{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T14:57:35Z","timestamp":1758121055470},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,2,3]],"date-time":"2020-02-03T00:00:00Z","timestamp":1580688000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,2,3]],"date-time":"2020-02-03T00:00:00Z","timestamp":1580688000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Trials"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>The GABA<jats:sub>A<\/jats:sub>-\u03b15 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods\/design<\/jats:title>\n                <jats:p>The 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\u2009years are included between 3 and 8\u2009days after the stroke onset. Approximately 580 patients are to be included.<\/jats:p>\n                <jats:p>The primary objective of the study is to demonstrate the superiority of at least one of the two doses of S44819 (150 or 300\u2009mg bid) compared to placebo on top of usual care on functional recovery measured with the modified Rankin scale at 3\u2009months. 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Discussion<\/jats:title>\n                <jats:p>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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>Randomized 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, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02877615\">NCT02877615<\/jats:ext-link>; Eudract 2016\u2013001005-16. Registered 24 August 2016<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13063-020-4072-2","type":"journal-article","created":{"date-parts":[[2020,2,3]],"date-time":"2020-02-03T18:05:30Z","timestamp":1580753130000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Randomized Efficacy and Safety Trial with Oral S 44819 after Recent ischemic cerebral Event (RESTORE BRAIN study): a placebo controlled phase II study"],"prefix":"10.1186","volume":"21","author":[{"given":"Hugues","family":"Chabriat","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio L.","family":"Bassetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ute","family":"Marx","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7oise","family":"Picarel-Blanchot","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aurore","family":"Sors","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celine","family":"Gruget","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Saba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marine","family":"Wattez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie-Laure","family":"Audoli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk M.","family":"Hermann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,2,3]]},"reference":[{"issue":"4","key":"4072_CR1","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/S1474-4422(12)70039-X","volume":"11","author":"DM Hermann","year":"2012","unstructured":"Hermann DM, Chopp M. Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation. Lancet Neurol. 2012;11(4):369\u201380.","journal-title":"Lancet Neurol"},{"issue":"12","key":"4072_CR2","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1038\/nrn2735","volume":"10","author":"TH Murphy","year":"2009","unstructured":"Murphy TH, Corbett D. Plasticity during stroke recovery: from synapse to behaviour. Nat Rev Neurosci. 2009;10(12):861\u201372.","journal-title":"Nat Rev Neurosci"},{"issue":"2","key":"4072_CR3","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1001\/archneurol.2011.1175","volume":"69","author":"ST Carmichael","year":"2012","unstructured":"Carmichael ST. Brain excitability in stroke: the yin and yang of stroke progression. Arch Neurol. 2012;69(2):161\u20137.","journal-title":"Arch Neurol"},{"key":"4072_CR4","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1016\/j.neuropharm.2017.08.012","volume":"125","author":"LA Etherington","year":"2017","unstructured":"Etherington LA, Mihalik B, Palvolgyi A, et al. Selective inhibition of extra-synaptic alpha5-GABAA receptors by S 44819, a new therapeutic agent. Neuropharmacology. 2017;125:353\u201364.","journal-title":"Neuropharmacology"},{"key":"4072_CR5","volume-title":"Annual meeting of the American Academy of Neurology","author":"Y-C Wang","year":"2017","unstructured":"Wang Y-C, Sanchez-Mendoza E, Silva de Carvahlo T, et al. Post-acute delivery of GABAA receptor alpha5-antagonist S 44819 promotes motor-coordination recovery, prevents secondary brain atrophy and reduces astrocytic scar formation after transient middle cerebral artery occlusion in mice [abstract]. In: Annual meeting of the American Academy of Neurology; 2017."},{"issue":"49","key":"4072_CR6","doi-asserted-by":"publisher","first-page":"12312","DOI":"10.1523\/JNEUROSCI.1689-16.2016","volume":"36","author":"G Darmani","year":"2016","unstructured":"Darmani G, Zipser CM, Bohmer GM, et al. Effects of the selective alpha5-GABAAR antagonist S 44819 on excitability in the human brain: a TMS-EMG and TMS-EEG phase I study. J Neurosci. 2016;36(49):12312\u201320.","journal-title":"J Neurosci"},{"key":"4072_CR7","first-page":"1","volume-title":"Points to consider on clinical investigation of medicinal products for the treatment of acute stroke. CPMP\/EWP\/560\/98","author":"EMA Guideline","year":"2001","unstructured":"EMA Guideline. Points to consider on clinical investigation of medicinal products for the treatment of acute stroke. CPMP\/EWP\/560\/98; 2001. p. 1\u20137."},{"key":"4072_CR8","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1212\/WNL.53.1.126","volume":"53","author":"HP Adams","year":"1999","unstructured":"Adams HP, Davis PH, Leira EC, Chang K-C, Bendixen BH, Clarke WR, Woolson RF, Hansen MD. Baseline NIH Stroke Scale score strongly predicts outcome after stroke: a report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology. 1999;53:126\u201331.","journal-title":"Neurology"},{"key":"4072_CR9","doi-asserted-by":"crossref","unstructured":"Wouters A, Nysten C, Thijs V, Lemmens R. Prediction of outcome in patients with acute ischemic stroke based on initial severity and improvement in the first 24 h. Front Neurol. 