Interventional Management of Stroke (IMS) III Trial

Condition(s) targeted: Stroke

Intervention: IV rt-PA alone (Drug); endovascular therapy (Other)

Phase: Phase 3

Status: Terminated

Sponsored by: Joseph Broderick

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

The purpose of this study is to compare two different treatment approaches to recanalization started within 3 hours of symptom onset—combined intravenous (IV) and endovascular therapy and standard intravenous (IV) rt-PA alone.

Official title: Interventional Management of Stroke Trial (IMS III): 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

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2.

Death Due to Any Cause

Symptomatic Intracranial Hemorrhage

Secondary outcome:

Incidence of Parenchymal Type II (PH2) Hematomas

Asymptomatic Intracranial Hemorrhage

National Institutes of Health Stroke Scale Score (NIHSS) >> Dichotomized 0-1 Versus 2 or Greater.

National Institutes of Health Stroke Scale Score (NIHSS) Dichotomized 0-1 Versus 2 or Greater.

Barthel Index (BI) Dichotomized 0-90 Versus 95-100

Trail Making Test Part A Time

Trail Making Test Part B Time

Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2

Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2

Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2

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 an endovascular therapy 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. While information on device use was collected, individual device performance was not a primary outcome. Nine hundred participants with moderate to severe ischemic stroke will be enrolled at more than 50 centers in the United States, Canada, Australia and Europe. Subjects will be randomized in a 2: 1 ratio to receive endovascular therapy or IV only with adjustment for clinical site and NIHSSS strata. If enrolled under Amendment 5 or later both treatment groups will receive the standard approved therapy dose of rt-PA (0. 9 mg/kg, 90 mg max) administered intravenously over one hour. The consent process and randomization can take place prior to or anytime up to forty minutes after the IV bolus dose. If, at the 40 minute time point, no consent has been obtained or randomization has not been completed, the patient will no longer be eligible for IMS III enrollment. After consent, the endovascular therapy group will then undergo immediate angiography. If clot is not demonstrated, no more treatment is administered. If clot is demonstrated, the neurointerventionalist will then choose from currently available but trial defined endovascular therapy approaches, choosing the treatment they feel will be most effective in attempting to reopen the blocked artery. These approaches utilize local regulatory, US FDA and IMS III Executive Committee approved devices for the intra-arterial infusion of investigational rt-PA using standard microcatheter or the EKOS Micro-Infusion Catheter® (in US) or embolectomy devices including the Concentric Retriever Device®, the Penumbra System ™, or the Solitaire™ FR Revascularization Device. All devices must be used per the manufacturer's instructions for use. Endovascular therapy, whether initially with the Merci® Retriever, EKOS Micro-Infusion Catheter, Penumbra System™, Solitaire™, a future device, or infusion of IA rt-PA via a standard microcatheter, must be started within 5 hours and completed within 7 hours of symptom onset. The maximum dose of IA rt-PA is 22mg (maximum 2 to 4 mg bolus and infusion at a rate of 10 mg/hr). Use of tandem devices (i. e. EKOS Micro-Infusion Catheter, Merci Retriever®, Penumbra System™, or Solitaire™) in a single case is a protocol violation. Only standard microcatheter rt-PA infusion therapy may be administered following attempt with a device. 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 endovascular therapy 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

had their 83rd birthday)

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

onset is defined as the last time when the subject 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 intravenous 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 BP to below these limits are needed.

- Presumed septic embolus, or suspicion of bacterial endocarditis

- Presumed pericarditis, including pericarditis after acute MI

- 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

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

deficiency or oral anticoagulant therapy require coagulation labs results prior to enrollment. Any subject with INR > 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

- Requires hemodialysis or peritoneal dialysis, or has a contraindication to an

angiogram for whatever reason

- Received heparin or a direct thrombin inhibitor (Angiomax, argatroban, Refludan,

Pradaxa) within 48 hours must have a normal partial thromboplastin time (PTT) to be eligible

- History of an arterial puncture at a non-compressible site or a lumbar puncture in

the previous 7 days

- History of seizure at onset of stroke

- History of 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 subject if Activase (Alteplase) therapy is initiated

- Current participation in another research drug treatment protocol

- Informed consent is not or cannot be obtained.

