Interventional Management of Stroke (IMS) III Trial (IMSIII)

This study has been terminated.
(NINDS/NIH-DSMB recommended halting trial due to futility, no safety concerns.)
Sponsor:
Collaborators:
Medical University of South Carolina
University of Calgary
Information provided by (Responsible Party):
Joseph Broderick, University of Cincinnati
ClinicalTrials.gov Identifier:
NCT00359424
First received: July 31, 2006
Last updated: November 19, 2013
Last verified: November 2013
  Purpose

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.


Condition Intervention Phase
Stroke
Drug: IV rt-PA alone
Other: endovascular therapy
Phase 3

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

Resource links provided by NLM:


Further study details as provided by University of Cincinnati:

Primary Outcome Measures:
  • Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2. [ Time Frame: at 90 days post randomization ] [ Designated as safety issue: No ]
    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.

  • Death Due to Any Cause [ Time Frame: within 90 days post randomization ] [ Designated as safety issue: Yes ]
  • Symptomatic Intracranial Hemorrhage [ Time Frame: within the first 30 hours post IV rt-PA ] [ Designated as safety issue: Yes ]
    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


Secondary Outcome Measures:
  • Incidence of Parenchymal Type II (PH2) Hematomas [ Time Frame: within 30 hours post IV rt-PA ] [ Designated as safety issue: Yes ]
    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.

  • Asymptomatic Intracranial Hemorrhage [ Time Frame: within 30 hours post IV rt-PA ] [ Designated as safety issue: Yes ]
    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.

  • National Institutes of Health Stroke Scale Score (NIHSS) >> Dichotomized 0-1 Versus 2 or Greater. [ Time Frame: at 24 hours post randomization ] [ Designated as safety issue: No ]

    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.


  • National Institutes of Health Stroke Scale Score (NIHSS) Dichotomized 0-1 Versus 2 or Greater. [ Time Frame: at 90 days post randomization ] [ Designated as safety issue: No ]
    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.

  • Barthel Index (BI) Dichotomized 0-90 Versus 95-100 [ Time Frame: at 90 days post randomization ] [ Designated as safety issue: No ]
    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.

  • Trail Making Test Part A Time [ Time Frame: 90 days post randomization ] [ Designated as safety issue: No ]
    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.

  • Trail Making Test Part B Time [ Time Frame: at 90 days post randomization ] [ Designated as safety issue: No ]
    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.

  • Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2 [ Time Frame: at 180 days ] [ Designated as safety issue: No ]
    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.

  • Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2 [ Time Frame: 270 days ] [ Designated as safety issue: No ]
    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.

  • Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2 [ Time Frame: 360 days post randomization ] [ Designated as safety issue: No ]
    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.


Enrollment: 656
Study Start Date: August 2006
Study Completion Date: April 2013
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: intravenous (IV) rt-PA alone
Group one will receive the standard dose of intravenous (IV) rt-PA alone given over an hour.
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 Name: Activase®, Actilyse®
Experimental: 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.
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 Name: Activase®, Actilyse®
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.
Other Name: Activase®, Actilyse®

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 82 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00359424

  Show 71 Study Locations
Sponsors and Collaborators
Joseph Broderick
Medical University of South Carolina
University of Calgary
Investigators
Principal Investigator: Joseph P. Broderick, MD Primary Neurologist Investigator, University of Cincinnati Academic Health Center
Principal Investigator: Thomas A. Tomsick, MD Primary Interventional Investigator, University of Cincinnati Academic Health Center
  More Information

No publications provided by University of Cincinnati

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

Responsible Party: Joseph Broderick, Professor and Chairman Department of Neurology, University of Cincinnati
ClinicalTrials.gov Identifier: NCT00359424     History of Changes
Other Study ID Numbers: U01NS052220, U01NS052220, U01NS054630, 2009-017454-12
Study First Received: July 31, 2006
Results First Received: July 4, 2013
Last Updated: November 19, 2013
Health Authority: United States: Food and Drug Administration
United States: Federal Government
Canada: Health Canada
Australia: Department of Health and Ageing Therapeutic Goods Administration
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Ethics Commission
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Spain: Ministry of Health
Switzerland: Swissmedic

Keywords provided by University of Cincinnati:
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

Additional relevant MeSH terms:
Stroke
Cerebral Infarction
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Brain Infarction
Brain Ischemia
Tissue Plasminogen Activator
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Cardiovascular Agents
Therapeutic Uses
Hematologic Agents

ClinicalTrials.gov processed this record on September 16, 2014