2018;9:308.","DOI":"10.3389\/fneur.2018.00308"},{"key":"4072_CR10","unstructured":"ICH E10 : choice of control group and related issues in clinical trials.CPMP\/ICH\/364\/96; 2001. p. 1\u201330."},{"issue":"5","key":"4072_CR11","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1177\/003693305700200504","volume":"2","author":"J Rankin","year":"1957","unstructured":"Rankin J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J. 1957;2(5):200\u201315.","journal-title":"Scott Med J"},{"issue":"7","key":"4072_CR12","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1001\/archneur.61.7.1061","volume":"61","author":"DJ Schlegel","year":"2004","unstructured":"Schlegel DJ, Tanne D, Demchuk AM, Levine SR, Kasner SE. Prediction of hospital disposition after thrombolysis for acute ischemic stroke using the National Institutes of Health Stroke Scale. Arch Neurol. 2004;61(7):1061\u20134.","journal-title":"Arch Neurol"},{"key":"4072_CR13","first-page":"61","volume":"14","author":"F Mahoney","year":"1965","unstructured":"Mahoney F, Barthel D. Functional evaulation: the barthel index. Md State Med J. 1965;14:61\u20135.","journal-title":"Md State Med J"},{"issue":"4","key":"4072_CR14","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1111\/j.1532-5415.2005.53221.x","volume":"53","author":"ZS Nasreddine","year":"2005","unstructured":"Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695\u20139.","journal-title":"J Am Geriatr Soc"},{"issue":"5","key":"4072_CR15","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1037\/h0044509","volume":"19","author":"RM Reitan","year":"1955","unstructured":"Reitan RM. The relation of the trail making test to organic brain damage. J Consult Psychol. 1955;19(5):393\u20134.","journal-title":"J Consult Psychol"},{"issue":"12","key":"4072_CR16","doi-asserted-by":"publisher","first-page":"1266","DOI":"10.1176\/appi.ajp.2011.10111704","volume":"168","author":"K Posner","year":"2011","unstructured":"Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266\u201377.","journal-title":"Am J Psychiatry"},{"issue":"24","key":"4072_CR17","doi-asserted-by":"publisher","first-page":"2257","DOI":"10.1002\/sim.4780122404","volume":"12","author":"J Whitehead","year":"1993","unstructured":"Whitehead J. Sample size calculations for ordered categorical data. Stat Med. 1993;12(24):2257\u201371.","journal-title":"Stat Med"},{"key":"4072_CR18","doi-asserted-by":"publisher","first-page":"1843","DOI":"10.1161\/STROKEAHA.106.478230","volume":"38","author":"Y Lampl","year":"2007","unstructured":"Lampl Y, Zivin JA, Fisher M, Lew R, Welin L, Dahlof B, Borenstein P, Andersson B, Perez J, Caparo C, Ilic S, Oron U. Infrared laser therapy for ischemic stroke: a new treatment strategy: results of the NeuroThera Effectiveness and Safety Trial\u20131 (NEST-1). Stroke. 2007;38:1843\u20139.","journal-title":"Stroke"},{"issue":"5","key":"4072_CR19","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1523\/JNEUROSCI.3834-03.2004","volume":"24","author":"J Biernaskie","year":"2004","unstructured":"Biernaskie J, Chernenko G, Corbett D. Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. J Neurosci. 2004;24(5):1245\u201354.","journal-title":"J Neurosci"},{"issue":"15","key":"4072_CR20","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1212\/01.wnl.0000341308.73506.b7","volume":"72","author":"JL Saver","year":"2009","unstructured":"Saver JL, Gornbein J. Treatment effects for which shift or binary analyses are advantageous in acute stroke trials. Neurology. 2009;72(15):1310\u20135.","journal-title":"Neurology"}],"container-title":["Trials"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-020-4072-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13063-020-4072-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-020-4072-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,2]],"date-time":"2021-02-02T02:12:18Z","timestamp":1612231938000},"score":1,"resource":{"primary":{"URL":"https:\/\/trialsjournal.biomedcentral.com\/articles\/10.1186\/s13063-020-4072-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,3]]},"references-count":20,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["4072"],"URL":"https:\/\/doi.org\/10.1186\/s13063-020-4072-2","relation":{},"ISSN":["1745-6215"],"issn-type":[{"value":"1745-6215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,3]]},"assertion":[{"value":"7 November 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 January 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 February 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The study is performed in accordance with the ethics principles stated in the Declaration of Helsinki 1964, as revised in Fortaleza, 2013.The study protocol, the \u201cParticipant information and consent form\u201d document, the \u201cAuthorised representative according to local regulations information and consent form\u201d document, the list of investigators document, the insurance documents, the investigator\u2019s brochure of S 44819 are be submitted to (an) Institutional Review Board(s)\/Independent Ethics Committee(s) by the investigator(s) or the national coordinator(s) or the sponsor in accordance with local regulations. The study does not start in a centre before written approval by corresponding Institutional Review Board(s)\/Independent Ethics Committee(s) has been obtained, the local regulatory requirements have been complied with, and the signed clinical study protocol of each contractual party involved has been obtained.The investigator or a person designated by him\/her is to collect written consent from each participant before his\/her participation in the study.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"C. Bassetti, H. Chabriat, and D. Hermann declare no competing interests.U. Marx, F. Picarel-Blanchot, A. Sors, C. Gruget-Petazzoni, B. Saba, M. Wattez, and M.L. Audoli are employees at Servier.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"136"}}