Interventional Management of Stroke (IMS) III Trial

Condition(s) targeted: Acute Ischemic Stroke

Intervention: IV rt-PA (Drug); IA rt-PA (Drug); Concentric Merci® Retriever (all FDA approved commercially available models) (Device); EKOS Micro-Infusion (NeuroWave Infusion) System (Device)

Phase: Phase 3

Status: Recruiting

Sponsored by: University of Cincinnati

Official(s) and/or principal investigator(s):
Joseph P. Broderick, MD, Principal Investigator, Affiliation: Primary Neurologist Investigator, University of Cincinnati Academic Health Center
Thomas A. Tomsick, MD, Principal Investigator, Affiliation: Primary Interventional Investigator, University of Cincinnati Academic Health Center

Overall contact:
Rose Beckmann, Phone: 513-558-3907, Email: beckmare@ucmail.uc.edu

The purpose of this study is to compare two different treatment approaches—combined intravenous and intra-arterial recombinant tissue plasminogen activator (rt-PA) and standard intravenous (IV) rt-PA—to restoring blood flow to the brain.

Official title: Interventional Management of Stroke Trial: A Phase III Clinical Trial Examining Whether a Combined Intravenous (IV) and Intra-Arterial (IA) Approach to Recanalization is Superior to Standard IV rt-PA (Activase®) Alone When Initiated Within Three Hours of Acute Ischemic Stroke Onset

Study design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome:

Efficacy: modified Rankin Scale score, dichotomized to 0-2 verses greater than 2.

Safety:(1) death due to any cause

(2) presence of symptomatic ICH (intracranial hemorrhage).

Secondary outcome:

Barthel Index, NIHSSS and Trail Making Test at 3 months; early response to treatment as determined by NIHSSS of 0-2 at 24 hours from randomization; and dichotomized mRS score (0-2) versus 306

Incidence of parenchymal Type II (PH2) hematomas and any asymptomatic ICH as determined by a standard head CT scan

Detailed description: Stroke remains a major cause of death and disability. Acute thrombolytic therapy offers the potential to achieve early recanalization (reopening of blocked arteries), save tissues, and improve outcome. Currently, intravenous (IV) recombinant tissue plasminogen activator (rt-PA) is the only approved acute stroke therapy. IV rt-PA is an effective therapy for acute ischemic stroke but has substantial limitations when used alone to open blocked arteries The Interventional Management of Stroke (IMS III) Trial is a multi-center study that will compare two different treatment approaches for restoring blood flow to the brain. One approach, giving the clot-dissolving drug rt-PA, is already FDA-approved when given through a vein (IV). This treatment will be compared to a new approach, giving rt-PA at a lower dose first through IV in the arm and then, if a blood clot in the brain artery is found, through a small tube or catheter at the site of the blood clot (intra-arterial or IA) to see which is better. Both approaches must be initiated within three hours of stroke onset.

The primary goal of this trial is to determine if individuals with ischemic stroke treated with rt-PA using a combined IV/IA approach to recanalization started within 3 hours of onset are more likely to have a better outcome than individuals treated with standard IV rt-PA alone.

Nine hundred participants with moderate to severe ischemic stroke will be enrolled at more than 50 centers in the United States, Canada, and Australia. Participants will be assigned randomly to one of 2 groups. Two participants will be randomized to the combined approach for every one participant randomized to standard IV rt-PA. Group one will receive the standard dose of IV rt-PA given over an hour. Group two will receive the standard dose of IV rt-PA for only 40 minutes and then undergo an angiogram test (cerebral angiography) right after the medicine is given to check for blood clots. If a clot is not seen then no more treatment will be given. If a clot is seen, the doctor (a neurointerventionalist) will then choose, based on the location and extent of the blood clot, one of 3 possible IA treatments given directly in the brain artery that will be most effective in reopening the blocked artery. All of the IA treatments used—embolectomy therapy with the Merci® Retriever, rt-PA infusion through the EKOS® Micro-Infusion Catheter concurrent with delivery of low-intensity ultrasound energy, or infusion of rt-PA though a standard microcatheter at the site of the blood clot in the brain artery—are FDA-approved.

The primary measure of benefit in this trial is the ability of the individual with stroke to live and function independently 3 months after the stroke. This trial will also determine and compare the safety and cost effectiveness of the combined IV/IA approach to the standard IV rt-PA approach.

Duration of the study for participants is approximately 12 months.

Minimum age: 18 Years. Maximum age: 82 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Age: 18 through 82 years (i. e., candidates must have had their 18th birthday, but not

their 83rd birthday).

