Interventional Management of Stroke (IMS) III Trial

Stroke Clinical Trial

— IMSIII  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00359424
• Other study ID #: U01NS052220
• Secondary ID: U01NS052220U01NS
• Status: Terminated
• Phase: Phase 3
• First received: July 31, 2006
• Last updated: November 19, 2013
• Start date: August 2006
• Est. completion date: April 2013

Study information

• Verified date: November 2013
• Source: University of Cincinnati
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Federal GovernmentCanada: Health CanadaAustralia: Department of Health and Ageing Therapeutic Goods AdministrationFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Ethics CommissionNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)Spain: Ministry of HealthSwitzerland: Swissmedic
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 656
• Est. completion date: April 2013
• Est. primary completion date: July 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 82 Years

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Stroke

Intervention

Drug:
• 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.

Other:
• endovascular therapy
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.

Locations

Country	Name	City	State
Australia	Royal Prince Alfred Hospital, Level 10 King George V Building, Missenden Rd	Camperdown
Australia	St. Vincent's Hospital, Clincial Trial Centre Level 5, 378 Victoria St., Darlinghurst	Sydney
Australia	Monash Medical Center, Dept. of Neurology, 246 Clayton Rd, Clayton	Victoria
Australia	Royal Melbourne Hospital, Dept. of Neurology, 4 East, Grattan St, Parkville	Victoria
Canada	University of Calgary, Calgary Health Region/Foothills Hospital, 1403 29th Street NW	Calgary	Alberta
Canada	Centre Hospital University of Montreal	Montreal	Quebec
Canada	The Ottawa Hospital, Civic Campus, CPC Main, RM 36, Box 608, 1053 Carling Avenue	Ottawa	Ontario
Canada	St. Michael's Hospital	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	Toronto Western Hospital, 5th Floor Rm. 447, 399 Bathurst St.	Toronto	Ontario
Canada	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
France	Bichat Stroke Centre	Paris	Cedex
Germany	Technische Universität, Dresden	Dresden
Germany	University of Freiburg	Freiburg
Germany	Ernst Moritz Arndt University	Greifswald
Germany	Martin-Luther University	Halle
Germany	Asklepios Klinik Nord Heidberg	Hamburg
Netherlands	St. Antonius Hospital	Nieuwegein
Spain	Hospital Universitari Germans Trias i Pujol	Badalona
Spain	Hospital Vall d´Hebron	Barcelona
Switzerland	University Hospital Basel	Basel
Switzerland	Centre Hospitalier, University Vaudois	Lausanne
United States	Abington Memorial Hospital	Abington	Pennsylvania
United States	Lehigh Valley Hospital Center, 1200 South Cedar Crest Blvd.	Allentown	Pennsylvania
United States	Mission Hospital, 509 Biltmore Avenue	Asheville	North Carolina
United States	University Medical Center at Brackenridge Hospital	Austin	Texas
United States	Johns Hopkins University, 1500 Orleans St. 3M South	Baltimore	Maryland
United States	University of Alabama Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital, 55 Fruit Street	Boston	Massachusetts
United States	Lahey Clinic Medical Center	Burlington	Massachusetts
United States	University of North Carolina, CB # 7025, 7003 Neurosciences Hospital, 7th Floor	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia Health System	Charlottesville	Virginia
