Interventional Management of Stroke (IMS) III Trial

Study Overview
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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.

Official Title
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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

Conditions
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Stroke

Intervention / Treatment
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* Drug: IV rt-PA alone
* Other: endovascular therapy


Participation Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 82 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: intravenous (IV) rt-PA alone<br>Group one will receive the standard dose of intravenous (IV) rt-PA alone given over an hour. | Drug: IV rt-PA alone<br>* 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.<br>* Other names: Activase®, Actilyse®;|
| Experimental: Endovascular therapy<br>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<br>* 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.<br>* Other names: Activase®, Actilyse®;Other: endovascular therapy<br>* 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.<br>* Other names: Activase®, Actilyse®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Death Due to Any Cause |  | within 90 days post randomization | 
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stroke, acute ischemic stroke, rt-PA, thrombolytic, recombinant tissue plasminogen activator, recanalization, blood clot, clot-dissolving, Activase®, Actilyse®, Concentric Merci® Retriever, EKOS® Micro-Infusion catheter (MicroLysus), The Penumbra System™, Standard microcatheter