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

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., Hill, T., Menys, A., Mainz, J. G., Barr, H., Gowland, P. A., Major, G., & Smyth, A. R. (2023). A randomised crossover trial of tezacaftor-ivacaftor for gut dysfunction in cystic fibrosis with magnetic resonance imaging (MRI) outcomes. NIHR Open Research, 3(65), 1-16. https://doi.org/10.3310/nihropenres.13510.1

• Journal Article Type: Article
• Acceptance Date: Nov 14, 2023
• Online Publication Date: Nov 27, 2023
• Publication Date: Nov 27, 2023
• Deposit Date: Jan 3, 2024
• Publicly Available Date: Jan 4, 2024
• Journal: NIHR Open Research
• Print ISSN: 2633-4402
• Publisher: F1000Research
• Peer Reviewed: Peer Reviewed
• Volume: 3
• Issue: 65
• Pages: 1-16
• DOI: https://doi.org/10.3310/nihropenres.13510.1
• Public URL: https://nottingham-repository.worktribe.com/output/29266313
• Publisher URL: https://openresearch.nihr.ac.uk/articles/3-65/v1
• Additional Information: 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.