{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:01:27Z","timestamp":1787061687137,"version":"build-2736575974"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,1,22]],"date-time":"2022-01-22T00:00:00Z","timestamp":1642809600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,1,22]],"date-time":"2022-01-22T00:00:00Z","timestamp":1642809600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100015150","name":"St. Michael's Hospital Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100015150","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pilot Feasibility Stud"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Benzodiazepines are considered first-line treatment for patients experiencing severe acute alcohol withdrawal syndrome (sAAWS). Although several medications have been evaluated as potential adjuvant treatments for sAAWS, barbiturates show particular promise.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>In the PHENOMANAL trial, we will assess the feasibility of conducting an allocation-concealed, quadruple-blinded, randomized controlled trial (RCT) comparing symptom-triggered benzodiazepine therapy with either a single dose of adjuvant intravenous (IV) phenobarbital (7.5 mg\/kg of ideal body weight) or a single dose of matching IV placebo for patients with sAAWS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We will recruit adult patients from the Emergency Department, Intensive Care Unit, or hospital wards with a Clinical Institute of Withdrawal \u2013 Adult revised (CIWA-Ar) score of 16 or more after receipt of at least 60 mg of diazepam or equivalent within 16 h of diagnosis of sAAWS, and an anticipated need for hospitalization. We will randomize participants (\n                      <jats:italic>n<\/jats:italic>\n                      =39) in a 2:1 manner to treatment and placebo groups, respectively. The primary objective of the PHENOMANAL pilot trial will be to demonstrate our ability to recruit the desired population over the trial period. As secondary objectives, we will evaluate clinician compliance with the treatment protocols, assess crossover rates from the placebo arm to the treatment arm, and obtain preliminary estimates of treatment effect. All trial participants will be followed for 7 days or until hospital discharge.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Relevance<\/jats:title>\n                    <jats:p>The PHENOMANAL trial is novel in investigating a new treatment for a common and understudied condition, repurposing an existing medication for a novel indication, and addressing an important evidence gap. Through conduct of the multidisciplinary pilot trial, we aim to advance methodology in acute care research through the use of a hybrid consent model and inform the design of a large-scale trial.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>\n                      ClinicalTrials.gov Registration\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03586089\">NCT03586089<\/jats:ext-link>\n                      ; first registered July 13, 2018.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40814-021-00963-4","type":"journal-article","created":{"date-parts":[[2022,1,22]],"date-time":"2022-01-22T05:03:37Z","timestamp":1642827817000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Phenobarbital for the management of severe acute alcohol withdrawal (the PHENOMANAL trial): a pilot randomized controlled trial"],"prefix":"10.1186","volume":"8","author":[{"given":"Niall","family":"Filewod","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian J.","family":"Turner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leena","family":"Rizvi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Gray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Klaiman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Buell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnathan","family":"Ailon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Caudarella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galo F.","family":"Ginocchio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlene","family":"Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gyan","family":"Sandhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norman","family":"Dewhurst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Sequeira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9967-5424","authenticated-orcid":false,"given":"Karen E. A.","family":"Burns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,22]]},"reference":[{"key":"963_CR1","volume-title":"The impact of substance abuse disorders on hospital use","author":"MM Young","year":"2014","unstructured":"Young MM, Jesserman R. The impact of substance abuse disorders on hospital use. Ottawa: Canadian Centre on Substance Abuse; 2014. http:\/\/www.ccsa.ca\/Resource%20Library\/CCSA-Substance-Use-Hospital-Impact-Report-2014-en.pdf"},{"issue":"18","key":"963_CR2","doi-asserted-by":"publisher","first-page":"1786","DOI":"10.1056\/NEJMra020617","volume":"348","author":"TR Kosten","year":"2003","unstructured":"Kosten TR, O\u2019Connor PG. Management of drug and alcohol withdrawal. New Engl JMed. 2003;348(18):1786\u201395.","journal-title":"New Engl JMed"},{"issue":"6","key":"963_CR3","doi-asserted-by":"publisher","first-page":"5783","DOI":"10.3390\/ijerph110605783","volume":"11","author":"J Doering-Silveira","year":"2014","unstructured":"Doering-Silveira J, Fidalgo TM, Nascimento CL, et al. Assessing alcohol dependence in hospitalized patients. Int J Environ Res Public Health. 