epub 2016 Nov 10.