- High density lesion consistent with hemorrhage of any degree on baseline imaging

- Significant mass effect with midline shift on baseline imaging

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

baseline CT scan. (ASPECTS of < 4 can be used as a guideline) Sulcal effacement and/or loss of grey-white differentiation are not contraindications to tx

- CT evidence of intrapararenchymal tumor

- Baseline CTA without evidence of arterial occlusion

Royal Prince Alfred Hospital, Level 10 King George V Building, Missenden Rd, Camperdown NSW 2050, Australia

St. Vincent's Hospital, Clincial Trial Centre Level 5, 378 Victoria St., Darlinghurst, Sydney NSW 2010, Australia

Monash Medical Center, Dept. of Neurology, 246 Clayton Rd, Clayton, Victoria 3168, Australia

Royal Melbourne Hospital, Dept. of Neurology, 4 East, Grattan St, Parkville, Victoria 3050, Australia

Technische Universität, Dresden, Dresden 01307, Germany

University of Freiburg, Freiburg 79106, Germany

Ernst Moritz Arndt University, Greifswald 17475, Germany

Martin-Luther University, Halle 06120, Germany

Asklepios Klinik Nord Heidberg, Hamburg 22417, Germany

St. Antonius Hospital, Nieuwegein 3435 CM, Netherlands

Hospital Universitari Germans Trias i Pujol, Badalona 8916, Spain

Hospital Vall d´Hebron, Barcelona 8035, Spain

University Hospital Basel, Basel 4031, Switzerland

Centre Hospitalier, University Vaudois, Lausanne 1011, Switzerland

University of Alabama Birmingham, Birmingham, Alabama 35294, United States

University of Calgary, Calgary Health Region/Foothills Hospital, 1403 29th Street NW, Calgary, Alberta T2N 2T9, Canada

Barrow Neurology Clinics at St. Joseph's Hospital and Medical Center, 222 W. Thomas Road, Suite 404, Phoenix, Arizona 85013, United States

Mayo Clinic Arizona, 5777 E. Mayo Blvd., Scottsdale, Arizona 85054, United States

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

UCLA Medical Center, 924 Westwood Blvd., Suite 300, Los Angeles, California 90024, United States

Hoag Memorial Hospital, Newport Beach, California 92658, United States

Santa Monica-UCLA Medical Center, 1250 16th Street, Santa Monica, California 90404, United States

Bichat Stroke Centre, Paris, Cedex 75018, France

Colorado Neurological Institute, Swedish Medical Center, 501 E. Hampden Ave., Englewood, Colorado 80113-2771, United States

Stroke Center at Hartford, 80 Seymour St. Rm JB603, Hartford, Connecticut 06102, United States

Morton Plant Mease Health Care, 300 Pinellas Street MS 49, Clearwater, Florida 33756, United States

University of Miami Miller School of Medicine, Miami, Florida 33136, United States

Alexian Brothers Medical Center, 800 Biesterfield Rd., Elk Grove Village, Illinois 60007, United States

Ruan Neurological Mercy Medical Center, 1111 6th Ave., Ste. 400, Des Moines, Iowa 50314, United States

St. Elizabeth Medical Center South, One Medical Village Drive, Edgewood, Kentucky 41017, United States

St Luke's West Hospital, 7380 Turfway Rd., Florence, Kentucky 41042, United States

St. Luke's Hospital East, 85 N. Grand Ave., Ft. Thomas, Kentucky 41075, United States

University of Louisville, Kentucky Neuroscience Research, Stroke Research, 401 East Chestnut Street, Suite 520, Louisville, Kentucky 40202, United States

