Gut Imaging for Function & Transit in CF - GIFT-CF 3 (GIFT-CF3)

Gut Imaging for Function & Transit in CF - GIFT-CF 3: Evaluation of Triple Combination Therapy.

An observational study of patients with cystic fibrosis (CF) starting treatment with Kaftrio (Elexacaftor / Tezacaftor / Ivacaftor) as part of routine clinical care, following EMA licensing (approved end of Aug 2020).

• Patients with CF who are p.Phe508del homozygotes will already be receiving the less effective CFTR modulator drug Symkevi (Tezacaftor / Ivacaftor) and will switch to KaftrioTM.
• Patients who are who are compound heterozygotes with at least 1 copy of p.Phe508del currently have access to no effective CFTR modulator and will be starting a CFTR modulator (Kaftrio) for the first time.

Participants attend a study visit before Kaftrio treatment commences, followed by visits at 12 and 24 weeks after starting treatment. At each visit they will be scanned before and after standardised meals in the morning and mid-day (11 scans in total over 6 hours). No intravenous contrast or bowel preparation will be used. Participants will complete questionnaires on gastrointestinal symptoms as well as providing stool and sputum samples for assessment of microbiome and stool for inflammatory mediators and pancreatic function (elastase).

**Following an extension, participants had a further visit at 76 weeks post starting Kaftrio, updated in detailed description**

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Diagnostic test: Magnetic Resonance Imaging (MRI)

Detailed Description

This is an observational study to observe the effects of Kaftrio (Elexacaftor / Tezacaftor / Ivacaftor) on the gut in people with CF.

Participants will attend 4 times, following an extension (pre-Kaftrio, at 12 weeks of Kaftrio at 24 weeks of Kaftrio and 76 weeks of Kaftrio) 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 and NCT04006873). 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.

They will also complete gut symptom questionnaires relating to the preceding 2 weeks and a 3 day food diary. They will also provide a sputum and stool sample.

Infection control requirements mean that only 1 participant will attend for MRI scanning per day. Extra COVID-19 precautions will also be taken throughout scan days.

***Please note, due to the timing of EMA approval for Kaftrio and ethics approval for the study granted on 21st Ocober 2020, the clinicaltrials.gov registration was created on 21st October 2020 and approved by the clinicaltrials.gov PRS team on 4th November 2020.***

• Study Type: Observational
• Enrollment (Actual): 24

Contacts and Locations

Study Locations

• United Kingdom
  • Nottinghamshire
    • Nottingham, Nottinghamshire, United Kingdom, NG7 2UH
      • Nottingham University Hospitals NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 60 years (Child, Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Probability Sample

Study Population

All CF patients who receive care by Nottingham University Hospitals NHS Trust and are eligible for the study will be approached by their usual care team.

Description

Inclusion Criteria:

• Age 12 - 60 years
• Capacity to consent, or to understand the requirements of the study where parental consent is needed.
• Confirmed diagnosis of CF, either by sweat test or genetic testing.
• Genotype homozygous p.Phe508del or compound heterozygous with at least 1 copy of p.Phe508del.
• Eligible for KaftrioTM (Elexacaftor / Tezacaftor / Ivacaftor) treatment but not yet commenced Kaftrio treatment as part of routine care.

Exclusion Criteria:

• Contra-indication to MRI scanning, such as embedded metal, pacemaker.
• FEV1 < 40% (% predicted using Global Lung Initiative values)
• Unable to stop medications directly prescribed to alter bowel habit, such as laxatives of anti-diarrhoeals, on the study day
• Previous resection of small bowel >20cm in length
• Intestinal stoma
• Diagnosis of inflammatory bowel disease or coeliac disease, confirmed by biopsy
• Gastrointestinal malignancy
• Unable to comply with dietary restrictions required for the study
• Pregnancy - tests are available at the SPMIC if participants are unsure
• Unable to speak or understand English

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
p.Phe508del homozygous genotype; People with CF with 2 copies of p.Phe508del and previously eligible for Symkevi (Tezacaftor/Ivacaftor)	Diagnostic test: Magnetic Resonance Imaging (MRI); MRI to study gut function and transit without the risk of exposure to ionising radiation.
p.Phe508del heterozygous genotype; People with CF with 1 copy of p.Phe508del and not previously eligible for any CFTR modulator	Diagnostic test: Magnetic Resonance Imaging (MRI); MRI to study gut function and transit without the risk of exposure to ionising radiation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in oro-caecal transit time (OCTT) in minutes at baseline and 24 weeks and baseline and 76 weeks	the time when the test meal is first detectable in the caecum	4 days of scanning