2014;11(6):5783\u201391.","journal-title":"Int J Environ Res Public Health."},{"issue":"9 Suppl","key":"963_CR4","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1097\/CCM.0b013e3181ec5412","volume":"38","author":"MC Sarff","year":"2010","unstructured":"Sarff MC, Gold JA. Alcohol withdrawal syndromes in the intensive care unit. Crit Care Med. 2010;38(9 Suppl):494\u2013501.","journal-title":"Crit Care Med"},{"key":"963_CR5","volume-title":"Cochrane Database of Systematic Reviews","author":"L Amato","year":"2010","unstructured":"Amato L, Minozzi S, Vecchi S, et al. Benzodiazepines for alcohol withdrawal. In: Amato L, editor. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2010."},{"key":"963_CR6","doi-asserted-by":"publisher","first-page":"885066619847119","DOI":"10.1177\/0885066619847119","volume":"23","author":"D Buell","year":"2019","unstructured":"Buell D, Filewod N, Ailon J, Burns KEA. Practice patterns in treating severe alcohol withdrawal: a multidisciplinary, survey. J Intensive Care Med. 2019;23:885066619847119. https:\/\/doi.org\/10.1177\/0885066619847119.","journal-title":"J Intensive Care Med."},{"issue":"22","key":"963_CR7","doi-asserted-by":"publisher","first-page":"2109","DOI":"10.1056\/NEJMra1407298","volume":"371","author":"MA Shuckit","year":"2014","unstructured":"Shuckit MA. Recognition and management of withdrawal delirium (delirium tremens). N Engl J Med. 2014;371(22):2109\u201313.","journal-title":"N Engl J Med."},{"key":"963_CR8","doi-asserted-by":"crossref","unstructured":"Minozzi S, Amato L, Vecchi S, et al. Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev. 2010;(3):CD005064.","DOI":"10.1002\/14651858.CD005064.pub3"},{"key":"963_CR9","doi-asserted-by":"crossref","unstructured":"Liu J, Wang L-N. Baclofen for alcohol withdrawal. Cochrane Database Syst Rev. 2015;(4):CD008502.","DOI":"10.1002\/14651858.CD008502.pub4"},{"key":"963_CR10","doi-asserted-by":"crossref","unstructured":"Mo Y, Thomas MC, Karras GE. Barbiturates for the treatment of alcohol withdrawal syndrome: A systematic review of clinical trials. J Crit Care. 2015.","DOI":"10.1016\/j.jcrc.2015.11.022"},{"key":"963_CR11","doi-asserted-by":"crossref","unstructured":"Leone MA, Vigna-Taglianti F, Avanzi G, et al. Gamma-hydroxybutyrate (GHB) for treatment of alcohol withdrawal and prevention of relapses. 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Management of alcohol withdrawal delirium: an evidence-based practice guideline. Arch Intern Med. 2004;164(13):1405.","journal-title":"Arch Intern Med."},{"key":"963_CR16","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1016\/j.jemermed.2012.07.056","volume":"44.3","author":"J Rosenson","year":"2013","unstructured":"Rosenson J, Clements C, Simon B, et al. Phenobarbital for acute alcohol withdrawal: a prospective randomized double-blind placebo-controlled study. J Emerg Med. 2013;44.3:592\u20138.","journal-title":"J Emerg Med"},{"issue":"2","key":"963_CR17","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1007\/BF03161171","volume":"2","author":"JB Hack","year":"2006","unstructured":"Hack JB, Hoffmann RS, Nelson LS. Resistant alcohol withdrawal: does an unexpectedly large sedative requirement identify these patients early? 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The Medical Research Council of Canada, Natural Sciences and Engineering Research Council & Social Sciences and Humanities Research Council, 1997."}],"container-title":["Pilot and Feasibility Studies"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40814-021-00963-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40814-021-00963-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40814-021-00963-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,22]],"date-time":"2022-01-22T05:07:57Z","timestamp":1642828077000},"score":1,"resource":{"primary":{"URL":"https:\/\/pilotfeasibilitystudies.biomedcentral.com\/articles\/10.1186\/s40814-021-00963-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,22]]},"references-count":19,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["963"],"URL":"https:\/\/doi.org\/10.1186\/s40814-021-00963-4","relation":{},"ISSN":["2055-5784"],"issn-type":[{"value":"2055-5784","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,22]]},"assertion":[{"value":"23 February 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 December 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 January 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethics approval was provided by the St. Michael\u2019s Hospital Research Ethics Board (Toronto, Canada). We will use a hybrid consent model (first party consent or deferred consent) to enroll patients in this trial. The hybrid consent model was approved by the St. Michael\u2019s Hospital Research Ethics Board.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors consent to the publication of the protocol manuscript. No restrictions have been placed on the publication of future data resulting from the trial.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"None of the authors have financial or non-financial competing interests related to the topic of the trial to declare.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"14"}}