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

Terminated

Phase 3 Results

Trial Description

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

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.

Trial Stopped: NINDS/NIH-DSMB recommended halting trial due to futility, no safety concerns.

Conditions

Interventions

  • Tissue plasminogen activator (Activase®)Drug
    Other Names: Alteplase; tPA
    Intervention Desc: Thrombolytic
  • Thrombectomy Device
    Other Names: Mechanical thrombectomy
    Intervention Desc: Catheter is inserted intra-arterially to open cerebral blood vessels and remove clot.
  • Catheter (NeuroFlo catheter)Other
    Intervention Desc: NeuroFlo catheter
  • IV rt-PA Drug
    Other Names: Alteplase, Activase
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: Group 1
    Description: 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.
    ARM 2: Kind: Experimental
    Label: standard dose IV rt-PA
    Description: 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.
    ARM 3: Kind: Experimental
    Label: IV/IA
    Description: 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.
  • IA rt-PA Drug
    Intervention Desc: Intra-Arterial
  • Concentric Merci Retrievers Other
    Intervention Desc: Remove the clot by putting an FDA approved device through the clot and pulling it back to remove the attached clot into the tube and pulling it out of your body. If your doctor first attempts to remove the clot with such a device, you may still receive rt-PA if some of the clot is still present.
  • EKOS Micro-Infusion (NeuroWave Infusion) System Device
    Intervention Desc: Consisting of the PT-2 (B) control Unit and Micro-infusion Catheter Models SV3014, Primo Family (Neurowave Catheters) Some participants may receive IA treatment via rt-PA infusion through the EKOS® Micro-Infusion Catheter concurrent with delivery of low-intensity ultrasound energy.
    ARM 1: Kind: Experimental
    Label: Group 2
    Description: Group two will receive the standard dose of IV rt-PA for only 40 minutes 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 doctor (a neurointerventionalist) will then choose, based on the location and extent of the blood clot, one of 4 possible IA treatments given directly in the brain artery that will be most effective in reopening the blocked artery. Two out of every 3 subjects will be in this group
  • IA rt-PA (Investigational) Drug
    Intervention Desc: This new approach gives 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). The doctor will choose--based on the location and extent of the blood clot--one of 4 possible IA treatments given directly in the brain artery that will be most effective in reopening the blocked artery. The IA treatments will use either: embolectomy therapy with the Merci® Retriever or the Penumbra System™, rt-PA infusion through the EKOS® Micro-Infusion Catheter concurrent with delivery of low-intensity ultrasound energy, or infusion of rt-PA though a standard microcatheter at the site of the blood clot in the brain artery.
    ARM 1: Kind: Experimental
    Label: Group 2
    Description: Group two will receive the standard dose of IV rt-PA for only 40 minutes 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 doctor (a neurointerventionalist) will then choose, based on the location and extent of the blood clot, one of 4 possible IA treatments given directly in the brain artery that will be most effective in reopening the blocked artery. Two out of every 3 subjects will be in this group
  • Standard Microcatheter Infusion (all commercially available models) Device
    Intervention Desc: Some participants may receive IA treatment via standard microcatheter infusion.
    ARM 1: Kind: Experimental
    Label: Group 2
    Description: Group two will receive the standard dose of IV rt-PA for only 40 minutes 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 doctor (a neurointerventionalist) will then choose, based on the location and extent of the blood clot, one of 4 possible IA treatments given directly in the brain artery that will be most effective in reopening the blocked artery. Two out of every 3 subjects will be in this group
  • Concentric Merci® Retriever (all FDA approved commercially available models) Device
    Intervention Desc: Used in embolectomy therapy for IA treatment
    ARM 1: Kind: Experimental
    Label: Group 2
    Description: Group two will receive the standard dose of IV rt-PA for only 40 minutes 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 doctor (a neurointerventionalist) will then choose, based on the location and extent of the blood clot, one of 4 possible IA treatments given directly in the brain artery that will be most effective in reopening the blocked artery. Two out of every 3 subjects will be in this group
  • The Penumbra System™ (all FDA approved commercially available models) Device
    Intervention Desc: Used in embolectomy therapy for IA treatment
    ARM 1: Kind: Experimental
    Label: Group 2
    Description: Group two will receive the standard dose of IV rt-PA for only 40 minutes 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 doctor (a neurointerventionalist) will then choose, based on the location and extent of the blood clot, one of 4 possible IA treatments given directly in the brain artery that will be most effective in reopening the blocked artery. Two out of every 3 subjects will be in this group
  • Solitaire™ FR Revascularization Device (investigational in the US, Canada and Australia) Device
    Intervention Desc: Used in embolectomy therapy for IA treatment
    ARM 1: Kind: Experimental
    Label: Group 2
    Description: Group two will receive the standard dose of IV rt-PA for only 40 minutes 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 doctor (a neurointerventionalist) will then choose, based on the location and extent of the blood clot, one of 4 possible IA treatments given directly in the brain artery that will be most effective in reopening the blocked artery. Two out of every 3 subjects will be in this group
  • Inter-arterial rt-PA Other
    Other Names: Activase®, Actilyse®
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: IV/IA
    Description: 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.
  • Endovascular Treatment Procedure
    Other Names: ET
    Intervention Desc: Endovascular treatment with or without inter-arterial rt-PA use.
    ARM 1: Kind: Experimental
    Label: IV/IA
    Description: 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.
  • Endovascular therapy Device
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: Endovascular therapy
    Description: 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.
  • IV rt-PA alone Drug
    Other Names: Activase®, Actilyse®
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: intravenous (IV) rt-PA alone
    Description: Group one will receive the standard dose of intravenous (IV) rt-PA alone given over an hour.
    ARM 2: Kind: Experimental
    Label: Endovascular therapy
    Description: 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.

