Background and Purpose - Most acute ischemic stroke patients arrive after the 3- hour time window for recombinant tissue plasminogen activator (rtPA) administration. The Desmoteplase In Acute Ischemic Stroke trial (DIAS) was a dose- finding randomized trial designed to evaluate the safety and efficacy of intravenous desmoteplase, a highly fibrin- specific and nonneurotoxic thrombolytic agent, administered within 3 to 9 hours of ischemic stroke onset in patients with perfusion/diffusion mismatch on MRI. Methods - DIAS was a placebo- controlled, double- blind, randomized, dose- finding phase II trial. Patients with National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20 and MRI evidence of perfusion/diffusion mismatch were eligible. Of 104 patients, the first 47 (referred to as Part 1) were randomized to fixed doses of desmoteplase (25 mg, 37.5 mg, or 50 mg) or placebo. Because of an excessive rate of symptomatic intracranial hemorrhage (sICH), lower weight- adjusted doses escalating through 62.5 μ g/kg, 90 μ g/kg, and 125 μ g/kg were subsequently investigated in 57 patients (referred to as Part 2). The safety endpoint was the rate of sICH. Efficacy endpoints were the rate of reperfusion on MRI after 4 to 8 hours and clinical outcome as assessed by NIHSS, modified Rankin scale, and Barthel Index at 90 days. Results - Part 1 was terminated prematurely because of high rates of sICH with desmoteplase (26.7% ). In Part 2, the sICH rate was 2.2% . No sICH occurred with placebo in either part. Reperfusion rates up to 71.4% (P=0.0012) were observed with desmoteplase (125 μ g/kg) compared with 19.2% with placebo. Favorable 90- day clinical outcome was found in 22.2% of placebo- treated patients and between 13.3% (62.5 μ g/kg; P=0.757) and 60.0% (125 μ g/kg; P=0.0090) of desmote- plase- treated patients. Early reperfusion correlated favorably with clinical outcome (P=0.0028). Favorable outcome occurred in 52.5% of patients experiencing reperfusion versus 24.6% of patients without reperfusion. Conclusions - Intravenous desmoteplase administered 3 to 9 hours after acute ischemic stroke in patients selected with perfusion/diffusion mismatch is associated with a higher rate of reperfusion and better clinical outcome compared with placebo. The sICH rate with desmoteplase was low, using doses up to 125 μ g/kg. Background and Purpose - Most acute ischemic stroke patients arrive after 3-hour time window for recombinant tissue plasminogen activator (rtPA) administration. The Desmoteplase In Acute Ischemic Stroke trial (DIAS) was a dose- finding randomized trial designed to evaluate the safety and efficacy of intravenous desmoteplase, a highly fibrin-specific and nonneurotoxic thrombolytic agent, administered within 3 to 9 hours of ischemic stroke onset in patients with perfusion / diffusion mismatch on MRI. Methods - DIAS was a placebo-controlled, double-blind, randomized, Patients with National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20 and MRI evidence of perfusion / diffusion mismatch were eligible. Of 104 patients, the first 47 (referred to as Part 1) were randomized to fixed doses of desmoteplase (25 mg, 37.5 mg, or 50 mg) or placebo. Because of an excessive rate of symptomatic intracranial hemorrhage (sICH), lower weight- adjusted doses es The safety endpoint was the rate of sICH. Efficacy of endpoints were the rate of reperfusion. on MRI after 4 to 8 hours and clinical outcome assessed by NIHSS, modified Rankin scale, and Barthel Index at 90 days. Results - Part 1 was terminated prematurely because of high rates of sICH with desmoteplase (26.7%). In Part 2, The sICH rate was 2.2%. No sICII occurred with placebo in either part. Reperfusion rates up to 71.4% (P = 0.0012) were observed with desmoteplase (125 μg / kg) compared with 19.2% with placebo. Favorable 90- day clinical The results were found in 22.2% of placebo-treated patients and between 13.3% (62.5 μg / kg; P = 0.757) and 60.0% (125 μg / kg; P = 0.0090) of desmote-plase-treated patients. Highly correlated with favorably with clinical outcome (P = 0.0028). Favorable outcome occurred in 52.5% of patients experiencing reperfusion versus 24.6 % of patients without reperfusion. Conclusions - Intravenous desmoteplase administered 3 to 9 hours after acute ischemic stroke in patients selected with perfusion / diffusion mismatch is associated with a higher rate of reperfusion and better clinical outcome compared with placebo. The sICH rate with desmoteplase was low, using doses up to 125 μ g / kg.