Abstract
BackgroundThe GABAA-α5 receptor antagonist S44819 is a promising candidate to enhance functional recovery after acute ischemic stroke (IS). S44819 is currently evaluated in this indication; RESTORE brain study started in Dec 2016 and was completed in March 2019.Methods/designThe study is a 3-month international, randomized, double-blind, parallel group, placebo-controlled phase II multicentre study. Patients in 14 countries who suffered an IS leading to a moderate or severe deficit defined by NIHSS score ranging from 7 to 20 and are aged between 18 to 85 years are included between 3 and 8 days after the stroke onset. Approximately 580 patients are to be included.The primary objective of the study is to demonstrate the superiority of at least one of the two doses of S44819 (150 or 300 mg bid) compared to placebo on top of usual care on functional recovery measured with the modified Rankin scale at 3 months. Comparisons between two doses of S44819 and placebo are assessed with ordinal logistic regression evaluating the odds of shifting from one category to the next in the direction of a better outcome at day 90. Secondary objectives include the evaluation of S44819 effects on neurological examination using the National Institute of Health Stroke Scale total score, activities of daily living using the Barthel Index total score, and cognitive performance using the Montreal Cognitive Assessment scale total score and Trail Making Test times. Safety and tolerability of the two doses of S44819 will also be analyzed.DiscussionThe RESTORE BRAIN study might represent the first proof of concept study of an innovative therapeutic approach that is primarily based on enhancing functional recovery after IS.Trial registrationRandomized Efficacy and Safety Trial with Oral S 44819 after Recent ischemic cerebral Event, an international, multi-centre, randomized, double-blind placebo-controlled phase II study. ClinicalTrials.gov, NCT02877615; Eudract 2016–001005-16. Registered 24 August 2016
Highlights
The GABAA-α5 receptor antagonist S44819 is a promising candidate to enhance functional recovery after acute ischemic stroke (IS)
The RESTORE BRAIN study might represent the first proof of concept study of an innovative therapeutic approach that is primarily based on enhancing functional recovery after IS
Post-stroke recovery relies on brain neuroplasticity [1, 2], which is compromised by the sustained hypoexcitability observed in the peri-infarct cortex due to the increased activity of GABAergic neurons [3]
Summary
The GABAA-α5 receptor antagonist S44819 is a promising candidate to enhance functional recovery after acute ischemic stroke (IS). Post-stroke recovery relies on brain neuroplasticity [1, 2], which is compromised by the sustained hypoexcitability observed in the peri-infarct cortex due to the increased activity of GABAergic neurons [3]. S44819 is a potent and selective antagonist of GABAAα5 receptors [4] that enhances motor and cognitive recovery when administered chronically from day 3 after IS in rodent models [5]. A transcranial magnetic stimulation study has demonstrated in humans that S44819 reaches the human cortex and is capable of increasing cortical and cortico-spinal excitability by reducing GABAA receptor-mediated activity [6]. The design of a phase II clinical trial testing the efficacy of two doses of S44819 on functional recovery after acute supratentorial IS is presented
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