United States	Good Samaritan Hospital, 375 Dixmyth Ave.	Cincinnati	Ohio
United States	Mercy Hospital Anderson, 7500 State Rd	Cincinnati	Ohio
United States	Mercy Hospital, Mt Airy, 2446 Kipling Ave.	Cincinnati	Ohio
United States	Mercy Hospital, Western Hills, 3131 Queen City Ave.	Cincinnati	Ohio
United States	The Christ Hospital, 2139 Auburn Ave.	Cincinnati	Ohio
United States	The Jewish Hospital of Cincinnati, 4777 East Galbraith Rd	Cincinnati	Ohio
United States	The University Hospital, 234 Goodman Ave.	Cincinnati	Ohio
United States	Morton Plant Mease Health Care, 300 Pinellas Street MS 49	Clearwater	Florida
United States	University Hospitals of Cleveland, Case Western Reserve University,Case Western Neurological Unit, 11100 Euclid Avenue, Lakeside 5508	Cleveland	Ohio
United States	Riverside Methodist Hospital, 3535 Olentangy River Road	Columbus	Ohio
United States	Ruan Neurological Mercy Medical Center, 1111 6th Ave., Ste. 400	Des Moines	Iowa
United States	Henry Ford Hospital, 2799 W Grand Blvd, CFP-260	Detroit	Michigan
United States	Michigan State University, Sparrow Hospital, B 401 Clinical Center	East Lansing	Michigan
United States	St. Elizabeth Medical Center South, One Medical Village Drive	Edgewood	Kentucky
United States	Alexian Brothers Medical Center, 800 Biesterfield Rd.	Elk Grove Village	Illinois
United States	Colorado Neurological Institute, Swedish Medical Center, 501 E. Hampden Ave.	Englewood	Colorado
United States	Mercy Hospital Fairfield, 3000 Mack Rd.	Fairfield	Ohio
United States	St Luke's West Hospital, 7380 Turfway Rd.	Florence	Kentucky
United States	St. Luke's Hospital East, 85 N. Grand Ave.	Ft. Thomas	Kentucky
United States	Stroke Center at Hartford, 80 Seymour St. Rm JB603	Hartford	Connecticut
United States	PENN State M.S. Hershey Medical Center, 500 University Drive MC: HS 86, Long Lane Rom HG:212	Hershey	Pennsylvania
United States	University of Texas Medical School at Houston, 6431 Fannin, MSB 7.044	Houston	Texas
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	UCLA Medical Center, 924 Westwood Blvd., Suite 300	Los Angeles	California
United States	University of Louisville, Kentucky Neuroscience Research, Stroke Research, 401 East Chestnut Street, Suite 520	Louisville	Kentucky
United States	University of Miami Miller School of Medicine	Miami	Florida
United States	Froedtert Hospital, Medical College of Wisconsin, 9200 W. Wisconsin Avenue	Milwaukee	Wisconsin
United States	Bethesda North Hospital, 10500 Montgomery Rd.	Montgomery	Ohio
United States	Hoag Memorial Hospital	Newport Beach	California
United States	Barrow Neurology Clinics at St. Joseph's Hospital and Medical Center, 222 W. Thomas Road, Suite 404	Phoenix	Arizona
United States	Allegheny General Hospital, 420 East North Avenue, East Wing Office Bldg., Suite 206	Pittsburgh	Pennsylvania
United States	University of Pittsburgh, Medical Center, 200 Lothrop Street, PUH C-400	Pittsburgh	Pennsylvania
United States	OHSU, Oregon Stroke Center, Providence St. Vincent's Hospital, Providence Portland Hospital	Portland	Oregon
United States	University of Rochester Medical Center	Rochester	New York
United States	Santa Monica-UCLA Medical Center, 1250 16th Street	Santa Monica	California
United States	Mayo Clinic Arizona, 5777 E. Mayo Blvd.	Scottsdale	Arizona
United States	Washington University/Barnes Jewish Hospital, 660 S. Euclid Avenue	St. Louis	Missouri
United States	Suny Upstate Medical University	Syracuse	New York

