Interventional Management of Stroke (IMS) III Trial (IMSIII)
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Purpose
The purpose of this study is to compare two different treatment approaches—combined intravenous and intra-arterial treatment including recombinant tissue plasminogen activator (rt-PA) and standard intravenous (IV) rt-PA—to restoring blood flow to the brain.
| Condition | Intervention | Phase |
|---|---|---|
|
Stroke |
Drug: IV rt-PA Other: inter-arterial rt-PA Other: Endovascular Treatment |
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 |
- modified Rankin Scale score [ Time Frame: at 90 days ] [ Designated as safety issue: No ]dichotomized to 0-2 versus greater than 2.
- death due to any cause [ Time Frame: within 90 days ] [ Designated as safety issue: Yes ]
- symptomatic intracranial hemorrhage [ Time Frame: within the first 30 hours ] [ Designated as safety issue: Yes ]
- Barthel Index [ Time Frame: at 90 days ] [ Designated as safety issue: No ]
- Incidence of parenchymal Type II (PH2) hematomas [ Time Frame: within 30 hours ] [ Designated as safety issue: Yes ]
- NIHSSS [ Time Frame: at 90 days ] [ Designated as safety issue: No ]
- Trail Making Test [ Time Frame: at 90 days ] [ Designated as safety issue: No ]
- NIHSSS [ Time Frame: at 24 hours ] [ Designated as safety issue: No ]
- modified Rankin Scale score [ Time Frame: at 180 days, 270 days and 360 days ] [ Designated as safety issue: No ]
- asymptomatic intracranial hemorrhage [ Time Frame: within 30 hours ] [ Designated as safety issue: Yes ]
| Estimated Enrollment: | 900 |
| Study Start Date: | August 2006 |
| Estimated Study Completion Date: | November 2015 |
| Estimated Primary Completion Date: | May 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: standard dose IV rt-PA
Group one will receive the standard dose of IV rt-PA given over an hour. One out of every 3 subjects will be in this group.
|
Drug: IV rt-PA
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. Group two will receive a lower dose or the standard dose of IV rt-PA.
Other Name: Activase®, Actilyse®
|
|
Experimental: IV/IA
Two out of every 3 subjects will be in the IV/IA group. 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 (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: IA rt-PA (inter-arterial rt-PA) only, IA rt-PA with device intervention, or device intervention without rt-PA.
|
Drug: IV rt-PA
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. Group two will receive a lower dose or the standard dose of IV rt-PA.
Other Name: Activase®, Actilyse®
Other: inter-arterial rt-PA
Two out of every 3 subjects will be in the IV/IA group. 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: IA rt-PA (inter-arterial rt-PA) only, IA rt-PA with device intervention, or device intervention without rt-PA.
Other Name: Activase®, Actilyse®
Other: Endovascular Treatment
Endovascular treatment with or without inter-arterial rt-PA use.
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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, Australia and Europe.
Subjects will be randomized in a 2:1 ratio with more subjects enrolled in the combined IV/IA group. 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 combined IV/IA 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 intra-arterial treatment 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. Intra-arterial 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 IV/IA approach to the standard IV rt-PA approach.
Duration of the study for participants is approximately 12 months.
Eligibility| Ages Eligible for Study: | 18 Years to 82 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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
Show 71 Study Locations| 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 |
| Last Updated: | January 15, 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 June 18, 2013