{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T19:24:10Z","timestamp":1789932250157,"version":"4.0.1"},"reference-count":11,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T00:00:00Z","timestamp":1653955200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000971","name":"ALS Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000971","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Muscle and Nerve"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction\/Aims<\/jats:title><jats:p>Trials incorporating placebo\u2010to\u2010active treatment crossover are encouraged in fatal conditions like amyotrophic lateral sclerosis (ALS) but may underestimate active treatment survival benefit. Here, we apply methods for modeling survival without crossover, including the rank\u2010preserving structural failure time model (RPSFTM), to data from the CENTAUR trial of sodium phenylbutyrate and taurursodiol (PB and TURSO) in ALS incorporating both randomized placebo\u2010controlled and open\u2010label extension (OLE) phases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Intent\u2010to\u2010treat (ITT) and RPSFTM survival analyses were performed with final data at a July 2020 cutoff date. Analyses of subgroups based on randomized treatment and OLE phase participation were also performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Hazard ratios (95% confidence intervals) of death for PB and TURSO versus participants initially on placebo were 0.57 (0.35\u20130.92) on ITT analysis and 0.39 (0.17\u20130.88) in the primary on\u2010treatment RPSFTM analysis (<jats:italic>p<\/jats:italic>\u00a0=\u00a0.023). Median ITT survival duration for PB and TURSO (25.8\u00a0mo) was 6.9\u00a0mo longer than placebo (18.9\u00a0mo) on ITT analysis and 10.6\u00a0mo longer than the median RPSFTM\u2010adjusted survival duration for placebo (15.2\u00a0mo). Median survival duration was 18.8\u00a0mo longer in the PB and TURSO\u2013randomized subgroup who continued into the OLE phase versus the placebo\u2010randomized subgroup who did not continue into the OLE phase (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.0001), although OLE phase selection bias may have potentially confounded these results.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Similar to the prespecified ITT analysis, post hoc analyses adjusting for treatment crossover in CENTAUR showed a significant survival benefit for PB and TURSO. Such methods may provide clinical context for observed survival outcomes in future ALS crossover trials.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mus.27569","type":"journal-article","created":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T03:20:51Z","timestamp":1651720851000},"page":"136-141","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Survival analyses from the <scp>CENTAUR<\/scp> trial in amyotrophic lateral sclerosis: Evaluating the impact of treatment crossover on outcomes"],"prefix":"10.1002","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0505-1168","authenticated-orcid":false,"given":"Sabrina","family":"Paganoni","sequence":"first","affiliation":[{"name":"Sean M. Healey and AMG Center for ALS &amp; the Neurological Clinical Research Institute Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"},{"name":"Spaulding Rehabilitation Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6475-2795","authenticated-orcid":false,"given":"Claire","family":"Watkins","sequence":"additional","affiliation":[{"name":"Maple Health Group  New York New York USA"},{"name":"Clarostat Consulting Ltd  Bollington, Cheshire UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Cawson","sequence":"additional","affiliation":[{"name":"Formerly with Maple Health Group  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Hendrix","sequence":"additional","affiliation":[{"name":"Pentara Corporation  Millcreek Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel P.","family":"Dickson","sequence":"additional","affiliation":[{"name":"Pentara Corporation  Millcreek Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Newman","family":"Knowlton","sequence":"additional","affiliation":[{"name":"Pentara Corporation  Millcreek Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Timmons","sequence":"additional","affiliation":[{"name":"Amylyx Pharmaceuticals, Inc.  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Machelle","family":"Manuel","sequence":"additional","affiliation":[{"name":"Amylyx Pharmaceuticals, Inc.  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merit","family":"Cudkowicz","sequence":"additional","affiliation":[{"name":"Sean M. Healey and AMG Center for ALS &amp; the Neurological Clinical Research Institute Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,31]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1080\/21678421.2020.1771734"},{"issue":"15","key":"e_1_2_11_3_1","first-page":"S327","article-title":"Disease\u2010modifying treatment of amyotrophic lateral sclerosis","volume":"24","author":"Schultz J","year":"2018","journal-title":"Am J Manag Care."},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1916945"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.27091"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40273-014-0145-y"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jval.2014.06.006"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0119632"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-017-0692-3"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1177\/0962280218780856"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jval.2019.10.015"},{"key":"e_1_2_11_12_1","volume-title":"NICE DSU technical support document 16: adjusting survival time estimates in the presence of treatment switching","author":"Latimer NR","year":"2014"}],"container-title":["Muscle &amp; Nerve"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mus.27569","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mus.27569","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mus.27569","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T07:42:17Z","timestamp":1692862937000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mus.27569"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,31]]},"references-count":11,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,8]]}},"alternative-id":["10.1002\/mus.27569"],"URL":"https:\/\/doi.org\/10.1002\/mus.27569","archive":["Portico"],"relation":{},"ISSN":["0148-639X","1097-4598"],"issn-type":[{"value":"0148-639X","type":"print"},{"value":"1097-4598","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,31]]},"assertion":[{"value":"2022-02-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-04-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-31","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}