- Initiation of IV rt-PA within 3 hours of onset of stroke symptoms. Time of onset is

defined as the last time when the patient was witnessed to be at baseline (i. e., subjects who have stroke symptoms upon awakening will be considered to have their onset at beginning of sleep).

- An NIHSSS ≥ 10 at the time that IV rt-PA is begun or an NIHSSS >7 and <10 with an

occlusion seen in M1, ICA or basilar artery on CTA at institutions where baseline CTA imaging is standard of care for acute stroke patients.

- Investigator verification that the subject has received/ is receiving the correct IV

rt-PA dose for the estimated weight prior to randomization

Exclusion Criteria:

- History of stroke in the past 3 months.

- Previous intra-cranial hemorrhage, neoplasm, subarachnoid hemorrhage, or

arteriovenous malformation.

- Clinical presentation suggests a subarachnoid hemorrhage, even if initial CT scan is

normal.

- Hypertension at time of treatment; systolic BP > 185 or diastolic > 110 mm Hg; or

aggressive measures to lower blood pressure to below these limits are needed.

- Presumed septic embolus, or suspicion of bacterial endocarditis

- Presumed pericarditis including pericarditis after acute myocardial infarction.

- Suspicion of aortic dissection

- Recent (within 30 days) surgery or biopsy of parenchymal organ.

- Recent (within 30 days) trauma, with internal injuries or ulcerative wounds.

- Recent (within 90 days) severe head trauma or head trauma with loss of consciousness.

- Any active or recent (within 30 days) hemorrhage.

- Patients with known hereditary or acquired hemorrhagic diathesis, coagulation factor

deficiency; or oral anticoagulant therapy require coagulation lab results prior to enrollment. Any subject with INR greater than 1. 7 or institutionally equivalent prothrombin time is excluded. Patients without history or suspicion of coagulopathy do not require INR or prothrombin time lab results to be available prior to enrollment.

- Females of childbearing potential who are known to be pregnant and/or lactating or

who have positive pregnancy tests on admission.

- Baseline lab values: glucose < 50 mg/dl or > 400 mg/dl, platelets <100,000, or Hct

<25

- Patients that require hemodialysis or peritoneal dialysis, or who have a

contradiction to an angiogram for whatever reason .

- Patients who have received heparin or a direct thrombin inhibitor (Angiomax™ or

argatroban, Refludan™) within 48 hours must have a normal partial thromboplastin time (PTT) to be eligible.

- Subjects with an arterial puncture at a non-compressible site or a lumbar puncture in

the previous 7 days.

- Patients with a seizure at onset of stroke

- Patients with a pre-existing neurological or psychiatric disease that would confound

the neurological or functional evaluations, mRS score at baseline must be < 2. This excludes patients who live in a nursing home or who are not fully independent for activities of daily living (toileting, dressing, eating, cooking and preparing meals, etc.)

- Other serious, advanced, or terminal illness.

- Any other condition that the investigator feels would pose a significant hazard to

the patient if Activase (Alteplase) therapy is initiated.

- Current participation in another research drug treatment protocol.

- Informed consent is not or cannot be obtained. For example, obtunded patients are not

automatically excluded from the study. However, if the next of kin or legal guardian (i. e., the individual legally empowered in the state where the consent is obtained) cannot provide consent, randomization and entry into the study could not proceed.

IMAGING Exclusion Criteria:

- High density lesion consistent with hemorrhage of any degree.

- Significant mass effect with midline shift.

- Large (more than 1/3 of the middle cerebral artery) regions of clear hypodensity on

the baseline imaging. An ASPECTS of < 4can be used as a guideline when evaluating >1/3 region of territory involvement. Sulcal effacement and / or loss of grey-white differentiation alone are not contraindications for treatment.

Rose Beckmann, Phone: 513-558-3907, Email: beckmare@ucmail.uc.edu

Royal Melbourne Hospital, Dept. of Neurology, 4 East, Grattan St, Parkville, Victoria 3050, Australia; Recruiting
Amanda Froelich, RN, Phone: +613 9342 8458
Bernard Yan, MD, Principal Investigator

Royal Prince Alfred Hospital, Level 10 King George V Building, Missenden Rd, Camperdown NSW 2050, Australia; Recruiting
Nadia Schweizer, RN, Phone: +613 (9515) 6658
Craig Anderson, MD, Principal Investigator

Monash Medical Center, Dept. of Neurology, 246 Clayton Rd, Clayton, Victoria 3168, Australia; Recruiting
Erika O'Dea, Phone: +61 3 9594 2240
Thanh Phan, MD, Principal Investigator

