title: Safety and Tolerability of Desmoteplase Within 3 to 9 Hours After Symptoms Onset in Japanese Patients With Ischemic Stroke.
abstract: OBJECTIVE
  This study investigated the safety and tolerability of desmoteplase administered within 3 to 9 hours after stroke symptoms onset in Japanese patients with acute ischemic stroke.
  
  
  METHODS
  Patients were randomized to treatment with either desmoteplase or placebo in a 2:1 ratio in 2 consecutive cohorts (70 μg/kg and then 90 μg/kg). Included patients had a baseline National Institutes of Health Stroke Scale score of 4 to 24 and occlusion or high-grade stenosis in the middle cerebral artery segment M1 or M2 on magnetic resonance angiography. The incidence of symptomatic intracranial hemorrhage (≤72 hours) was defined as the primary end point. The occurrence of asymptomatic ICH, symptomatic cerebral edemas, and adverse events were other safety outcomes of special interest.
  
  
  RESULTS
  Symptomatic intracranial hemorrhage was observed within 72 hours in 2 patients treated with placebo and in 1 patient treated with 70 μg/kg desmoteplase. Any ICH (symptomatic or asymptomatic ICH) within 72 hours were observed in 7 (43.8%) patients treated with placebo, in 8 (50%) patients treated with 70 μg/kg desmoteplase, and in 9 (56.3%) patients treated with 90 μg/kg desmoteplase. Desmoteplase treatment with 70 or 90 μg/kg was not associated with an increased risk of symptomatic cerebral edema compared with placebo. There were no other serious safety concerns associated with desmoteplase.
  
