{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T18:22:20Z","timestamp":1774290140124,"version":"3.50.1"},"reference-count":18,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020977","name":"Canadian Frailty Network","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020977","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000241","name":"Physicians' Services Incorporated Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000241","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Hamilton Academic Health Sciences Organization"},{"DOI":"10.13039\/100010564","name":"Academic Medical Organization of Southwestern Ontario","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010564","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100032345","name":"St. Joseph's Healthcare Hamilton","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100032345","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009776","name":"McMaster University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009776","id-type":"DOI","asserted-by":"publisher"}]},{"name":"iHealth"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The enrollment of a patient into more than one study (i.e., coenrollment) has risks which warrant exploration, particularly with respect to possible effects on trial outcomes. This pre-planned secondary analysis will examine the sensitivity of treatment effects to coenrollment in an international critical care trial (Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Objective(s)<\/jats:title>\n                    <jats:p>The primary objective is to evaluate the sensitivity of the effect of probiotics on the primary endpoint of VAP to patient coenrollment in at least one other study. The secondary objectives are to describe the characteristics of coenrolled patients and the studies they were coenrolled into; examine any differences in baseline traits; understand differences in center-level characteristics between coenrolling and non-coenrolling centers; identify factors associated with coenrollment; and explore the relationship between coenrollment status and the incidence of adverse events.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We developed a protocol and statistical analysis plan (SAP) for this secondary analysis involving the conduct of a Cox regression model, including treatment allocation, coenrollment status, and the interaction between the two as independent variables. We also describe our planned statistical analyses for the secondary objectives, involving descriptive statistics, univariable analyses, and multivariable analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The results of this study will be published in a peer-reviewed journal focused on critical care research or trial methodology, and presented at local, national, and international conferences. As a secondary analysis, this study will not undergo secondary research ethics board approval. Data will be presented in aggregate and without patient identifiers.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0345656","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T17:25:02Z","timestamp":1774286702000},"page":"e0345656","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Coenrollment of critically ill patients in PROSPECT: A protocol and statistical analysis plan"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1516-9584","authenticated-orcid":true,"given":"Alex","family":"Thabane","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diane","family":"Heels-Ansdell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Zytaruk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deborah","family":"Cook","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"for the PROSPECT Investigators and the Canadian Critical Care Trials Group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"issue":"1","key":"pone.0345656.ref001","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1164\/rccm.201412-2316OC","article-title":"Determining the ideal strategy for ventilator-associated pneumonia prevention. Cost-benefit analysis","volume":"192","author":"W Branch-Elliman","year":"2015","journal-title":"Am J Respir Crit Care Med"},{"issue":"3","key":"pone.0345656.ref002","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1097\/CCM.0b013e3181c8fe4b","article-title":"Impact of the administration of probiotics on the incidence of ventilator-associated pneumonia: a meta-analysis of randomized controlled trials","volume":"38","author":"II Siempos","year":"2010","journal-title":"Crit Care Med"},{"issue":"8","key":"pone.0345656.ref003","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.3390\/nu14081600","article-title":"Probiotics for the prevention of ventilator-associated pneumonia: an updated systematic review and meta-analysis of randomised controlled trials","volume":"14","author":"HA Cheema","year":"2022","journal-title":"Nutrients"},{"issue":"1","key":"pone.0345656.ref004","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1186\/s12890-022-01965-5","article-title":"Probiotic in the prevention of