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NCT00359424

Interventional Management of Stroke (IMS) III Trial

Last Updated: 2013-12-13

Study Results

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Basic Information

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Recruitment Status

TERMINATED

Clinical Phase

PHASE3

Total Enrollment

656 participants

Study Classification

INTERVENTIONAL

Study Start Date

2006-08-31

Study Completion Date

2013-04-30

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Stroke

Keywords

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acute ischemic stroke rt-PA thrombolytic recombinant tissue plasminogen activator recanalization blood clot stroke clot-dissolving Activase® Actilyse® Concentric Merci® Retriever EKOS® Micro-Infusion catheter (MicroLysus) The Penumbra System™ Standard microcatheter

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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intravenous (IV) rt-PA alone

Group one will receive the standard dose of intravenous (IV) rt-PA alone given over an hour.

Group Type ACTIVE_COMPARATOR

IV rt-PA alone

Intervention Type DRUG

Intravenous (IV) recombinant tissue plasminogen activator (rt-PA) is the only approved acute stroke therapy; Group one will receive the standard dose of IV rt-PA given over an hour.

Endovascular therapy

Group two will receive a lower dose or a standard dose of IV rt-PA 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 neurointerventionalist will then choose (based on the location and extent of the blood clot) a protocol approved endovascular treatment given directly in the brain artery that will be most effective in reopening the blocked artery.

Group Type EXPERIMENTAL

IV rt-PA alone

Intervention Type DRUG

Intravenous (IV) recombinant tissue plasminogen activator (rt-PA) is the only approved acute stroke therapy; Group one will receive the standard dose of IV rt-PA given over an hour.

endovascular therapy

Intervention Type OTHER

Group two will receive a lower dose or the standard dose of IV rt-PA 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 neurointerventionalist will then choose a protocol approved endovascular treatment given directly in the brain artery that will be most effective in reopening the blocked artery. Endovascular therapy can be implemented with or without interarterial rt-PA use.

Interventions

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IV rt-PA alone

Intravenous (IV) recombinant tissue plasminogen activator (rt-PA) is the only approved acute stroke therapy; Group one will receive the standard dose of IV rt-PA given over an hour.

Intervention Type DRUG

endovascular therapy

Intervention Type OTHER

Other Intervention Names

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Activase®, Actilyse® Activase®, Actilyse®

Eligibility Criteria

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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

Minimum Eligible Age

18 Years

Maximum Eligible Age

82 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Responsible Party

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Joseph Broderick

Professor and Chairman Department of Neurology

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Joseph P. Broderick, MD

Role: PRINCIPAL_INVESTIGATOR

Primary Neurologist Investigator, University of Cincinnati Academic Health Center

Thomas A. Tomsick, MD

Role: PRINCIPAL_INVESTIGATOR

Primary Interventional Investigator, University of Cincinnati Academic Health Center

Locations

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University of Alabama Birmingham

Birmingham, Alabama, United States

Site Status

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

Phoenix, Arizona, United States

Site Status

Mayo Clinic Arizona, 5777 E. Mayo Blvd.

Scottsdale, Arizona, United States

Site Status

UCLA Medical Center, 924 Westwood Blvd., Suite 300

Los Angeles, California, United States

Site Status

Hoag Memorial Hospital

Newport Beach, California, United States

Site Status

Santa Monica-UCLA Medical Center, 1250 16th Street

Santa Monica, California, United States

Site Status

Colorado Neurological Institute, Swedish Medical Center, 501 E. Hampden Ave.

Englewood, Colorado, United States

Site Status

Stroke Center at Hartford, 80 Seymour St. Rm JB603

Hartford, Connecticut, United States

Site Status

Morton Plant Mease Health Care, 300 Pinellas Street MS 49

Clearwater, Florida, United States

Site Status

University of Miami Miller School of Medicine

Miami, Florida, United States

Site Status

Alexian Brothers Medical Center, 800 Biesterfield Rd.

Elk Grove Village, Illinois, United States

Site Status

Ruan Neurological Mercy Medical Center, 1111 6th Ave., Ste. 400

Des Moines, Iowa, United States

Site Status

St. Elizabeth Medical Center South, One Medical Village Drive

Edgewood, Kentucky, United States

Site Status

St Luke's West Hospital, 7380 Turfway Rd.

Florence, Kentucky, United States

Site Status

St. Luke's Hospital East, 85 N. Grand Ave.

Fort Thomas, Kentucky, United States

Site Status

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

Louisville, Kentucky, United States

Site Status

Johns Hopkins University, 1500 Orleans St. 3M South

Baltimore, Maryland, United States

Site Status

Massachusetts General Hospital, 55 Fruit Street

Boston, Massachusetts, United States

Site Status

Lahey Clinic Medical Center

Burlington, Massachusetts, United States

Site Status

Henry Ford Hospital, 2799 W Grand Blvd, CFP-260

Detroit, Michigan, United States

Site Status

Michigan State University, Sparrow Hospital, B 401 Clinical Center

East Lansing, Michigan, United States

Site Status

University of Mississippi Medical Center

Jackson, Mississippi, United States

Site Status

Washington University/Barnes Jewish Hospital, 660 S. Euclid Avenue

St Louis, Missouri, United States

Site Status

University of Rochester Medical Center

Rochester, New York, United States

Site Status

Suny Upstate Medical University

Syracuse, New York, United States

Site Status

Mission Hospital, 509 Biltmore Avenue

Asheville, North Carolina, United States

Site Status