St. Vincent's Hospital, Clincial Trial Centre Level 5, 378 Victoria St., Darlinghurst, Sydney NSW 2010, Australia; Recruiting
Kitty Wong, RN, Phone: +61 2 8382 2919
Romesh Markus, MD, Principal Investigator

University of Calgary, Calgary Health Region/Foothills Hospital, 1403 29th Street NW, Calgary, Alberta T2N 2T9, Canada; Recruiting
Karla Ryckborst, RN, Phone: 403-944-2863
Andrew Demchuk, MD, Principal Investigator

Barrow Neurology Clinics at St. Joseph's Hospital and Medical Center, 222 W. Thomas Road, Suite 404, Phoenix, Arizona 85013, United States; Recruiting
Bonnie Kasel, RN, Phone: 602-406-6267
James Frey, MD, Principal Investigator

Mayo Clinic Arizona, 5777 E. Mayo Blvd., Scottsdale, Arizona 85054, United States; Recruiting
Erica Boyd, RN, BSN, Phone: 480-342-1316
Bart Demaerschalk, MD, Principal Investigator

University of British Columbia, Vancouver General Hospital, VGH Stroke Program, Gordon & Leslie Diamond Healthcare Centre, 2775 Laurel St., 8th Fl., Ste. 8295, Vancouver, British Columbia V5Z 1M9, Canada; Recruiting
Karina Murray, BSN, RN, Phone: 604-875-4554
Andrew Woolfenden, MD, Principal Investigator

UCLA Medical Center, 924 Westwood Blvd., Suite 300, Los Angeles, California 90024, United States; Recruiting
Judy Guzy, RN, Phone: 310-794-0581
Sidney Starkman, MD, Principal Investigator

Santa Monica-UCLA Medical Center, 1250 16th Street, Santa Monica, California 90404, United States; Recruiting
Judy Guzy, RN, Phone: 310-794-0581
Sidney Starkman, MD, Principal Investigator

St. John's Health Center, 1328 22nd St., Santa Monica, California 90404, United States; Not yet recruiting
Judy Guzy, RN, Phone: 310-794-0581
Sidney Starkman, MD, Principal Investigator

Northridge Hospital Medical Center, 18300 Roscoe Boulevard, Northridge, California 91328, United States; Not yet recruiting
Judy Guzy, RN, Phone: 310-794-0581
Sidney Starkman, MD, Principal Investigator

Colorado Neurological Institute, Swedish Medical Center, 501 E. Hampden Ave., Englewood, Colorado 80113-2771, United States; Recruiting
Carol Greenwald, RN, Phone: 303-806-7418
Christopher Fanale, MD, Principal Investigator

Stroke Center at Hartford, 80 Seymour St. Rm JB603, Hartford, Connecticut 06102, United States; Recruiting
Martha Ahlquist, RN, Phone: 860-545-6047
Lincoln Abbott, MD, Principal Investigator

Morton Plant Mease Health Care, 300 Pinellas Street MS 49, Clearwater, Florida 33756, United States; Recruiting
Victoria Bernsee-Lindemann, RN, Phone: 727-461-8885
Ajay Arora, MD, Principal Investigator

University of Miami Miller School of Medicine, Miami, Florida 33136, United States; Recruiting
Amie Gimon, Phone: 305-243-3958
Dileep Yavagal, MD, Principal Investigator

Alexian Brothers Medical Center, 800 Biesterfield Rd., Elk Grove Village, Illinois 60007, United States; Recruiting
Ginger Reilly, NP, MSN, Phone: 847-981-3630
Tim Malish, MD, Principal Investigator

Central DuPage Hospital, 25 North Winfield Road, Winfield, Illinois 60190, United States; Recruiting
Joyce Smith, RN, Phone: 630-933-6027
Harish Shownkeen, MD, Principal Investigator

Methodist Research Institute, 1812 N. Capitol Ave. Suite 120, Indianapolis, Indiana 46202, United States; Recruiting
Judy Jackson, RN, Phone: 317-962-3183
John A. Scott, MD, Principal Investigator

Ruan Neurological Mercy Medical Center, 1111 6th Ave., Ste. 400, Des Moines, Iowa 50314, United States; Recruiting
Cheryl Inman, RN, Phone: 515-358-0023
Michael Jacoby, MD, Principal Investigator

St. Elizabeth Medical Center South, One Medical Village Drive, Edgewood, Kentucky 41017, United States; Recruiting
Joyce Zeigler, Phone: 513-558-3628
Joe Broderick, MD, Principal Investigator

