{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T22:18:14Z","timestamp":1781129894137,"version":"3.54.1"},"reference-count":44,"publisher":"National Institute for Health and Care Research","license":[{"start":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T00:00:00Z","timestamp":1744243200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","award":["NIHR1304554"],"award-info":[{"award-number":["NIHR1304554"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Belfast Health and Social Care Trust Charitable Trust Funds Research","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["openresearch.nihr.ac.uk"],"crossmark-restriction":false},"short-container-title":["NIHR Open Res"],"abstract":"\n Background Usual airway clearance management in critically ill patients with acute respiratory failure includes suctioning, humidification, use of isotonic saline, and respiratory physiotherapy techniques. Escalation to use of mucoactives occurs when secretions are difficult to clear. Use of mucoactives in clinical practice for this patient population is extensive, yet empirical and variable. Carbocisteine and hypertonic saline are the most used agents, but evidence for their effectiveness is absent or minimal. The lack of existing large-scale randomised trials comparing mucoactives to usual airway clearance management alone in critically ill patients with acute respiratory failure highlights the urgency and necessity of this study. Aim To determine whether the use of mucoactives in critically ill patients with acute respiratory failure improves clinical outcomes and is cost effective, compared to usual airway clearance management alone. Methods A UK multi-centre, 2x2 factorial, randomised, controlled, open-label, Phase 3, pragmatic, clinical and cost effectiveness trial with internal pilot. The target sample is 1956 critically ill adults. Participants will be equally allocated across four trial arms. All participants will receive usual airway clearance management. In three intervention groups, participants will receive either carbocisteine, hypertonic saline, or a combination of carbocisteine and hypertonic saline. In the fourth comparator group, participants will receive usual airway clearance management alone. The primary outcome is the duration of mechanical ventilation with secondary clinical, safety, and health resource utilisation outcomes. The trial will be reported in accordance with CONSORT guidelines. Ethical approval was granted by Leeds East (Yorkshire & The Humber) Research Ethics Committee (reference 21\/YH\/0234) on 28\n th<\/ns3:sup>\n October 2021. All participants will provide written, informed consent via either Personal or Professional Legal Representatives, and subsequently directly once capacity is regained. Trial registration Main trial: ISRCTN17683568,\n https:\/\/www.isrctn.com\/ISRCTN17683568<\/ns3:ext-link>\n , 25\n th<\/ns3:sup>\n November 2021 Study Within A Trial: ISRCTN16675252,\n https:\/\/www.isrctn.com\/ISRCTN16675252<\/ns3:ext-link>\n , 3\n rd<\/ns3:sup>\n November 2021 EudraCT Number, 2021-003763-94\n <\/ns3:p>","DOI":"10.3310\/nihropenres.13905.1","type":"journal-article","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T08:55:11Z","timestamp":1744275311000},"page":"30","update-policy":"https:\/\/doi.org\/10.3310\/nihropenres.crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Effectiveness of mucoactives (carbocisteine and hypertonic saline) in addition to usual airway clearance management with usual airway clearance management alone in acute respiratory failure (MARCH): study protocol for a multi-centre 2x2 factorial, randomised, controlled, open-label, Phase 3, pragmatic, clinical and cost-effectiveness trial with internal pilot"],"prefix":"10.3310","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5676-5497","authenticated-orcid":false,"given":"Bronwen","family":"Connolly","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Dickson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Agus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4583-5381","authenticated-orcid":false,"given":"Bronagh","family":"Blackwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3249-1508","authenticated-orcid":false,"given":"Mark","family":"Borthwick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy","family":"Martina 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Why blinded trials are not always best.","volume":"368","author":"R Anand","year":"2020","journal-title":"BMJ."},{"key":"ref-37","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.c869","article-title":"CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials.","volume":"340","author":"D Moher","year":"2010","journal-title":"Br Med J."},{"key":"ref-38","article-title":"NHS improvement reference costs: national schedule of reference costs"},{"key":"ref-39","article-title":"NICE PMG9 guide to the methods of technology appraisal 2013","year":"2013"},{"key":"ref-40","doi-asserted-by":"publisher","first-page":"2814-30","DOI":"10.1002\/sim.7322","article-title":"Economic evaluation of factorial Randomised Controlled Trials: challenges, methods and recommendations.","volume":"36","author":"H Dakin","year":"2017","journal-title":"Stat Med."