A randomised crossover trial of tezacaftor-ivacaftor for gut dysfunction in cystic fibrosis with magnetic resonance imaging (MRI) outcomes: a pilot study

Ng, Christabella; Dellschaft, Neele S; Hoad, Caroline; Marciani, Luca; Spiller, Robin; Crooks, Colin; Hill, Trevor; Menys, Alex; Mainz, Jochen G; Barr, Helen; Gowland, Penny A.; Major, Giles; Smyth, Alan R

Abstract

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 >360minutes [225,>360] vs. placebo 330minutes [285,>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)

Citation

Ng, C., Dellschaft, N. S., Hoad, C., Marciani, L., Spiller, R., Crooks, C., …Smyth, A. R. (2024). A randomised crossover trial of tezacaftor-ivacaftor for gut dysfunction in cystic fibrosis with magnetic resonance imaging (MRI) outcomes: a pilot study. NIHR Open Research, 3, Article 65. https://doi.org/10.3310/nihropenres.13510.2

• Journal Article Type: Article
• Acceptance Date: Nov 27, 2023
• Online Publication Date: Mar 19, 2024
• Publication Date: 2024
• Deposit Date: Apr 16, 2024
• Publicly Available Date: Apr 18, 2024
• Journal: NIHR Open Research
• Print ISSN: 2633-4402
• Publisher: F1000Research
• Peer Reviewed: Peer Reviewed
• Volume: 3
• Article Number: 65
• DOI: https://doi.org/10.3310/nihropenres.13510.2
• Public URL: https://nottingham-repository.worktribe.com/output/32754777
• Additional Information: Referee status: Approved with reservations, Approved; Referee Report: 10.3310/nihropenres.14661.r30806, Onur Cil, University of California San Diego, San Diego, California, 14 Dec 2023, version 1, 1 approved, 1 approved with reservations; Referee Report: 10.3310/nihropenres.14661.r30972, Drucy Borowitz, University at Buffalo, Buffalo, 04 Jan 2024, version 1, 1 approved, 1 approved with reservations; Grant Information: 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.; Copyright: 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.