St. Luke's Hospital East, 85 N. Grand Ave., Ft. Thomas, Kentucky 41075, United States; Recruiting
Joyce Zeigler, Phone: 513-558-2869
Joe Broderick, MD, Principal Investigator

St Luke's West Hospital, 7380 Turfway Rd., Florence, Kentucky 41042, United States; Recruiting
Joyce Zeigler, Phone: 513-558-3628
Joe Broderick, MD, Principal Investigator

University of Louisville, Kentucky Neuroscience Research, Stroke Research, 401 East Chestnut Street, Suite 520, Louisville, Kentucky 40202, United States; Recruiting
Ann Jerde, RN, Phone: 502-813-6579
Alex Abou-Chebl, MD, Principal Investigator

Johns Hopkins University, 1500 Orleans St. 3M South, Baltimore, Maryland 21231, United States; Recruiting
Susan Rice, RN, MPH, CCRP, Phone: 410-614-3460
Victor C. Urrutia, MD, Principal Investigator

Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, United States; Recruiting
Shihab Masrur, MD, Phone: 617-724-4941
Lee Schwamm, MD, Principal Investigator

Lahey Clinic Medical Center, Burlington, Massachusetts 01805, United States; Recruiting
Claudia Fitzgerald, Phone: 781-744-2603
Seon Kyu Lee, MD, Principal Investigator

William Beaumont Hospital, 3811 W. 13 Mile Rd., Royal Oak, Michigan 48073, United States; Withdrawn

Henry Ford Hospital, 2799 W Grand Blvd, CFP-260, Detroit, Michigan 48202, United States; Recruiting
Paula Crouse, RN, Phone: 313-916-8730
Christopher Lewandowski, MD, Principal Investigator

Michigan State University, Sparrow Hospital, B 401 Clinical Center, East Lansing, Michigan 48824, United States; Recruiting
Sue Wehner, MSN, Phone: 517-353-8122, Ext: 139
Arshad Majid, MD, Principal Investigator

St. John Providence Medical Center, 16001 West Nine Mile Road, Southfield, Michigan 48075, United States; Recruiting
Kathy Telck, RN, Phone: 248-849-3104
Richard Fessler, MD, Principal Investigator

Park Nicollet Neurology, Methodist Hospital, 6500 Excelsior Boulevard, Room 1225, St. Louis Park, Minnesota 55416, United States; Recruiting
Amy Castle, Phone: 952-993-2755
Sandra Hanson, MD, Principal Investigator

Washington University/Barnes Jewish Hospital, 660 S. Euclid Avenue, St. Louis, Missouri 63110, United States; Recruiting
Jill Newgent, RN, Phone: 314-747-3795
Colin Derdeyn, MD, Principal Investigator

NNI Research Foundation, 3131 La Canada, Suite 101, Las Vegas, Nevada 89109, United States; Recruiting
Kyle Malone, Phone: 702-731-8291
Scott Selco, MD, PhD, Principal Investigator

University of North Carolina, CB # 7025, 7003 Neurosciences Hospital, 7th Floor, Chapel Hill, North Carolina 27599, United States; Recruiting
Roxanne Poole, Phone: 919-966-3816
Sen Souvic, MD, Principal Investigator

Mission Hospital, 509 Biltmore Avenue, Asheville, North Carolina 28801, United States; Recruiting
Claudine Cuento, BSN, RN, CCRC, Phone: 828-213-7033
Alexander Schneider, MD, Principal Investigator

The University Hospital, 234 Goodman Ave., Cincinnati, Ohio 45219, United States; Recruiting
Joyce Zeigler, Phone: 513-558-3628
Joe Broderick, MD, Principal Investigator

The Jewish Hospital of Cincinnati, 4777 East Galbraith Rd, Cincinnati, Ohio 45236, United States; Recruiting
Joyce Zeigler, Phone: 513-558-3628
Joe Broderick, MD, Principal Investigator

Good Samaritan Hospital, 375 Dixmyth Ave., Cincinnati, Ohio 45220-2489, United States; Recruiting
Joyce Zeigler, Phone: 513-558-3628
Joe Broderick, MD, Principal Investigator

Bethesda North Hospital, 10500 Montgomery Rd., Montgomery, Ohio 45242, United States; Recruiting
Joyce Zeigler, Phone: 513-558-3628
Joe Broderick, MD, Principal Investigator

The Christ Hospital, 2139 Auburn Ave., Cincinnati, Ohio 45219, United States; Recruiting
Joyce Zeigler, Phone: 513-558-3628
Joe Broderick, MD, Principal Investigator

