Safety and efficacy of GABA
A α5 antagonist S44819 in patients with ischaemic stroke: a multicentre, double-blind, randomised, placebo-controlled trial
The Lancet Neurology. 2020-03-01; 19(3): 226-233
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Chabriat H(1), Bassetti CL(2), Marx U(3), Audoli-Inthavong ML(3), Sors A(3), Lambert E(3), Wattez M(3), Hermann DM(4); RESTORE BRAIN study investigators.
Collaborators: Althaus K, Amaro S, Bae HJ, Bak Z, Barbarini L, Bassi P, Bazan R,
Bereczki D, Berkowicz T, Berrouschot J, Blacquiere D, Brola W, Butcher K,
Cardona P, Cha JK, Cloud G, Cohen D, Cordonnier C, Csanyi A, Czlonkowska A,
Davis S, Dawson J, DE Klippel N, Denier C, Desfontaines P, Diener HC, Dioszeghy
P, Dippel DW, Dorado L, Folyovich A, Freitas GR, Friedrich MA, Fryze W,
Gagliardi RJ, Gottschal M, Grimley R, Grond M, Gröschel K, Hosseini H, Hwang Y,
Kallmuenzer B, Khan U, Kim JS, Kleinig T, Koves A, Lago Martin A, Lasek-Bal A,
Lembo G, Lemmens R, Lindert R, Porcello Marrone LC, Martinez Zabaleta M, Mas JL,
Masjuan Vallejo J, Mazighi M, Minelli C, Mistri A, Molina C, Moniche Alvarez F,
Cabral Moro CH, Mulleners W, Nabavi D, Neau JP, O’Brien B, Ovary C, Panczel G,
Park MS, Phan T, Ragab S, Rejdak K, Rodriguez DE Freitas G, Roffe C, Roquer
Gonzalez J, Rover L, Sampaio Silva G, Schellinger P, Segura Martin T, Shaw L,
Sibon I, Skoda O, Smadja D, Sobolewski P, Soda H, Sprigg N, Swiat M, Szapary L,
Szegedi N, Toni D, Valikovics A, Vanhooren G, Vecsei L, Wein T, Wong A, Ximenez
(1)Department of Neurology, Lariboisière Hospital, Paris Diderot University and
INSERM U1141, Paris, France.
(2)Department of Neurology, University Hospital Berne, Berne, Switzerland.
(3)Institut de Recherches Internationales Servier (IRIS), Suresnes, France.
(4)Department of Neurology, University Hospital Essen, University of
Duisburg-Essen, Essen, Germany. Electronic address: .
Lancet Neurol. 2020 Mar;19(3):197-198.
Lancet Neurol. 2020 May;19(5):381-382.
BACKGROUND: S44819, a selective GABAA α5 receptor antagonist, reduces tonic
post-ischaemic inhibition of the peri-infarct cortex. S44819 improved stroke
recovery in rodents and increased cortical excitability in a transcranial
magnetic stimulation study in healthy volunteers. The Randomized Efficacy and
Safety Trial of Oral GABAA α5 antagonist S44819 after Recent ischemic Event
(RESTORE BRAIN) aimed to evaluate the safety and efficacy of S44819 for
enhancing clinical recovery of patients with ischaemic stroke.
METHODS: RESTORE BRAIN was an international, randomised, double-blind,
parallel-group, placebo-controlled, multicentre phase 2 trial that evaluated the
safety and efficacy of oral S44189 in patients with recent ischaemic stroke. The
study was done in specialised stroke units in 92 actively recruiting centres in
14 countries: ten were European countries (Belgium, Czech Republic, France,
Germany, Hungary, Italy, Netherlands, Poland, Spain, and the UK) and four were
non-European countries (Australia, Brazil, Canada, and South Korea). Patients
aged 18-85 years with acute ischaemic stroke involving cerebral cortex (National
Institute of Health Stroke Scale [NIHSS] score 7-20) without previous disability
were eligible for inclusion. Participants were randomly assigned to receive 150
mg S44819 twice a day, 300 mg S44819 twice a day, or placebo twice a day by a
balanced, non-adaptive randomisation method with a 1:1:1 ratio. Treatment
randomisation and allocation were centralised via the interactive web response
system using computer-generated random sequences with a block size of 3.