Sponsors (4)

Lead Sponsor	Collaborator
Joseph Broderick	Medical University of South Carolina, National Institute of Neurological Disorders and Stroke (NINDS), University of Calgary

Countries where clinical trial is conducted

United States,  Australia,  Canada,  France,  Germany,  Netherlands,  Spain,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2.	The modified Rankin Scale (mRS) runs from 0-6 running from perfect health without symptoms to death. 0 - No symptoms at all. 1 - No significant disability. Able to carry out all usual duties and activities. 2 - Slight disability. Unable to carry out all previous activities but able to look after own affairs without assistance. 3 - Moderate disability. Requires some help, but able to walk unassisted. 4 - Moderately severe disability. Unable to walk unassisted and unable to attend to own bodily needs without assistance. 5 - Severe disability. Bedridden, incontinent, and requires constant nursing care and attention. 6 - Dead. Persons with a Rankin of 0-2 are considered functionally independent.	at 90 days post randomization	No
Primary	Death Due to Any Cause		within 90 days post randomization	Yes
Primary	Symptomatic Intracranial Hemorrhage	Symptomatic Intracranial Hemorrhage- Symptomatic ICH is defined as an intracranial hemorrhage temporally related to a decline in neurological status as well as new or worsening neurologic symptoms in the judgment of the clinical investigator and which may warrant medical intervention. These events are identified via Adverse Event CRF submitted by the site	within the first 30 hours post IV rt-PA	Yes
Secondary	Incidence of Parenchymal Type II (PH2) Hematomas	a dense intracerebral hematoma involving more than 30% of the infarcted area with substantial space-occupying effect or any hemorrhagic area outside the infarcted area, determined via central read of the submitted CT scans.	within 30 hours post IV rt-PA	Yes
Secondary	Asymptomatic Intracranial Hemorrhage	Asymptomatic intracranial hemorrhage is defined as an intracranial hemorrhage without evidence of decline in neurological status or new or worsening neurologic symptoms in the judgment of the clinical investigator. These events are identified via Adverse Event CRF submitted by the site.	within 30 hours post IV rt-PA	Yes
Secondary	National Institutes of Health Stroke Scale Score (NIHSS) >> Dichotomized 0-1 Versus 2 or Greater.	The National Institutes of Health Stroke Scale (NIHSS), a serial measure of neurologic deficit, is a 42-point scale that >> quantifies neurologic deficits in 11 categories, with 0 indicating normal function without neurologic deficit and higher; >> scores indicating greater severity of deficit.	at 24 hours post randomization	No
Secondary	National Institutes of Health Stroke Scale Score (NIHSS) Dichotomized 0-1 Versus 2 or Greater.	The National Institutes of Health Stroke Scale (NIHSS), a serial measure of neurologic deficit, is a 42-point scale that quantifies neurologic deficits in 11 categories, with 0 indicating normal function without neurologic deficit and higher scores indicating greater severity of deficit.	at 90 days post randomization	No
Secondary	Barthel Index (BI) Dichotomized 0-90 Versus 95-100	The Barthel Index (BI)is an ordinal scale used to measure a subject's performance in activities of daily living (ADL) in ten variables- feeding, transfer (bed to chair), grooming, toilet use, bathing, mobility on a level surface, stair use, dressing, bowels and bladder. It is an assessment of independence in ADL and is scored in increments of 5 points. The lowest possible score on the index is 0 which implies total dependence on others for ADL and the highest total score is 100 which indicate full independent in ADL. A higher score is associated with a greater likelihood of being able to live at home with a degree of independence.	at 90 days post randomization	No
Secondary	Trail Making Test Part A Time	The Trail Making Test is a neuropsychological test of visual attention and task switching that is thought to be sensitive to the presence of cerebral dysfunction. It is a timed test consisting of two parts where the subject is asked to draw a "trail" made by connecting numbers in sequential order (part A) and then in part B the combination of numbers and letters. Scoring is calculated separately for Parts A and B but both scores are provided as the minutes and seconds it takes for the subject to complete each part. Normally, the entire test (A and B) can be completed in 5 to 10 minutes.	90 days post randomization	No
Secondary	Trail Making Test Part B Time	The Trail Making Test is a neuropsychological test of visual attention and task switching that is thought to be sensitive to the presence of cerebral dysfunction. It is a timed test consisting of two parts where the subject is asked to draw a "trail" made by connecting numbers in sequential order (part A) and then in part B the combination of numbers and letters. Scoring is calculated separately for Parts A and B but both scores are provided as the minutes and seconds it takes for the subject to complete each part. Normally, the entire test (A and B) can be completed in 5 to 10 minutes.	at 90 days post randomization	No
Secondary	Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2	The modified Rankin Scale (mRS) runs from 0-6 running from perfect health without symptoms to death. 0 - No symptoms at all. 1 - No significant disability. Able to carry out all usual duties and activities. 2 - Slight disability. Unable to carry out all previous activities but able to look after own affairs without assistance. 3 - Moderate disability. Requires some help, but able to walk unassisted. 4 - Moderately severe disability. Unable to walk unassisted and unable to attend to own bodily needs without assistance. 5 - Severe disability. Bedridden, incontinent, and requires constant nursing care and attention. 6 - Dead. Persons with a Rankin of 0-2 are considered functionally independent.	at 180 days	No
Secondary	Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2	The modified Rankin Scale (mRS) runs from 0-6 running from perfect health without symptoms to death. 0 - No symptoms at all. 1 - No significant disability. Able to carry out all usual duties and activities. 2 - Slight disability. Unable to carry out all previous activities but able to look after own affairs without assistance. 3 - Moderate disability. Requires some help, but able to walk unassisted. 4 - Moderately severe disability. Unable to walk unassisted and unable to attend to own bodily needs without assistance. 5 - Severe disability. Bedridden, incontinent, and requires constant nursing care and attention. 6 - Dead. Persons with a Rankin of 0-2 are considered functionally independent.	270 days	No
Secondary	Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2	The modified Rankin Scale (mRS) runs from 0-6 running from perfect health without symptoms to death. 0 - No symptoms at all. 1 - No significant disability. Able to carry out all usual duties and activities. 2 - Slight disability. Unable to carry out all previous activities but able to look after own affairs without assistance. 3 - Moderate disability. Requires some help, but able to walk unassisted. 4 - Moderately severe disability. Unable to walk unassisted and unable to attend to own bodily needs without assistance. 5 - Severe disability. Bedridden, incontinent, and requires constant nursing care and attention. 6 - Dead. Persons with a Rankin of 0-2 are considered functionally independent.	360 days post randomization	No