Gut Imaging for Function & Transit in Cystic Fibrosis Study 2 V1.0
Research type
Research Study
Full title
A Randomised Cross-Over Pilot Study of the Effects of Tezacaftor/Ivacaftor and Ivacaftor combination regimen on Gastrointestinal Function using Magnetic Resonance Imaging Parameters in People with Cystic Fibrosis
IRAS ID
254559
Contact name
Alan Smyth
Contact email
Sponsor organisation
Nottingham University Hospitals NHS Trust
Clinicaltrials.gov Identifier
Duration of Study in the UK
1 years, 0 months, 31 days
Research summary
Research Summary
People with Cystic Fibrosis (CF) have problems digesting their food properly. More than 8 in 10 patients must take medication to assist their digestion. In spite of this, complications such as bowel blockage occur.Finding out how already licenced drugs for CF work in the gut is the first step in repurposing medications. Tezacaftor/Ivacaftor with Ivacaftor (active drug) is a drug combination which corrects the basic defect in CF and has shown improvements on lung function.
We are inviting 15 people with CF, who are not currently taking a CF modifying drug, to compare the effects of active drug on the gut.
Participants will be randomised to take active drug or a matched placebo drug for 28 days then switch to the alternate drug after a 28 day washout period.Before participants commence treatment, they will have blood pressure and baseline blood tests.
Participants will attend once per treatment period for MRI scanning. We will use the same MRI protocol as used in the pilot study (GIFT-CF). We will take a total of 11 scans each lasting about 15 minutes and requiring short breath holds. Participants will arrive fasted in the morning and receive a standardised meal right after the first and ninth scan.
Our primary outcome is orocaecal transit time, which we hypothesise to be shorter in people with taking active drug. Other outcomes include gastric volume, small bowel water content, colonic volume, and water and fat content of colonic chyme.
We will recheck blood pressure and blood tests to ensure there are no side effects from the treatment. If there is any suspicion that participants are experiencing side effects that could be harmful, the research doctors will make a decision whether the patient needs to stop treatment and be excluded from the study.
Summary of Results
We recruited 15 participants with CF (aged 13-36 years, 9 males), of whom 3 dropped out, leaving the planned sample size of 12. The reasons for dropout included one non-attendance for study visits, one inability to complete the first test meal and one experienced claustrophobia when positioned in the MRI scanner. Four participants were unable to complete the study per protocol due to the COVID-19 pandemic. Instead, these 4 participants underwent observer blind MRI scans whilst on tezacaftor-ivacaftor (TEZ/IVA) and within participant comparisons were made from their baseline scans unless they completed the first treatment arm with placebo. There were 8 participants included in the primary per protocol analysis. A post hoc analysis to compare participants on and off TEZ/IVA was performed in 12 participants.
All blood pressure and blood tests (including liver function tests) for safety monitoring were within normal limits. There were no adverse events during the study.For the primary analysis, there was no difference in the primary endpoint orocaecal transit time, OCTT (TEZ/IVA median >360 mins [IQR 225,>360) vs. placebo 330 mins [285,>360], p=0.8). An upper limit of detection was imposed by the timing of the last scan, 360 minutes post-prandial. By this point, the meal had still not reached the caecum suggesting an oro-caecal transit time greater than 360 minutes and was confirmed by the high intensity of the meal still seen within the small bowel at 360 minutes. There were two participants whose OCTT was longer than 360 minutes in both treatment periods. There was one participant whose OCTT was incomplete during the placebo period only and two participants whose OCTT was incomplete during the TEZ/IVA period only.
There was no statistical significance in the secondary endpoints (gastric half emptying time, corrected delta TI (change in small bowel water content, SBWC), corrected SBWC AUC (area under the curve), corrected colonic volumes AUC, gut symptom questionnaires) in the primary per protocol analysis.
There was no statistical significance in the exploratory outcomes (terminal ileum motility, fasting T1 relaxation time of the ascending colon, faecal elastase, faecal calprotectin, fasting terminal ileum diameter).
REC name
West Midlands - South Birmingham Research Ethics Committee
REC reference
19/WM/0130
Date of REC Opinion
7 May 2019
REC opinion
Favourable Opinion