title: Safety and tolerability of arundic acid in acute ischemic stroke.
abstract: Arundic acid (AA; ONO-2506), a novel modulator of astrocyte activation, may improve neuronal survival after stroke. We conducted a multicenter, dose-escalating, randomized, double-blind Phase I trial of AA in acute ischemic stroke. Subjects were randomized to treatment with AA or placebo in sequential dose tiers of 2-12 mg/kg/h (10-16 patients/group) within 24 h of stroke onset. Study drug was infused for 1 h daily over 7 days, and follow-up terminated at 40 days. Neurological and functional outcomes were evaluated through Day 40 as exploratory endpoints. A total of 92 subjects were enrolled with no dose-related pattern of serious adverse events (AEs). Premature terminations caused by AEs occurred in four (8.2%) patients treated with AA and five (11.6%) treated with placebo. Two subjects treated with AA (4.1%) and four given placebo (9.3%) died. Exploratory efficacy analysis showed a trend toward improvement in the change from baseline National Institutes of Health Stroke Scale (NIHSS) in the 8 mg/kg/h AA group on Days 3 (p=0.023 vs. placebo), 7 (p=0.002), 10 (p=0.003), and 40 (p=0.018). A dose of 8 mg/kg/h AA produced a favorable trend in reduction of NIHSS that should be confirmed in a future clinical trial.
authors.affiliation: Stroke Program, Sanders-Brown Center on Aging, and Department of Neurology, 101 Sanders-Brown Building, University of Kentucky Medical Center, Lexington, KY 40536-0230, USA. cpetti@uky.edu
authors.forename: L Creed
authors.initials: LC
authors.lastname: Pettigrew
authors.forename: Scott E
authors.initials: SE
authors.lastname: Kasner
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Albers
authors.forename: Mark
authors.initials: M
authors.lastname: Gorman
authors.forename: James C
authors.initials: JC
authors.lastname: Grotta
authors.forename: David G
authors.initials: DG
authors.lastname: Sherman
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Funakoshi
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Ishibashi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002210:Caprylates / Q000009:adverse effects / Q000627:therapeutic use*; D003710:Demography; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D012720:Severity of Illness Index; D016019:Survival Analysis
chemical_list: D002210:Caprylates; D018696:Neuroprotective Agents; C459360:ONO2506