{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T02:00:29Z","timestamp":1772244029133,"version":"3.50.1"},"update-to":[{"DOI":"10.3310\/nihropenres.13510.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T00:00:00Z","timestamp":1710806400000}}],"reference-count":33,"publisher":"National Institute for Health and Care Research","license":[{"start":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T00:00:00Z","timestamp":1710806400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020624","name":"NIHR Nottingham Biomedical Research Centre","doi-asserted-by":"publisher","award":["PumpPrimingAward"],"award-info":[{"award-number":["PumpPrimingAward"]}],"id":[{"id":"10.13039\/501100020624","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["SMYTH18A0-I-Smyth"],"award-info":[{"award-number":["SMYTH18A0-I-Smyth"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000292","name":"Cystic Fibrosis Trust","doi-asserted-by":"publisher","award":["VIA061"],"award-info":[{"award-number":["VIA061"]}],"id":[{"id":"10.13039\/501100000292","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011022","name":"Vertex Pharmaceuticals","doi-asserted-by":"crossref","award":["IIS-2018-106697"],"award-info":[{"award-number":["IIS-2018-106697"]}],"id":[{"id":"10.13039\/100011022","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Nottingham Hospitals Charity","award":["Research Pump Priming Competition"],"award-info":[{"award-number":["Research Pump Priming Competition"]}]}],"content-domain":{"domain":["openresearch.nihr.ac.uk"],"crossmark-restriction":false},"short-container-title":["NIHR Open Res"],"abstract":"<ns3:p>Background People with cystic fibrosis (CF) can experience recurrent chest infections, pancreatic exocrine insufficiency and gastrointestinal symptoms. New cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs improve lung function but gastrointestinal effects are unclear. We aimed to see if a CFTR modulator (tezacaftor-ivacaftor,TEZ\/IVA) improves gastrointestinal outcomes in CF. Methods We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (2019-2020) at Nottingham University Hospitals. The effects of TEZ\/IVA on gut physiology were measured using MRI. Participants were randomly assigned to treatment sequences AB or BA (A:TEZ\/IVA, B:placebo, each 28 days), with a 28-day washout period. Participants had serial MRI scans at baseline and after 19-23 days of each treatment. Due to the COVID-19 pandemic, a protocol amendment allowed for observer-blind comparisons prior to and during TEZ\/IVA. In such cases, participants were not blind to the treatment but researchers remained blind. The primary outcome was oro-caecal transit time (OCTT). Secondary outcomes included MRI metrics, symptoms and stool biomarkers. Results We randomised 13 participants. Before the COVID-19 pandemic 8 participants completed the full protocol and 1 dropped out. The remaining 4 participants followed the amended protocol. There were no significant differences between placebo and TEZ\/IVA for OCTT (TEZ\/IVA &gt;360minutes [225,&gt;360] vs. placebo 330minutes [285,&gt;360], p=0.8) or secondary outcomes. There were no adverse events. Conclusions Our data contribute to a research gap in the extra-pulmonary effects of CFTR modulators. We found no effect after TEZ\/IVA on MRI metrics of gut function, GI symptoms or stool calprotectin. Effects might be detectable with larger studies, longer treatment or more effective CFTR modulators. ClinicalTrials.gov registration NCT04006873 (02\/07\/2019)<\/ns3:p>","DOI":"10.3310\/nihropenres.13510.2","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T12:30:06Z","timestamp":1710851406000},"page":"65","update-policy":"https:\/\/doi.org\/10.3310\/nihropenres.crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A randomised crossover trial of tezacaftor-ivacaftor for gut dysfunction in cystic fibrosis with magnetic resonance imaging (MRI) outcomes: a pilot study."],"prefix":"10.3310","volume":"3","author":[{"given":"Christabella","family":"Ng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neele S","family":"Dellschaft","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline","family":"Hoad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Marciani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robin","family":"Spiller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin","family":"Crooks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0277-4988","authenticated-orcid":false,"given":"Trevor","family":"Hill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Menys","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jochen G","family":"Mainz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4388-2563","authenticated-orcid":false,"given":"Helen","family":"Barr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Penny A.","family":"Gowland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giles","family":"Major","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5494-5438","authenticated-orcid":false,"given":"Alan R","family":"Smyth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"6221","published-online":{"date-parts":[[2024,3,19]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"2519-31","DOI":"10.1016\/S0140-6736(16)00576-6","article-title":"Cystic fibrosis.","volume":"388","author":"J Elborn","year":"2016","journal-title":"Lancet."