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)

BACKGROUND AND PURPOSE—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 exposu...

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Bibliographic Details
Published in:Stroke (1970) 2009-11, Vol.40 (11), p.3518-3525
Main Authors: Teal, Philip, Davis, Stephen, Hacke, Werner, Kaste, Markku, Lyden, Patrick D, Fierus, Monika
Format: Article
Language:English
Subjects:
Aged
Aged, 80 and over
Benzopyrans - administration & dosage
Benzopyrans - adverse effects
Benzopyrans - pharmacology
Biological and medical sciences
Brain Ischemia - blood
Brain Ischemia - drug therapy
Cardiovascular system
Dose-Response Relationship, Drug
Double-Blind Method
Drug Delivery Systems - methods
Female
Humans
Infusions, Intravenous
Internationality
Male
Medical sciences
Middle Aged
Neurology
Pharmacology. Drug treatments
Stroke - blood
Stroke - drug therapy
Thiazoles - administration & dosage
Thiazoles - adverse effects
Thiazoles - pharmacology
Vascular diseases and vascular malformations of the nervous system
Vasodilator agents. Cerebral vasodilators
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Summary:BACKGROUND AND PURPOSE—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 (α≤0.10) as measured by the response rate on the primary efficacy variable, Barthel Index (≥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.
ISSN:0039-2499
1524-4628
DOI:10.1161/STROKEAHA.109.551382