Blinding of treatment was achieved by identical appearance and taste of all
sachets. Patients, investigators and individuals involved in the analysis of the
trial were masked to group assignment. The primary endpoint was the modified
Rankin Scale (mRS) score 90 days from onset of treatment, evaluated by shift
analysis (predefined main analysis) or by dichotomised analyses using 0-1 versus
2-6 and 0-2 versus 3-6 cutoffs (predefined secondary analysis). Secondary
endpoints were the effects of S44819 on the NIHSS and Montreal Cognitive
Assessment (MoCA) scores, time needed to complete parts A and B of the Trail
Making Test, and the Barthel index. Efficacy analyses were done on all patients
who received at least one dose of treatment and had at least one mRS score taken
after day 5 (specifically, on or after day 30). Safety was compared across
treatment groups for all patients who received at least one dose of treatment.
The study was registered at ClinicalTrials.gov, NCT02877615.
FINDINGS: Between Dec 19, 2016, and Nov 16, 2018, 585 patients were enrolled in
the study. Of these, 197 (34%) were randomly assigned to receive 150 mg S44819
twice a day, 195 (33%) to receive 300 mg S44819 twice a day, and 193 (33%) to
receive placebo twice a day. 189 (96%) of 197 patients in the 150 mg S44819
group, 188 (96%) of 195 patients in the 300 mg S44819 group, and 191 (99%)
patients in the placebo group received at least one dose of treatment and had at
least one mRS score taken after day 5, and were included in efficacy analyses.
195 (99%) of 197 patients in the 150 mg S44819 group, 194 (99%) of 195 patients
in the 300 mg S44819 group, and 193 (100%) patients in the placebo group
received at least one dose of treatment, and were included in safety analyses.
The primary endpoint of mRS at day 90 did not differ between each of the two
S44819 groups and the placebo group (OR 0·91 [95% CI 0·64-1·31]; p=0·80 for 150
mg S44819 compared with placebo and OR 1·17 [95% CI 0·81-1·67]; p=0·80 for 300
mg S44819 compared with placebo). Likewise, dichotomised mRS scores at day 90
(mRS 0-2 vs 3-6 or mRS 0-1 vs 2-6) did not differ between groups. Secondary
endpoints did not reveal any significant group differences. The median NIHSS
score at day 90 did not differ between groups (4 [IQR 2-8] in 150 mg S44819
group, 4 [2-7] in 300 mg S44819 group, and 4 [2-6] in placebo group), nor did
the number of patients at day 90 with an NIHSS score of up to 5 (95 [61%] of 156
in 150 mg S44819 group, 106 [66%] of 161 in 300 mg S44819 group, and 104 [66%]
of 157 in placebo group) versus more than 5 (61 [39%] in 150 mg S44819 group, 55
[34%] in 300 mg S44819 group, and 53 [34%] in placebo group). Likewise, the
median MoCA score (22·0 [IQR 17·0-26·0] in 150 mg S44819 group, 23·0 [19·0-26·5]
in 300 mg S44819 group, and 22·0 [17·0-26·0] in placebo group), time needed to
complete parts A (50 s [IQR 42-68] in 150 mg S44819 group, 49 s [36-63] in 300
mg S44819 group, and 50 s [38-68] in placebo group) and B (107 s [81-144] in 150
mg S44819 group, 121 s [76-159] in 300 mg S44819 group, and 130 s [86-175] in
placebo group) of the Trail Making Test, and the Barthel index (90 [IQR 60-100]
in 150 mg S44819 group, 90 [70-100] in 300 mg S44819 group, and 90 [70-100] in
placebo group) were similar in all groups. Number and type of adverse events
were similar between the three groups. There were no drug-related adverse events
and no drug-related deaths.
INTERPRETATION: There was no evidence that S44819 improved clinical outcome in
patients after ischaemic stroke, and thus S44819 cannot be recommended for
stroke therapy. The concept of tonic inhibition after stroke should be
re-evaluated in humans.
Copyright © 2020 Elsevier Ltd. All rights reserved.
PMID: 32085836 [Indexed for MEDLINE]