Gut Imaging for Function & Transit in Cystic Fibrosis Study 2
Condition: Cystic Fibrosis
MeSH terms: Cystic Fibrosis; Fibrosis
Study type: Interventional
Phase: Phase 2

Summary: 
      People with Cystic Fibrosis (CF) have problems digesting their food properly. More than 8 in
      10 people with CF 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 is a drug combination which
      corrects the basic defect in CF an has shown improvements on lung function.

      The purpose of this study is to evaluate, using Magnetic Resonance Imaging (MRI) and
      patient-reported outcomes, whether Tezacaftor/Ivacaftor with Ivacaftor has an effect on
      improving gastrointestinal problems in CF.
    

Detailed description: 
      This is a small pilot study to compare the effects of active drug (Tezacaftor/Ivacaftor with
      Ivacaftor) on the gut in people with CF.

      Participants will be randomised to take active drug or matched placebo 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 at the Sir Peter
      Mansfield Imaging Centre, after an overnight fast. On this day, participants will be asked to
      withhold any medicines directly altering bowel habit such as laxatives. They will continue to
      take pancreatic enzyme replacement therapy and other medications for CF.

      The Investigators will use the same MRI protocol as described in GIFT-CF (NCT03566550).
      Participants will have their first MRI scan fasted. After the first scan, they will eat a
      first standardised meal . They will then have 7 MRI scans at half hourly intervals and 3 MRI
      scans at hourly intervals. Participants will be given a second standardised meal after their
      ninth MRI scan. Each MRI scan will last approximately 15 minutes. After each MRI scan,
      participants will complete a validated gastrointestinal symptom questionnaire
      (Gastrointestinal Symptom Rating Scale). In between scans, participants will have access to
      an adjacent room with Wifi and television access.

      During the day, participants will have their lung function, blood pressure and blood tests
      taken. They will also provide a sputum and stool sample.

      Infection control requirements mean that only 1 participant will attend for MRI scanning per
      day.

      ***Amendment to study due to COVID-19*** From mid-March 2020, all face to face clinical
      research in the UK has been suspended (apart from studies directly related to the COVID-19
      pandemic). Patients in the GIFT-CF 2 trial who had not yet completed the full trial protocol
      were therefore unable to continue. Funding for SymkeviTM (tezacaftor/ivacaftor and ivacaftor)
      in the UK was announced at the end of 2019 and some of the trial participants, who have not
      completed GIFT-CF 2, may be prescribed SymkeviTM by their CF team. It will therefore not be
      possible for them to complete the placebo controlled cross-over trial, once COVID
      restrictions are eased. We plan to mitigate the effects of COVID-related disruption by
      ensuring all trial participants have had the full, protocol-defined, scan sequence both on
      and off SymkeviTM. When restrictions are eased, we will invite participants who have been
      prescribed SymkeviTM by their CF centre to attend for scanning, if they have not previously
      had an "on treatment" scan. We will follow the same scanning protocol. We will ensure that
      adherence to SymkeviTM is good and they have received at least 21 days of treatment (as
      specified in the trial protocol). 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 SymkeviTM with their outcome measures previously recorded at baseline
      (off treatment). The personnel interpreting the MRI scans will be blind to whether they were
      performed on or off SymkeviTM - reducing the probability of observer bias.

      ***Post hoc analysis*** For participants who are invited for an open-label "on treatment" MRI
      scan day, the statistical analysis will involve a comparison between their pre-treatment MRI
      scans and the open-label scan. The researcher analysing the images will remain blinded.
      Statistical analysis for these participants will be a comparison between their pre-treatment
      scan and open-label on-treatment scan. Motility outcomes will not be analysed as the specific
      MR sequencing was adapted to focus on the terminal ileum in the cross-over trial, whilst in
      the pre-treatment scans, the motility was across the whole small bowel.
    

Intervention name(s): Tezacaftor/Ivacaftor + Ivacaftor; Placebo oral tablet
Intervention type(s): Drug; Drug
Intervention description(s): As per description in arms.; As per description in arms
Other intervention name(s): VX-661 100mg / VX-770 150mg active tablets; VX-770 150mg active tablets; Matching placebo tablets
Intervention MeSH terms: Ivacaftor
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Other