},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"388-90","DOI":"10.1136\/thoraxjnl-2017-210473","article-title":"The top 10 research priorities in cystic fibrosis developed by a partnership between people with CF and healthcare providers.","volume":"73","author":"N Rowbotham","year":"2018","journal-title":"Thorax."},{"key":"ref-3","doi-asserted-by":"publisher","first-page":"419-28","DOI":"10.1007\/s40271-019-00361-2","article-title":"Validity and Reliability of a Novel Multimodal Questionnaire for the Assessment of Abdominal Symptoms in People with Cystic Fibrosis (CFAbd-Score).","volume":"12","author":"A Jaudszus","year":"2019","journal-title":"Patient."},{"key":"ref-4","doi-asserted-by":"publisher","DOI":"10.1136\/bmjresp-2020-000614","article-title":"How can we relieve gastrointestinal symptoms in people with cystic fibrosis? 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Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/3-65\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/3-65\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/3-65\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T09:40:18Z","timestamp":1718703618000},"score":1,"resource":{"primary":{"URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/3-65\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,19]]},"references-count":33,"URL":"https:\/\/doi.org\/10.3310\/nihropenres.13510.2","relation":{"has-version":[{"id-type":"doi","id":"10.3310\/nihropenres.13510.1","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.3310\/nihropenres.14726.r31310","asserted-by":"subject"},{"id-type":"doi","id":"10.3310\/nihropenres.14726.r31412","asserted-by":"subject"},{"id-type":"doi","id":"10.3310\/nihropenres.14726.r31309","asserted-by":"subject"},{"id-type":"doi","id":"10.3310\/nihropenres.14726.r31411","asserted-by":"subject"},{"id-type":"doi","id":"10.3310\/nihropenres.14726.r31309","asserted-by":"object"},{"id-type":"doi","id":"10.3310\/nihropenres.14726.r31412","asserted-by":"object"},{"id-type":"doi","id":"10.3310\/nihropenres.14726.r31411","asserted-by":"object"},{"id-type":"doi","id":"10.3310\/nihropenres.14726.r31310","asserted-by":"object"}]},"ISSN":["2633-4402"],"issn-type":[{"value":"2633-4402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,19]]},"assertion":[{"value":"Indexed","URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/3-65\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.3310\/nihropenres.14726.r31310, Onur Cil, University of California San Diego, San Diego, California, 29 Mar 2024, version 2, indexed","URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/3-65\/v2#referee-response-31310","order":0,"name":"referee-response-31310","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.3310\/nihropenres.14726.r31309, Drucy Borowitz, University at Buffalo, Buffalo, 29 Mar 2024, version 2, indexed","URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/3-65\/v2#referee-response-31309","order":1,"name":"referee-response-31309","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.3310\/nihropenres.14726.r31411, Mette Frahm Olsen, University of Copenhagen, Copenhagen, 12 Apr 2024, version 2, indexed","URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/3-65\/v2#referee-response-31411","order":2,"name":"referee-response-31411","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Alan Smyth<\/b>; \n<i>Posted: 12 Apr 2024<\/i>; Dear Dr Olsen. Thank you for your interest in our research and for taking the time to review our paper.  \n<b>Reviewer's question : <\/b> Abstract: It is unclear why the protocol was amended with observer-blind assessments due to COVID-19. Could you clarify how this was a consequence of the pandemic?  \n<b>Response:<\/b> Study enrolment commenced in September 2019. In March 2020, in line with UK government rules to restrict the transmission of SARS-CoV2 virus, our centre suspended all research involving direct contact with participants (apart from COVID-19 studies). Our trial was paused between mid-March and August 2020. During this period, reimbursement of TEZ\/IVA was introduced in the UK and 4 participants commenced TEZ\/IVA as part of their routine CF treatment. It was unethical to request their return to the study protocol involving \n<u>placebo<\/u> treatment. These 4 participants therefore completed observer-blind study visits when research resumed. Observer-blind visits were single-blind, where the observers conducting the analysis were blind to treatment status. These 4 participants had MRI studies pre-treatment and whilst taking&nbsp;TEZ\/IVA prescribed by their CF Centre.&nbsp;This is explained in the METHODS section under &quot;Mitigations for COVID-19 pandemic disruptions&quot;. &nbsp; \n<b>Reviewer's question :<\/b> Methods: The study design is described as double-blind here, but some participants were not blinded. You could describe it as outcome assessor\/observer blind or explain further.  \n<b>Response:&nbsp;<\/b>See above. The 4 study participants who had an MRI study on routinely prescribed&nbsp;TEZ\/IVA knew what treatment they were taking but the research staff, who scanned the participant and interpreted the scans, were blind to whether or not the participant was taking&nbsp;TEZ\/IVA (observer blind). This is explained in the METHODS section under &quot;Mitigations for COVID-19 pandemic disruptions&quot;.  \n<b>Reviewer's question :&nbsp;<\/b>What was the reason for the age range of invited patients (12-40 y)?  \n<b>Response:&nbsp;<\/b>This is the age group for whom&nbsp;TEZ\/IVA was licensed in the UK.  \n<b>Reviewer's question :&nbsp;<\/b>The age range is not mentioned as an inclusion criteria in Table 1. Please add.  \n<b>Response:<\/b>&nbsp;People with CF aged from 12 to 40 years, homozygous for p.Phe508del and eligible for TEZ\/IVA, were invited to participate.&nbsp;This is explained in the METHODS section under &quot;Study population&quot;.  \n<b>Reviewer's question :&nbsp;<\/b>Was the randomization blocked?  \n<b>Response: <\/b>No we used simple randomization.  \n<b>Reviewer's question :&nbsp;<\/b>Please clarify the timing of study visits. You write that all measurements were done on one day between day 19 and 23 of treatment. This is then repeated for the two periods of the cross-over study, right?  \n<b>Response: <\/b>Correct. We aimed to do the scan on day 21 of treatment but had to have a window of&nbsp;day 19 to 23 of treatment to allow for participants having other commitments on day 21 or the scanner having a previous booking for that day.  \n<b>Reviewer's question :&nbsp;<\/b>You write that it was unethical for participants to be blinded to their treatment status after the COVID interruption. I am not sure I understand why is blinding was considered unethical to participants after COVID \u2013 but not before?  \n<b>Response: <\/b>We planned a placebo controlled study because TEZ\/IVA was licensed in the UK at the time but was not reimbursed and so not routinely prescribed in UK CF Centres. The study was paused, due to the COVID pandemic, from March-August 2020. Reimbursement for TEZ\/IVA was&nbsp;introduced by the UK Department of Health and Social Care in mid-2020 and so 4 patients received the drug from their CF Centre during the study pause. We felt it would be unethical to ask these patients to continue on a protocol which required 28 days TEZ\/IVA - 28 days washout - 28 days placebo (or the reverse order) as both the washout and placebo periods would deny them modulator treatment. We therefore undertook an observer blind MRI assessment whilst the participant was on TEZ\/IVA treatment and compared that to the same participant's baseline MRI (no modulator&nbsp;treatment).&nbsp;  \n<b>Reviewer's question :&nbsp;<\/b> Results: Please add the two study arms to the CONSORT flow chart (fig 3), i.e. treatment\/placebo and placebo\/treatment  \n<b>Response:<\/b> We think this will add to the complexity of the CONSORT diagram and will make the diagram difficult for the reader to interpret easily.  \n<b>Reviewer's question :&nbsp;<\/b>Add a brief explanation of the GIFT-CF 1 study (overall aim, methods and perhaps findings)  \n<b>Response:&nbsp;<\/b>This is a separate study and is cited as reference 13.&nbsp; Ng C, Dellschaft NS, Hoad CL, et al.: Postprandial changes in gastrointestinal function and transit in cystic fibrosis assessed by Magnetic Resonance Imaging. J Cyst Fibros. 2020; 20(4): 591\u20137.&nbsp; https:\/\/doi.org\/10.1016\/j.jcf.2020.06.004  \n<b>Reviewer's question :&nbsp;<\/b>Please clarify if higher scores of the various patient-reported outcomes indicate worse or better outcomes. &nbsp;  \n<b>Response:&nbsp;<\/b>For the PAC-SYM, CFAbdScore and the Likert score, a high score = more severe symptoms.  \n<b>Reviewer's question :&nbsp;<\/b> Discussion: Please comment on potential impact of the double-blinding vs observer-blinding. Do you consider your outcomes to be prone to bias when the participant is not blinded? I would assume that your primary outcome is objective enough to not be affected by detection bias, so why have you chosen the smaller blinded group for your primary analysis?  \n<b>Response:&nbsp;<\/b>Thank you for raising this important point. We agree that the MRI studies are an objective measure and are unlikely to be subject to detection bias - particularly as the staff conducting and interpreting the scans were blinded.  The primary analysis was specified in our clinical trials.gov protocol which we published before commencing this trial and amended in the light of the COVID pandemic. The COVID amendment says: &quot;Our primary analysis will be on the patients who completed the trial per protocol but we will present a secondary analysis on all 12 patients, comparing outcome measures on Symkevi\n<sup>TM<\/sup> with their outcome measures previously recorded at baseline (off treatment)...&quot;  See: https:\/\/clinicaltrials.gov\/study\/NCT04006873?tab=table&nbsp;  This aligns with the METHODS section, under &quot;Statistical analysis&quot;, we state: &quot;In view of COVID-19 disruptions, we completed a primary per protocol analysis for all participants who were blind to treatment. A secondary post-hoc intention-to-treat analysis compared all enrolled participants who attended study visits on and off TEZ\/IVA.&quot;.","URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/3-65\/v2#referee-comment-3318","order":3,"name":"referee-comment-3318","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.3310\/nihropenres.14726.r31412, Dipesh Vasant, Manchester University NHS FoundationTrust, Manchester, 29 Apr 2024, version 2, indexed","URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/3-65\/v2#referee-response-31412","order":4,"name":"referee-response-31412","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The study was funded by the US Cystic Fibrosis Foundation (574248), UK Cystic Fibrosis Trust (VIA061), Vertex Pharmaceuticals Incorporated (IIS-2018-106697) and Nottingham University Hospitals Charity (CRF-MAJOR-NOV 2018). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":5,"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"}]}}