• 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 ]
  

• 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 ]
  

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 3 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 the Merci® Retriever, 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—are FDA-approved.

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.