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).
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.
Teal
Philip
P
University of British Columbia, Vancouver, British Columbia, Canada.
Davis
Stephen
S
Hacke
Werner
W
Kaste
Markku
M
Lyden
Patrick D
PD
Fierus
Monika
M
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
D001578:Benzopyrans; D013844:Thiazoles; C111221:repinotan hydrochloride