Mercy Hospital, Mt Airy, 2446 Kipling Ave., Cincinnati, Ohio 45239, United States; Recruiting
Joyce Zeigler, Phone: 513-558-3628
Joe Broderick, MD, Principal Investigator

Mercy Hospital, Western Hills, 3131 Queen City Ave., Cincinnati, Ohio 45238, United States; Recruiting
Joyce Zeigler, Phone: 513-558-3628
Joe Broderick, MD, Principal Investigator

Mercy Hospital Anderson, 7500 State Rd, Cincinnati, Ohio 45255, United States; Recruiting
Joyce Zeigler, Phone: 513-558-3628
Joe Broderick, MD, Principal Investigator

Mercy Hospital Fairfield, 3000 Mack Rd., Fairfield, Ohio 45014, United States; Recruiting
Joyce Zeigler, Phone: 513-558-3628
Joe Broderick, MD, Principal Investigator

University Hospitals of Cleveland, Case Western Reserve University,Case Western Neurological Unit, 11100 Euclid Avenue, Lakeside 5508, Cleveland, Ohio 44106, United States; Recruiting
David Korosec, RN, BSN, CCRP, Phone: 216-844-1800
Robert Tarr, MD, Principal Investigator

Riverside Methodist Hospital, 3535 Olentangy River Road, Columbus, Ohio 43214, United States; Recruiting
Nancy Sample, RN, CCRC, Phone: 614-566-3908
Ronald Budzik, MD, Principal Investigator

Toronto Western Hospital, 5th Floor Rm. 447, 399 Bathurst St., Toronto, Ontario M5T 2S8, Canada; Recruiting
Cherissa Astorga, RN, Phone: 416-603-5573
Frank Silver, MD, Principal Investigator

The Ottawa Hospital, Civic Campus, CPC Main, RM 36, Box 608, 1053 Carling Avenue, Ottawa, Ontario K1Y 4E9, Canada; Recruiting
Melodie Mortensen, RN, Phone: 613-798-5555, Ext: 16217
Grant Stotts, MD, Principal Investigator

OHSU, Oregon Stroke Center, Providence St. Vincent's Hospital, Providence Portland Hospital, Portland, Oregon 97239, United States; Recruiting
Monica Dolan, RN, Phone: 503-494-7224
Wayne Clark, MD, Principal Investigator

Lehigh Valley Hospital Center, 1200 South Cedar Crest Blvd., Allentown, Pennsylvania 18103, United States; Recruiting
Kathleen Bernini Knapp, BS, RN, Phone: 610-402-9004
Yevgeniy Isayev, MD, Principal Investigator

PENN State M.S. Hershey Medical Center, 500 University Drive MC: HS 86, Long Lane Rom HG:212, Hershey, Pennsylvania 17033, United States; Recruiting
Deborah Hoffman, RN, Phone: 717-531-0003, Ext: 283063
Kevin Cockroft, MD, Principal Investigator

University of Pittsburgh, Medical Center, 200 Lothrop Street, PUH C-400, Pittsburgh, Pennsylvania 15213, United States; Recruiting
Jennifer Oakley, Phone: 412-647-1618
Lawrence Wechsler, MD, Principal Investigator

Allegheny General Hospital, 420 East North Avenue, East Wing Office Bldg., Suite 206, Pittsburgh, Pennsylvania 15212, United States; Recruiting
Melissa Tian, RN, BSN, Phone: 412-359-3748
Ashis Tayal, MD, Principal Investigator

Brown Hospitals, Brown University, Rhode Island Hospital/Miriam Hospital, 593 Eddy Street, Providence, Rhode Island 02903, United States; Withdrawn

Medical University of South Carolina, Charleston, South Carolina 29425, United States; Recruiting
Marc LaPointe, Phone: 843-792-2993
Nikolas Papamitsakis, MD, Principal Investigator

Erlanger Health Care System, Chattanooga Ctr. for Neurological Research, 979 East Third Street, Suite C-835, Chattanooga, Tennessee 37403, United States; Recruiting
Katrina Barton, Phone: 423-648-0304
Tom Devlin, MD, Principal Investigator

University of Texas Medical School at Houston, 6431 Fannin, MSB 7.044, Houston, Texas 77030, United States; Recruiting
Mary Jane Hess, RN, BSN, Phone: 713-500-7078
James Grotta, MD, Principal Investigator

Froedtert Hospital, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, Wisconsin 53226, United States; Recruiting
Joanna Delap, RN, Phone: 414-805-9824
Michael Torbey, MD, Principal Investigator

Starting date: August 2006
Ending date: December 2012
Last updated: May 26, 2009