Johns Hopkins University, 1500 Orleans St. 3M South, Baltimore, Maryland 21231, United States

Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, United States

Lahey Clinic Medical Center, Burlington, Massachusetts 01805, United States

Henry Ford Hospital, 2799 W Grand Blvd, CFP-260, Detroit, Michigan 48202, United States

Michigan State University, Sparrow Hospital, B 401 Clinical Center, East Lansing, Michigan 48824, United States

University of Mississippi Medical Center, Jackson, Mississippi 39216, United States

Washington University/Barnes Jewish Hospital, 660 S. Euclid Avenue, St. Louis, Missouri 63110, United States

University of Rochester Medical Center, Rochester, New York 14642, United States

Suny Upstate Medical University, Syracuse, New York 13210, United States

Mission Hospital, 509 Biltmore Avenue, Asheville, North Carolina 28801, United States

University of North Carolina, CB # 7025, 7003 Neurosciences Hospital, 7th Floor, Chapel Hill, North Carolina 27599, United States

Good Samaritan Hospital, 375 Dixmyth Ave., Cincinnati, Ohio 45220-2489, United States

Mercy Hospital Anderson, 7500 State Rd, Cincinnati, Ohio 45255, United States

Mercy Hospital, Mt Airy, 2446 Kipling Ave., Cincinnati, Ohio 45239, United States

Mercy Hospital, Western Hills, 3131 Queen City Ave., Cincinnati, Ohio 45238, United States

The Christ Hospital, 2139 Auburn Ave., Cincinnati, Ohio 45219, United States

The Jewish Hospital of Cincinnati, 4777 East Galbraith Rd, Cincinnati, Ohio 45236, United States

The University Hospital, 234 Goodman Ave., Cincinnati, Ohio 45219, United States

University Hospitals of Cleveland, Case Western Reserve University,Case Western Neurological Unit, 11100 Euclid Avenue, Lakeside 5508, Cleveland, Ohio 44106, United States

Riverside Methodist Hospital, 3535 Olentangy River Road, Columbus, Ohio 43214, United States

Mercy Hospital Fairfield, 3000 Mack Rd., Fairfield, Ohio 45014, United States

Bethesda North Hospital, 10500 Montgomery Rd., Montgomery, Ohio 45242, United States

The Ottawa Hospital, Civic Campus, CPC Main, RM 36, Box 608, 1053 Carling Avenue, Ottawa, Ontario K1Y 4E9, Canada

St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada

Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada

Toronto Western Hospital, 5th Floor Rm. 447, 399 Bathurst St., Toronto, Ontario M5T 2S8, Canada

OHSU, Oregon Stroke Center, Providence St. Vincent's Hospital, Providence Portland Hospital, Portland, Oregon 97239, United States

Abington Memorial Hospital, Abington, Pennsylvania 19001, United States

Lehigh Valley Hospital Center, 1200 South Cedar Crest Blvd., Allentown, Pennsylvania 18103, United States

PENN State M.S. Hershey Medical Center, 500 University Drive MC: HS 86, Long Lane Rom HG:212, Hershey, Pennsylvania 17033, United States

Allegheny General Hospital, 420 East North Avenue, East Wing Office Bldg., Suite 206, Pittsburgh, Pennsylvania 15212, United States

University of Pittsburgh, Medical Center, 200 Lothrop Street, PUH C-400, Pittsburgh, Pennsylvania 15213, United States

Centre Hospital University of Montreal, Montreal, Quebec H2L4M1, Canada

Medical University of South Carolina, Charleston, South Carolina 29425, United States

University Medical Center at Brackenridge Hospital, Austin, Texas 78701, United States

University of Texas Medical School at Houston, 6431 Fannin, MSB 7.044, Houston, Texas 77030, United States

University of Virginia Health System, Charlottesville, Virginia 22908, United States

Froedtert Hospital, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, Wisconsin 53226, United States

Starting date: August 2006
Last updated: November 19, 2013