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Small bowel water content (SBWC) area under the curve (AUC), corrected for body surface area, measured in L.min/m^2 between 0 and 360 minutes at baseline, 12 weeks, 24 weeks and 76 weeks	A measure of small bowel water representing secretions	4 days of scanning
Change in SBWC between 240 and 300 minutes (delta DTI) at baseline, 12 weeks, 24 weeks and 76 weeks	These are small bowel water measurements before and after the second test meal	4 days of scanning
Colonic volume area under the curve (AUC), corrected for body surface area at baseline, 12 weeks, 24 weeks and 76 weeks	volume of colon representing ease of chyme passage through colon	4 days of scanning
Stool calprotectin at baseline, 12 weeks, 24 weeks and 76 weeks	A measure of gut inflammation	4 days of scanning
Stool and sputum microbiome at baseline, 12 weeks, 24 weeks and 76 weeks	A measure of types of microbiome present in the stool and sputum	4 days of scanning
Stool elastase at baseline, 12 weeks, 24 weeks and 76 weeks	A marker of pancreatic exocrine function	4 days of scanning
Terminal ileum motility at baseline, 12 weeks, 24 weeks and 76 weeks	A measure of motility at the terminal ileum using the GIQuant tool in arbitrary units	4 days of scanning
Abdominal symptoms as measured by the CFAbd-Score	A measure of gut symptoms over the preceding 2 weeks and during the study day, where a high score indicates more severe abdominal symptoms	4 days of scanning
Abdominal symptoms as measured by the PAC-SYM score	A measure of gut symptoms over the preceding 2 weeks and during the study day, where a high score indicates more severe abdominal symptoms	4 days of scanning
Abdominal symptoms as measured by 3 domains from the Gastrointestinal Symptoms Rating Scale (GSRS)	A measure of gut symptoms over the preceding 2 weeks and during the study day,, where a high score indicates more severe abdominal symptoms	4 days of scanning
Spirometry (FEV1) at baseline, 12 weeks, 24 weeks and 76 weeks	A measure of lung function	4 days of scanning
Weight (kg) at baseline, 12 weeks, 24 weeks and 76 weeks	A measure of body mass	4 days of scanning
Height (m) at baseline, 12 weeks, 24 weeks and 76 weeks	A measure of growth	4 days of scanning

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
T1 relaxation of ascending colon chyme at baseline, 12 weeks, 24 weeks and 76 weeks	An approximate measure of water content in chyme present in the ascending colon	4 days of scanning
T2* of the terminal ileum	An approximate measure of gas bubbles in the terminal ileum	4 days of scanning
Terminal ileum diameter at baseline, 12 weeks, 24 weeks and 76 weeks	A measure of the diameter of the terminal ileum in millimeters	4 days of scanning
Terminal ileum volume at baseline,12 weeks, 24 weeks and 76 weeks	Volume of the terminal ileum	4 days of scanning
Colonic volume area under the curve, corrected for body surface area, of individual segments of the colon i.e. ascending, transverse, descending and rectosigmoid colon at baseline, 12 weeks, 24 weeks and 76 weeks	Volume of the ascending colon, transverse colon, descending colon and rectosigmoid colon representing of chyme/faeces passage through individual segments of the colon	4 days of scanning

Collaborators and Investigators

• Sponsor: Nottingham University Hospitals NHS Trust
• Collaborators: Manchester Metropolitan University; Vertex Pharmaceuticals Incorporated
• Investigators: Principal Investigator: Alan Smyth, University of Nottingham

Study record dates

Study Major Dates

• Study Start (Actual): October 21, 2020
• Primary Completion (Actual): June 28, 2023
• Study Completion (Actual): June 28, 2023

Study Registration Dates

• First Submitted: October 23, 2020
• First Submitted That Met QC Criteria: November 4, 2020
• First Posted (Actual): November 5, 2020

Study Record Updates

• Last Update Posted (Actual): May 23, 2024
• Last Update Submitted That Met QC Criteria: May 22, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Magnetic Resonance Imaging; Gastrointestinal symptoms; Small bowel water; Oro-caecal transit time; Colonic volume; Stool and sputum microbiome; CFTR modulator
• Additional Relevant MeSH Terms: Digestive System Diseases; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Cystic Fibrosis
• Other Study ID Numbers: 20CS036

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No