ventilator-associated pneumonia in critically ill patients: evidence from meta-analysis and trial sequential analysis of randomized clinical trials","volume":"22","author":"Y-C Sun","year":"2022","journal-title":"BMC Pulm Med"},{"issue":"11","key":"pone.0345656.ref005","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1001\/jama.2021.13355","article-title":"Effect of probiotics on incident ventilator-associated pneumonia in critically ill patients: a randomized clinical trial","volume":"326","author":"J Johnstone","year":"2021","journal-title":"JAMA"},{"key":"pone.0345656.ref006","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/1471-2288-13-92","article-title":"A tutorial on sensitivity analyses in clinical trials: the what, why, when and how","volume":"13","author":"L Thabane","year":"2013","journal-title":"BMC Med Res Methodol"},{"issue":"7","key":"pone.0345656.ref007","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.1097\/CCM.0b013e31817c00b0","article-title":"Enrollment of intensive care unit patients into clinical studies: a trinational survey of researchers\u2019 experiences, beliefs, and practices","volume":"36","author":"DJ Cook","year":"2008","journal-title":"Crit Care Med"},{"issue":"2","key":"pone.0345656.ref008","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1097\/CCM.0000000000000692","article-title":"Coenrollment in a randomized trial of high-frequency oscillation: prevalence, patterns, predictors, and outcomes*","volume":"43","author":"DJ Cook","year":"2015","journal-title":"Crit Care Med"},{"issue":"1","key":"pone.0345656.ref009","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1186\/1745-6215-15-470","article-title":"Ethical and scientific considerations for patient enrollment into concurrent clinical trials","volume":"15","author":"PS Myles","year":"2014","journal-title":"Trials"},{"issue":"6","key":"pone.0345656.ref010","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2018-025228","article-title":"Evaluating probiotics for the prevention of ventilator-associated pneumonia: a randomised placebo-controlled multicentre trial protocol and statistical analysis plan for PROSPECT","volume":"9","author":"J Johnstone","year":"2019","journal-title":"BMJ Open"},{"key":"pone.0345656.ref011","doi-asserted-by":"crossref","first-page":"107938","DOI":"10.1016\/j.cct.2025.107938","article-title":"Coenrollment in a critical care trial: Characteristics and consequences","volume":"154","author":"F Clarke","year":"2025","journal-title":"Contemp Clin Trials"},{"issue":"1","key":"pone.0345656.ref012","doi-asserted-by":"crossref","DOI":"10.1186\/cc11917","article-title":"Co-enrollment of critically ill patients into multiple studies: patterns, predictors and consequences","volume":"17","author":"D Cook","year":"2013","journal-title":"Crit Care"},{"issue":"10","key":"pone.0345656.ref013","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1097\/00003246-198510000-00009","article-title":"APACHE II: a severity of disease classification system","volume":"13","author":"WA Knaus","year":"1985","journal-title":"Crit Care Med"},{"issue":"5","key":"pone.0345656.ref014","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1503\/cmaj.050051","article-title":"A global clinical measure of fitness and frailty in elderly people","volume":"173","author":"K Rockwood","year":"2005","journal-title":"CMAJ"},{"key":"pone.0345656.ref015","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1186\/s13063-016-1495-x","article-title":"Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial-PROSPECT: a pilot trial","volume":"17","author":"DJ Cook","year":"2016","journal-title":"Trials"},{"issue":"1","key":"pone.0345656.ref016","doi-asserted-by":"crossref","DOI":"10.1186\/s40814-015-0013-3","article-title":"Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial\u2014PROSPECT: protocol for a feasibility randomized pilot trial","volume":"1","author":"J Johnstone","year":"2015","journal-title":"Pilot Feasibility Stud"},{"issue":"6","key":"pone.0345656.ref017","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1093\/aje\/kwk052","article-title":"Relaxing the rule of ten events per variable in logistic and Cox regression","volume":"165","author":"E Vittinghoff","year":"2007","journal-title":"Am J Epidemiol"},{"issue":"8","key":"pone.0345656.ref018","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0041791","article-title":"Making co-enrolment feasible for randomised controlled trials in paediatric intensive care","volume":"7","author":"K Harron","year":"2012","journal-title":"PLoS One"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0345656","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T17:25:06Z","timestamp":1774286706000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0345656"}},"subtitle":[],"editor":[{"given":"Ant\u00f3nio","family":"Machado","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,3,23]]},"references-count":18,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3,23]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0345656","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,23]]}}}