• Efficacy: modified Rankin Scale score, dichotomized to 0-2 verses greater than 2. [ Time Frame: at 3 months from randomization ] [ Designated as safety issue: No ]
• Safety:(1) death due to any cause [ Time Frame: within 3 months ] [ Designated as safety issue: Yes ]
• (2) presence of symptomatic ICH (intracranial hemorrhage). [ Time Frame: within the first 24 (+ 6 hours) hours ] [ Designated as safety issue: Yes ]

• Efficacy: modified Rankin Scale score, dichotomized to 0-2 verses greater than 2 at 3 months from randomization.
• Safety:(1) death due to any cause within 3 months
• (2) presence of symptomatic ICH (intracranial hemorrhage) within the first 24 (+ 6 hours) hours.

• 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 [ Time Frame: at 6, 9, and 12 months from randomization ] [ Designated as safety issue: No ]
• Incidence of parenchymal Type II (PH2) hematomas and any asymptomatic ICH as determined by a standard head CT scan [ Time Frame: obtained within the first 24(+ 6hours) of randomization ] [ Designated as safety issue: Yes ]

• 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 [ Time Frame: at 6, 9, and 12 months from randomization ] [ Designated as safety issue: No ]
• Incidence of parenchymal Type II (PH2) hematomas and any asymptomic ICH as determined by a standard head CT scan [ Time Frame: obtained within the first 24(+ 6hours) of randomization ] [ Designated as safety issue: Yes ]

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.

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, and Australia. Participants will be assigned randomly to one of 2 groups. Two participants will be randomized to the combined approach for every one participant randomized to standard IV rt-PA. Group one will receive the standard dose of IV rt-PA given over an hour. 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. All of the IA treatments used—embolectomy therapy with either the Merci® Retriever or The Penumbra System™, or 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.

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.

• Drug: IV rt-PA
• Drug: IA rt-PA (Investigational)
• Device: Standard Microcatheter Infusion (all commercially available models)
• Device: EKOS Micro-Infusion (NeuroWave Infusion) System
• Device: Concentric Merci® Retriever (all FDA approved commercially available models)
• Device: The Penumbra System™ (all FDA approved commercially available models)

• Active Comparator: 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.
• Active Comparator: 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

Inclusion Criteria:

• Age: 18 through 82 years (i.e., candidates must have had their 18th birthday, but not their 83rd birthday).
• Initiation of IV rt-PA within 3 hours of onset of stroke symptoms. Time of onset is defined as the last time when the patient 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 IV 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 blood pressure to below these limits are needed.
• Presumed septic embolus, or suspicion of bacterial endocarditis
• Presumed pericarditis including pericarditis after acute myocardial infarction.
• 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.
• Patients with known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency; or oral anticoagulant therapy require coagulation lab results prior to enrollment. Any subject with INR greater than 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
• Patients that require hemodialysis or peritoneal dialysis, or who have a contradiction to an angiogram for whatever reason .
• Patients who have received heparin or a direct thrombin inhibitor (Angiomax™ or argatroban, Refludan™) within 48 hours must have a normal partial thromboplastin time (PTT) to be eligible.
• Subjects with an arterial puncture at a non-compressible site or a lumbar puncture in the previous 7 days.
• Patients with a seizure at onset of stroke
• Patients with 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 patient if Activase (Alteplase) therapy is initiated.
• Current participation in another research drug treatment protocol.
• Informed consent is not or cannot be obtained. For example, obtunded patients are not automatically excluded from the study. However, if the next of kin or legal guardian (i.e., the individual legally empowered in the state where the consent is obtained) cannot provide consent, randomization and entry into the study could not proceed.

IMAGING Exclusion Criteria:

• High density lesion consistent with hemorrhage of any degree.
• Significant mass effect with midline shift.
• Large (more than 1/3 of the middle cerebral artery) regions of clear hypodensity on the baseline imaging. An ASPECTS of < 4can be used as a guideline when evaluating >1/3 region of territory involvement. Sulcal effacement and / or loss of grey-white differentiation alone are not contraindications for treatment.

• National Institute of Neurological Disorders and Stroke (NINDS)
• Medical University of South Carolina
• University of Calgary