  
  CONCLUSIONS
  Desmoteplase in both 70 and 90 μg/kg doses had a favorable safety profile and was well tolerated in Japanese patients with acute ischemic stroke when administered 3 to 9 hours after stroke symptoms onset.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT01104467.
authors.affiliation: From the Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan (E.M.); Department of Cerebrovascular Medicine (K.M., T.Y.), Department of Integrative Stroke Imaging Center (J.N.), National Cerebral and Cardiovascular Center, Suita, Japan; Department of Neurology, St. Marianna University School of Medicine, Kawasaki, Japan (Y.H.); Department of Neurosurgery, University of Tokushima Graduate School, Tokushima, Japan (S.N.); Department of Cerebrovascular Disease, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan (Y.O.); International Clinical Research Neurology (T.T.), Biostatistics (A.L.), H. Lundbeck A/S, Valby, Denmark; and Department of Neurosurgery, Iwate Medical University, Morioka, Japan (A.O.). morie@med.tohoku.ac.jp.
authors.forename: Etsuro
authors.initials: E
authors.lastname: Mori
authors.affiliation: From the Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan (E.M.); Department of Cerebrovascular Medicine (K.M., T.Y.), Department of Integrative Stroke Imaging Center (J.N.), National Cerebral and Cardiovascular Center, Suita, Japan; Department of Neurology, St. Marianna University School of Medicine, Kawasaki, Japan (Y.H.); Department of Neurosurgery, University of Tokushima Graduate School, Tokushima, Japan (S.N.); Department of Cerebrovascular Disease, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan (Y.O.); International Clinical Research Neurology (T.T.), Biostatistics (A.L.), H. Lundbeck A/S, Valby, Denmark; and Department of Neurosurgery, Iwate Medical University, Morioka, Japan (A.O.).
authors.forename: Kazuo
authors.initials: K
authors.lastname: Minematsu
authors.affiliation: From the Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan (E.M.); Department of Cerebrovascular Medicine (K.M., T.Y.), Department of Integrative Stroke Imaging Center (J.N.), National Cerebral and Cardiovascular Center, Suita, Japan; Department of Neurology, St. Marianna University School of Medicine, Kawasaki, Japan (Y.H.); Department of Neurosurgery, University of Tokushima Graduate School, Tokushima, Japan (S.N.); Department of Cerebrovascular Disease, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan (Y.O.); International Clinical Research Neurology (T.T.), Biostatistics (A.L.), H. Lundbeck A/S, Valby, Denmark; and Department of Neurosurgery, Iwate Medical University, Morioka, Japan (A.O.).
authors.forename: Jyoji
authors.initials: J
authors.lastname: Nakagawara
authors.affiliation: From the Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan (E.M.); Department of Cerebrovascular Medicine (K.M., T.Y.), Department of Integrative Stroke Imaging Center (J.N.), National Cerebral and Cardiovascular Center, Suita, Japan; Department of Neurology, St. Marianna University School of Medicine, Kawasaki, Japan (Y.H.); Department of Neurosurgery, University of Tokushima Graduate School, Tokushima, Japan (S.N.); Department of Cerebrovascular Disease, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan (Y.O.); International Clinical Research Neurology (T.T.), Biostatistics (A.L.), H. Lundbeck A/S, Valby, Denmark; and Department of Neurosurgery, Iwate Medical University, Morioka, Japan (A.O.).
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: From the Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan (E.M.); Department of Cerebrovascular Medicine (K.M., T.Y.), Department of Integrative Stroke Imaging Center (J.N.), National Cerebral and Cardiovascular Center, Suita, Japan; Department of Neurology, St. Marianna University School of Medicine, Kawasaki, Japan (Y.H.); Department of Neurosurgery, University of Tokushima Graduate School, Tokushima, Japan (S.N.); Department of Cerebrovascular Disease, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan (Y.O.); International Clinical Research Neurology (T.T.), Biostatistics (A.L.), H. Lundbeck A/S, Valby, Denmark; and Department of Neurosurgery, Iwate Medical University, Morioka, Japan (A.O.).
authors.forename: Shinji
authors.initials: S
authors.lastname: Nagahiro
authors.affiliation: From the Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan (E.M.); Department of Cerebrovascular Medicine (K.M., T.Y.), Department of Integrative Stroke Imaging Center (J.N.), National Cerebral and Cardiovascular Center, Suita, Japan; Department of Neurology, St. Marianna University School of Medicine, Kawasaki, Japan (Y.H.); Department of Neurosurgery, University of Tokushima Graduate School, Tokushima, Japan (S.N.); Department of Cerebrovascular Disease, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan (Y.O.); International Clinical Research Neurology (T.T.), Biostatistics (A.L.), H. Lundbeck A/S, Valby, Denmark; and Department of Neurosurgery, Iwate Medical University, Morioka, Japan (A.O.).
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okada
authors.affiliation: From the Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan (E.M.); Department of Cerebrovascular Medicine (K.M., T.Y.), Department of Integrative Stroke Imaging Center (J.N.), National Cerebral and Cardiovascular Center, Suita, Japan; Department of Neurology, St. Marianna University School of Medicine, Kawasaki, Japan (Y.H.); Department of Neurosurgery, University of Tokushima Graduate School, Tokushima, Japan (S.N.); Department of Cerebrovascular Disease, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan (Y.O.); International Clinical Research Neurology (T.T.), Biostatistics (A.L.), H. Lundbeck A/S, Valby, Denmark; and Department of Neurosurgery, Iwate Medical University, Morioka, Japan (A.O.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Truelsen
authors.affiliation: From the Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan (E.M.); Department of Cerebrovascular Medicine (K.M., T.Y.), Department of Integrative Stroke Imaging Center (J.N.), National Cerebral and Cardiovascular Center, Suita, Japan; Department of Neurology, St. Marianna University School of Medicine, Kawasaki, Japan (Y.H.); Department of Neurosurgery, University of Tokushima Graduate School, Tokushima, Japan (S.N.); Department of Cerebrovascular Disease, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan (Y.O.); International Clinical Research Neurology (T.T.), Biostatistics (A.L.), H. Lundbeck A/S, Valby, Denmark; and Department of Neurosurgery, Iwate Medical University, Morioka, Japan (A.O.).
authors.forename: Annika
authors.initials: A
authors.lastname: Lindsten
authors.affiliation: From the Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan (E.M.); Department of Cerebrovascular Medicine (K.M., T.Y.), Department of Integrative Stroke Imaging Center (J.N.), National Cerebral and Cardiovascular Center, Suita, Japan; Department of Neurology, St. Marianna University School of Medicine, Kawasaki, Japan (Y.H.); Department of Neurosurgery, University of Tokushima Graduate School, Tokushima, Japan (S.N.); Department of Cerebrovascular Disease, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan (Y.O.); International Clinical Research Neurology (T.T.), Biostatistics (A.L.), H. Lundbeck A/S, Valby, Denmark; and Department of Neurosurgery, Iwate Medical University, Morioka, Japan (A.O.).
authors.forename: Akira
authors.initials: A
authors.lastname: Ogawa
authors.affiliation: From the Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan (E.M.); Department of Cerebrovascular Medicine (K.M., T.Y.), Department of Integrative Stroke Imaging Center (J.N.), National Cerebral and Cardiovascular Center, Suita, Japan; Department of Neurology, St. Marianna University School of Medicine, Kawasaki, Japan (Y.H.); Department of Neurosurgery, University of Tokushima Graduate School, Tokushima, Japan (S.N.); Department of Cerebrovascular Disease, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan (Y.O.); International Clinical Research Neurology (T.T.), Biostatistics (A.L.), H. Lundbeck A/S, Valby, Denmark; and Department of Neurosurgery, Iwate Medical University, Morioka, Japan (A.O.).
authors.forename: Takenori
authors.initials: T
authors.lastname: Yamaguchi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000188:drug therapy*; D003251:Constriction, Pathologic / Q000473:pathology; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D007564:Japan; D008297:Male; D008875:Middle Aged; D010960:Plasminogen Activators / Q000008:administration & dosage* / Q000009:adverse effects*; D020521:Stroke / Q000188:drug therapy*; D015912:Thrombolytic Therapy / Q000009:adverse effects* / Q000379:methods; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; C069588:salivary plasminogen activator alpha 1, Desmodus rotundus; D010960:Plasminogen Activators
keywords: DIAS-J; acute ischemic stroke; desmoteplase; fibrin-dependent plasminogen activator; safety; thrombolysis