title: Randomized, Open-Label, Phase 1/2a Study to Determine the Maximum Tolerated Dose of Intraventricular Sustained Release Nimodipine for Subarachnoid Hemorrhage (NEWTON [Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage]).
abstract: We conducted a randomized, open-label, phase 1/2a, dose-escalation study of intraventricular sustained-release nimodipine (EG-1962) to determine safety, tolerability, pharmacokinetics, and clinical effects in aneurysmal subarachnoid hemorrhage.
  
  
  
  Subjects with aneurysmal subarachnoid hemorrhage repaired by clipping or coiling were randomized to EG-1962 or enteral nimodipine. Subjects were World Federation of Neurological Surgeons grade 2 to 4 and had an external ventricular drain. Cohorts of 12 subjects received 100 to 1200 mg EG-1962 (9 per cohort) or enteral nimodipine (3 per cohort). The primary objective was to determine the maximum tolerated dose.
  
  
  
  Fifty-four subjects in North America were randomized to EG-1962, and 18 subjects were randomized to enteral nimodipine. The maximum tolerated dose was 800 mg. One serious adverse event related to EG-1962 (400 mg) and 2 EG-1962 dose-limiting toxicities were without clinical sequelae. There was no EG-1962-related hypotension compared with 17% (3/18) with enteral nimodipine. Favorable outcome at 90 days on the extended Glasgow outcome scale occurred in 27/45 (60%, 95% confidence interval 46%-74%) EG-1962 subjects (5/9 with 100, 6/9 with 200, 7/9 with 400, 4/9 with 600, and 5/9 with 800 mg) and 5/18 (28%, 95% confidence interval 7%-48%, relative risk reduction of unfavorable outcome; 1.45, 95% confidence interval 1.04-2.03; P=0.027) enteral nimodipine subjects. EG-1962 reduced delayed cerebral ischemia (14/45 [31%] EG-1962 versus 11/18 [61%] enteral nimodipine) and rescue therapy (11/45 [24%] versus 10/18 [56%]).
  
  
  
  EG-1962 was safe and tolerable to 800 mg, and in this, aneurysmal subarachnoid hemorrhage population was associated with reduced delayed cerebral ischemia and rescue therapy. Overall, the rate of favorable clinical outcome was greater in the EG-1962-treated group.
  
  
  
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT01893190.
authors.affiliation: From the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.). daniel.haenggi@medma.uni-heidelberg.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hänggi
authors.affiliation: From the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.).
authors.forename: Nima
authors.initials: N
authors.lastname: Etminan
authors.affiliation: From the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.).
authors.forename: Francois
authors.initials: F
authors.lastname: Aldrich
authors.affiliation: From the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.).
authors.forename: Hans Jakob
authors.initials: HJ
authors.lastname: Steiger
authors.affiliation: From the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.).
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Mayer
authors.affiliation: From the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.).
authors.forename: Michael N
authors.initials: MN
authors.lastname: Diringer
authors.affiliation: From the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.).
authors.forename: Brian L
authors.initials: BL
authors.lastname: Hoh
authors.affiliation: From the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.).
authors.forename: J
authors.initials: J
authors.lastname: Mocco
authors.affiliation: From the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.).
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Faleck
authors.affiliation: From the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.).
authors.forename: R Loch
authors.initials: RL
authors.lastname: Macdonald
mesh_terms: D000328:Adult; D000368:Aged; D002121:Calcium Channel Blockers / Q000008:administration & dosage; D015331:Cohort Studies; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D020714:Maximum Tolerated Dose; D008863:Microspheres; D008875:Middle Aged; D009553:Nimodipine / Q000008:administration & dosage*; D020127:Recovery of Function / Q000187:drug effects*; D013345:Subarachnoid Hemorrhage / Q000175:diagnosis* / Q000188:drug therapy*
chemical_list: D002121:Calcium Channel Blockers; D003692:Delayed-Action Preparations; D009553:Nimodipine
keywords: brain ischemia; hypotension; nimodipine; subarachnoid hemorrhage; sustained release formulation