},{"key":"ref-41","doi-asserted-by":"publisher","DOI":"10.1186\/1745-6215-16-S2-O1","article-title":"Good practice principles for sharing individual participant data from publicly funded Clinical Trials.","volume":"16","author":"C Tudur Smith","year":"2015","journal-title":"Trials."},{"key":"ref-42","doi-asserted-by":"publisher","DOI":"10.1186\/s13063-017-2067-4","article-title":"Resource implications of preparing individual participant data from a Clinical Trial to share with external researchers.","volume":"18","author":"C Tudur Smith","year":"2017","journal-title":"Trials."},{"key":"ref-43","article-title":"Monthly critical care beds and cancelled urgent operations (MSITREP) data, England, July 2019","year":"2019"},{"key":"ref-44","article-title":"Online repository for extended data relating to MARCH study protocol","author":"B Connolly","journal-title":"figshare."}],"container-title":["NIHR Open Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/5-30\/v1\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/5-30\/v1\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/5-30\/v1\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,9]],"date-time":"2025-08-09T04:55:10Z","timestamp":1754715310000},"score":1,"resource":{"primary":{"URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/5-30\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,10]]},"references-count":44,"URL":"https:\/\/doi.org\/10.3310\/nihropenres.13905.1","relation":{"has-review":[{"id-type":"doi","id":"10.3310\/nihropenres.15112.r35606","asserted-by":"subject"},{"id-type":"doi","id":"10.3310\/nihropenres.15112.r35228","asserted-by":"subject"},{"id-type":"doi","id":"10.3310\/nihropenres.15112.r35228","asserted-by":"object"},{"id-type":"doi","id":"10.3310\/nihropenres.15112.r35606","asserted-by":"object"}]},"ISSN":["2633-4402"],"issn-type":[{"value":"2633-4402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,10]]},"assertion":[{"value":"Indexed","URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/5-30\/v1#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.3310\/nihropenres.15112.r35228, Bodil S Rasmussen, Aalborg University Hospital, Aalborg, 14 May 2025, version 1, indexed","URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/5-30\/v1#referee-response-35228","order":0,"name":"referee-response-35228","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.3310\/nihropenres.15112.r35606, Bairbre A McNicholas, University of Galway, Galway, 12 Jun 2025, version 1, indexed","URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/5-30\/v1#referee-response-35606","order":1,"name":"referee-response-35606","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"Bronwen Connolly<\/b>; \nPosted: 17 Jul 2025<\/i>; Thank you for these comments on this protocol.  In response to the two specific points raised: 1. Can they clarify how they will deal with cross over i.e. for the control group where physicians feel that mucoactive is required as part of usual care? \nResponse<\/i> Data regarding delivery of non-trial mucoactives within the trial will be reported as part of intervention delivery across all four groups.  All randomised patients will be analysed on an intention-to-treat basis regardless of any subsequent treatment.  We will conduct a sensitivity analysis to to investigate the impact of cross over between the interventions.  Exploratory analyses for the primary outcome will be conducted using interaction tests (treatment group by subgroup) and 99% confidence intervals, and use of non-trial mucoactives will be one sub-group of this analysis. 2. Can they clarify mucoactive related side effects as this is mentioned earlier on but its not specifically mentioned in adverse event reporting and harm \nResponse<\/i> We have included a secondary outcome of safety, measured by the occurrence of any one of four different safety events that reflect potential mucoactive-related side effects; these are detailed in Table 1.  Safety outcomes are collected across all four groups of the trial, regardless of mucoactive administration.  With regard adverse event reporting and harm - events that are collected as safety outcomes do not require additional reporting as adverse events, nor does any event considered to expected in the population as a consequence of critical illness itself.  Only serious adverse events that are judged to be related (possibly, probably, or definitely) to a mucoactive are required to be reported (i.e. serious adverse reaction).","URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/5-30\/v1#referee-comment-3460","order":2,"name":"referee-comment-3460","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This project is funded by the National Institute for Health and Care Research (NIHR) under its [\u2018Health Technology Assessment Programme\u2019 (Grant Reference Number: NIHR130454)]. Additional funding is from the Belfast Health and Social Care Trust Charitable Trust Funds Research. The views expressed are those of the author\/s and not necessarily those of the NIHR or the Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}