{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T03:00:44Z","timestamp":1790823644548,"version":"4.1.0"},"reference-count":42,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T00:00:00Z","timestamp":1696377600000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011725","name":"Servier","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Autism Research"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The efficacy and safety of bumetanide oral solution for the treatment of autism spectrum disorder (ASD) in children and adolescents was evaluated in two international, multi\u2010center, randomized, double\u2010blind, placebo\u2010controlled phase III trials; one enrolled patients aged 7\u201317\u2009years (SIGN 1 trial) and the other enrolled younger patients aged 2\u20136\u2009years (SIGN 2). In both studies, patients were randomized to receive bumetanide oral solution twice daily (BID) or placebo BID during a 6\u2010month double\u2010blind treatment period. The primary endpoint was change in Childhood Autism Rating Scale 2 (CARS2) total raw score from baseline to Week 26. Key secondary endpoints included changes in Social Responsiveness Scale\u20102, Clinical Global Impression Scale, and Vineland Adaptive Behavior Scale. Each study enrolled 211 patients (bumetanide, <jats:italic>n<\/jats:italic>\u2009=\u2009107; placebo, <jats:italic>n<\/jats:italic>\u2009=\u2009104). Both studies were terminated early due to absence of any significant difference between bumetanide and placebo in the overall studied populations. In both studies, CARS2 total raw score decreased from baseline to Week 26 in the bumetanide and placebo groups, with no statistically significant difference between groups. No differences were observed between treatment groups for any of the secondary efficacy endpoints in either study. In both studies, treatment\u2010emergent adverse events that occurred more frequently with bumetanide than placebo included thirst, polyuria, hypokalemia, and dry mouth. These large phase III trials failed to demonstrate a benefit of bumetanide for the treatment of pediatric ASD compared with placebo. Consequently, the sponsor has discontinued the development of bumetanide for the treatment of this condition.<\/jats:p><jats:p><jats:bold><jats:italic>Trial registration<\/jats:italic>:<\/jats:bold> <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\">https:\/\/clinicaltrials.gov<\/jats:ext-link>: SIGN 1: NCT03715166; SIGN 2: NCT03715153.<\/jats:p>","DOI":"10.1002\/aur.3005","type":"journal-article","created":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T19:30:48Z","timestamp":1696534248000},"page":"2021-2034","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Bumetanide oral solution for the treatment of children and adolescents with autism spectrum disorder: Results from two randomized phase <scp>III<\/scp> studies"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5488-5543","authenticated-orcid":false,"given":"Joaquin","family":"Fuentes","sequence":"first","affiliation":[{"name":"Child &amp; Adolescent Psychiatry Service Policl\u00ednica Gipuzkoa &amp; GAUTENA Autism Society  San Sebasti\u00e1n Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7977-3601","authenticated-orcid":false,"given":"Mara","family":"Parellada","sequence":"additional","affiliation":[{"name":"Servicio de Psiquiatr\u00eda del Ni\u00f1o y del Adolescente Hospital General Universitario Gregorio Mara\u00f1\u00f3n, CIBERSAM, IiSGM  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Georgoula","sequence":"additional","affiliation":[{"name":"ReCognition Health  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7049-1277","authenticated-orcid":false,"given":"Guiomar","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Neurodevelopmental and Autism Unit from Child Developmental Center and Centro de Investiga\u00e7\u00e3o e Forma\u00e7\u00e3o Cl\u00ednica, Hospital Pedi\u00e1trico Centro Hospitalar e Universit\u00e1rio de Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2858-148X","authenticated-orcid":false,"given":"St\u00e9phane","family":"Marret","sequence":"additional","affiliation":[{"name":"Department of Neonatal Pediatrics, Intensive Care, and Neuropediatrics, Rouen University Hospital and INSERM U 1245 Team 4 Neovasc, School of Medicine Normandy University  Rouen France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0261-0999","authenticated-orcid":false,"given":"V\u00e9ronique","family":"Crutel","sequence":"additional","affiliation":[{"name":"Neuro Immuno\u2010Inflammation Therapeutic Area Institut de Recherches Internationales Servier  Suresnes CEDEX France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Albarran","sequence":"additional","affiliation":[{"name":"Neuro Immuno\u2010Inflammation Therapeutic Area Institut de Recherches Internationales Servier  Suresnes CEDEX France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estelle","family":"Lambert","sequence":"additional","affiliation":[{"name":"Neuro Immuno\u2010Inflammation Therapeutic Area Institut de Recherches Internationales Servier  Suresnes CEDEX France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre\u2010Fran\u00e7ois","family":"P\u00e9n\u00e9laud","sequence":"additional","affiliation":[{"name":"Neuro Immuno\u2010Inflammation Therapeutic Area Institut de Recherches Internationales Servier  Suresnes CEDEX France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Ravel","sequence":"additional","affiliation":[{"name":"Initial R&amp;D Consulting  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6208-8480","authenticated-orcid":false,"given":"Yehezkel","family":"Ben Ari","sequence":"additional","affiliation":[{"name":"Neurochlore  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,10,4]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.books.9780890425596"},{"key":"e_1_2_10_3_1","volume-title":"DSM\u20105\u00ae update. 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