Trial Design

  • Allocation: Randomized
  • Masking: Open Label
  • Purpose: Treatment
  • Endpoint: Safety/Efficacy Study
  • Intervention: Parallel Assignment

Patient Involvement

Subjects will be randomized in a 2:1 ratio to the IV/IA group and the IV rt-PA alone group respectively. The IV rt-PA group will receive the full standard dose (0.9 mg/kg, 90 mg max [10% as bolus]) of rt-PA intravenously over an hour. The combined IV/IA group will receive a lower dose of rt-PA (~ 0.6 mg/kg, 60 mg max) over 40 minutes followed by immediate angiography. If a treatable thrombus is not demonstrated, no IA therapy will be administered. If an appropriate thrombus is identified, treatment will continue with either the Concentric Merci® thrombus-removal device, infusion of rt-PA and delivery of low-intensity ultrasound at the site of the occlusion via the EKOS® Micro-Infusion Catheter, or infusion of rt-PA via a standard micro-catheter. The choice of IA strategy will be made by the treating neurointerventionalist based upon the location of the thrombus and associated vascular anatomy, prior experience and training with the Concentric Merci® Retriever and/or the EKOS® Micro-Infusion catheter, and specifications from the instructions for use (IFUs) of each device. A maximum dose of 22 mg of rt-PA will be administered intra-arterially, and IA treatment must begin within 5 hours and be completed within 7 hours of stroke onset.

Outcomes

Type Measure Time Frame Safety Issue
Primary Favorable clinical outcome, defined as a modified Rankin Score (mRS) of 0-2 at 3 months. Primary safety measures are mortality at 3 months and symptomatic ICH within the first 30 hours after onset.
Secondary Barthel Index, Glasgow Outcome Scale, NIHSSS, EuroQol EQ-5D, and Trail Making Test, Parts A and B, at 3 months; early response to treatment as determined by an NIHSSS of 0-2 at 24 hours; a CT angiography assessment of intracranial vascular patency at 24 hours (both treatment groups); the volume of cerebral infarction as measured by a CT scan at 24 +/- 6 hours from onset; the rate of TICI Grade II or III perfusion flow and recanalization of the primary arterial occlusion at completion of angiography (combined IV/IA group only). Secondary safety measures: the proportion of subjects with Type II parenchymal intracerebral hematomas within the first 36 hours, and the incidence of any asymptomatic hemorrhage within the first 24 hours. A secondary objective of the IMS III Trial is to determine the cost-effectiveness of the combined IV/IA approach as compared to standard IV rt-PA by measuring differences in utilization of resources and quality of life.
Primary Efficacy: modified Rankin Scale score, dichotomized to 0-2 verses greater than 2. at 3 months from randomization No
Primary Safety:(1) death due to any cause within 3 months Yes
Primary (2) presence of symptomatic ICH (intracranial hemorrhage). within the first 24 (+ 6 hours) hours Yes
Secondary Barthel Index, NIHSSS and Trail Making Test at 3 months; early response to treatment as determined by NIHSSS of 0-2 at 24 hours from randomization; and dichotomized mRS score (0-2) versus 306 at 6, 9, and 12 months from randomization No
Secondary Incidence of parenchymal Type II (PH2) hematomas and any asymptomatic ICH as determined by a standard head CT scan obtained within the first 24(+ 6hours) of randomization Yes
Primary modified Rankin Scale score at 90 days No
Primary death due to any cause within 90 days Yes
Primary symptomatic intracranial hemorrhage within the first 30 hours Yes
Secondary Barthel Index at 90 days No
Secondary Incidence of parenchymal Type II (PH2) hematomas within 30 hours Yes
Secondary NIHSSS at 90 days No
Secondary Trail Making Test at 90 days No
Secondary asymptomatic intracranial hemorrhage within 30 hours Yes
Primary Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2. at 90 days post randomization No
Secondary National Institutes of Health Stroke Scale Score (NIHSS) >> Dichotomized 0-1 Versus 2 or Greater. at 24 hours post randomization No
Secondary National Institutes of Health Stroke Scale Score (NIHSS) Dichotomized 0-1 Versus 2 or Greater. at 90 days post randomization No
Secondary Barthel Index (BI) Dichotomized 0-90 Versus 95-100 at 90 days post randomization No
Secondary Trail Making Test Part A Time 90 days post randomization No
Secondary Trail Making Test Part B Time at 90 days post randomization No
Secondary Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2 at 180 days No

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