A Study of Intravenous Thrombolysis With Alteplase in MRI-Selected Patients (MR WITNESS)

• ClinicalTrials.gov Identifier: NCT01282242
• Recruitment Status: Completed
• First Posted: January 24, 2011
• Results First Posted: April 11, 2017
• Last Update Posted: June 15, 2017
• Sponsor: Lee Schwamm
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); Genentech, Inc.
• Information provided by (Responsible Party): Lee Schwamm, Massachusetts General Hospital

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Acute Stroke	Drug: IV rt-PA	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 88 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: MR WITNESS: A Phase IIa Safety Study of Intravenous Thrombolysis With Alteplase in MRI-Selected Patients
• Study Start Date: January 2011
• Actual Primary Completion Date: January 2016
• Actual Study Completion Date: May 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: IV rt-PA; open-label	Drug: IV rt-PA; open-label; Other Name: Alteplase, Activase

Outcome Measures

Primary Outcome Measures :

1. Number of Subjects With Symptomatic Intracerebral Hemorrhage [ Time Frame: Within 7 days from tPA administration. ]
   Safety of IV rt-PA as evident by rates of symptomatic ICH defined by an increase of 4 points or more on the NIHSS .

Secondary Outcome Measures :

1. Number of Subjects With Symptomatic Cerebral Edema [ Time Frame: Within 96 hours of tPA administration ]
   Safety of IV rt-PA as evident by rates of symptomatic cerebral edema defined as brain edema with mass effect as the predominant cause of clinical deterioration.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Arizona

University of Arizona

Tucson, Arizona, United States, 85724

United States, California

Cedars Sinai Medical Center

Los Angeles, California, United States, 90048

Ronald Reagan UCLA Medical Center

Los Angeles, California, United States, 90095

United States, Illinois

Rush University Medical Center

Chicago, Illinois, United States, 60612

United States, Iowa

University of Iowa

Iowa City, Iowa, United States, 52242

United States, Maryland

NIH/ NINDS, Washington Hospital, Suburban Hospital

Bethesda, Maryland, United States, 20892

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Boston Medical Center

Boston, Massachusetts, United States, 02118

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

University of Massachusetts

Worcester, Massachusetts, United States, 01655

United States, Missouri

Washington University School of Medicine/Barnes Jewish Hospital

Saint Louis, Missouri, United States, 63110

United States, Tennessee

University of Tennessee Health Science Center

Memphis, Tennessee, United States, 38105

United States, Texas

Seton/UT Southwestern Medical Center

Austin, Texas, United States, 78701

United States, Utah

Intermountain Healthcare

Murray, Utah, United States, 84107

Sponsors and Collaborators

Lee Schwamm

National Institute of Neurological Disorders and Stroke (NINDS)

Genentech, Inc.

Investigators

• Principal Investigator: Lee Schwamm, MD; Massachusetts General Hospital
• Principal Investigator: Steven Warach, MD, PhD; NINDS/Seton/UT Southwestern Clinical Research Institute of Austin
• Principal Investigator: Ona Wu, PhD; Massachusetts General Hospital
• Principal Investigator: Lawrence Latour, PhD; NIH Intramural Stroke Program/Suburban Hospital/Washington Hospital Center

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: Lee Schwamm, Vice Chairman, Department of Neurology, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT01282242
• Other Study ID Numbers: 2010P001880
• First Posted: January 24, 2011
• Results First Posted: April 11, 2017
• Last Update Posted: June 15, 2017
• Last Verified: May 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Lee Schwamm, Massachusetts General Hospital:

acute stroke, IV rt-PA, Activase, Alteplase

Additional relevant MeSH terms:

Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Tissue Plasminogen Activator; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action