title: A randomized, double-blind, placebo-controlled trial to evaluate the efficacy, safety, tolerability, and pharmacokinetic/pharmacodynamic effects of a targeted exposure of intravenous repinotan in patients with acute ischemic stroke: modified Randomized Exposure Controlled Trial (mRECT).
abstract: OBJECTIVE
  Repinotan hydrochloride is a serotonin (5-HT)(1A) receptor full agonist with evidence of neuroprotection in animal models of permanent and transient focal ischemia. The purpose of this Phase IIb study was to investigate the efficacy, safety, and tolerability of a targeted exposure to repinotan in patients with acute ischemic stroke.
  
  
  METHODS
  This was a double-blind, placebo-controlled, parallel-group, multicenter study of 681 patients stratified according to whether or not tissue plasminogen activator was administered and then randomly assigned to treatment with repinotan or placebo. A continuous 72-hour intravenous infusion of repinotan or placebo was to be started within 4.5 hours from the onset of ischemic symptoms. A Point-of-Care test was used to adjust the infusion rate if appropriate. The goal of Modified Randomized Exposure Controlled Trial (mRECT) was to show whether repinotan is statistically superior to placebo (alpha <or= 0.10) as measured by the response rate on the primary efficacy variable, Barthel Index (>or=85) at 3 months, using a Cochran-Mantel-Haenszel test.
  
  
  RESULTS
  For the intention-to-treat population at 3 months, the response rate on the Barthel Index was 37.1% (127 of 342) for patients on repinotan and 42.4% (143 of 337) for patients taking the placebo (Cochran-Mantel-Haenszel probability value=0.149). No apparent safety concerns were identified.
  
  
  CONCLUSIONS
  mRECT demonstrated the feasibility of conducting a rigorous trial using a short therapeutic window demanding clinical and radiographic criteria to optimize patient selection and a Point-of-Care test to achieve a targeted exposure to repinotan. The study failed to demonstrate a clinical benefit of repinotan. The development of repinotan in acute ischemic stroke was discontinued.
authors.affiliation: University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: Teal
authors.forename: Stephen
authors.initials: S
authors.lastname: Davis
authors.forename: Werner
authors.initials: W
authors.lastname: Hacke
authors.forename: Markku
authors.initials: M
authors.lastname: Kaste
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Lyden
authors.forename: Monika
authors.initials: M
authors.lastname: Fierus
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001578:Benzopyrans / Q000008:administration & dosage* / Q000009:adverse effects* / Q000494:pharmacology; D002545:Brain Ischemia / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D038622:Internationality; D008297:Male; D008875:Middle Aged; D020521:Stroke / Q000097:blood / Q000188:drug therapy*; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D001578:Benzopyrans; D013844:Thiazoles; C111221:repinotan hydrochloride