CFTR-MAGIC: CFTR Modulators and Gastrointestinal Complications

Sponsor

Nottingham University Hospitals NHS Trust (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT05253859

Collaborator

The Leeds Teaching Hospitals NHS Trust (Other), Royal Brompton & Harefield NHS Foundation Trust (Other), University of Washington (Other), Seattle Children's Hospital (Other)

40,000

Enrollment

Location

Anticipated Duration (Months)

1670.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To elucidate the similarities and distinctions in non-pulmonary manifestations of cystic fibrosis (CF) including distal intestinal obstruction syndrome (DIOS) incidence and pancreatic enzyme replacement therapy (PERT) use between US and UK CF populations in a parallel study using data from the UK and US CF registries. To assess how CFTR modulators impacted upon recorded PERT use and incidence of DIOS.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis Gastrointestinal System Disease Distal Intestinal Obstruction Syndrome Pancreatic Enzyme Abnormality Pancreatic Disease Lung Diseases Digestive System Disease	Other: No intervention

Detailed Description

Cystic fibrosis (CF) is a autosomal recessive multi-system disorder caused by mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene. As well as the documented respiratory complications of CF, gastrointestinal manifestations are of clinical importance. CFTR mutations in the gastrointestinal tract are responsible for pancreatic exocrine insufficiency in around 85% of people with CF (pwCF). In addition a severe gastrointestinal complication in CF is distal intestinal obstructive syndrome (DIOS), affecting 5.7% pwCF in the UK (2.5% in <16 years and 7.7% in adults) and 2.1% in the US (<18 years 1.7%, adult 2.4%) in 2019.

This is a parallel data registry study using data from the UK and US CF registries, with data provided for the time period 2007-2018. As such no individual participants will be recruited to the study. The CFTR modulators to be studies are Ivacaftor and lumacaftor/ivacaftor.

Study aims;

Describe DIOS events and PERT usage in UK and US registries
Determine the effect of CFTR modulators on the incidence of DIOS and use of PERT: population time series
Determine the effect of CFTR modulators on the incidence of DIOS and use of PERT: patient-level time series

The outcomes of the above aims will be used to generate hypotheses regarding the effect of the newer CFTR modulators such as Symdeko/Symkevi and Tricaftor/Kaftrio on PERT usage and DIOS incidence in CF registry data post 2018. This will form the basis of future studies.

Study Design

Study Type:

Observational

Anticipated Enrollment :

40000 participants

Observational Model:

Other

Time Perspective:

Retrospective

Official Title:

CFTR Modulators and Gastrointestinal Complications

Actual Study Start Date :

Oct 1, 2021

Anticipated Primary Completion Date :

Sep 30, 2023

Anticipated Study Completion Date :

Sep 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Cystic fibrosis registry (UK or US) People with cystic fibrosis of any genotype registered on either the UK or US CF registry	Other: No intervention Registry study: No intervention

Arm

Intervention/Treatment

Cystic fibrosis registry (UK or US)

People with cystic fibrosis of any genotype registered on either the UK or US CF registry

Other: No intervention

Registry study: No intervention

Outcome Measures

Primary Outcome Measures

Describe DIOS events and PERT usage in UK and US registries 2007-2018 [2 years]
Descriptive analysis to include cumulative incidence of DIOS and prevalence of PERT usage in the UK and US. PERT use will be dichotomised (i.e use/no use), incidence of DIOS (event/no event), plotted by year, separated by registry. Trends will be described according to age range (<6, 6-11, 12+), sex, BMI, ethnicity, antibiotic use, gastrointestinal co-morbidities and FEV1 lung function. These demographics will also be used for demographic propensity matching to define a control group of non-eligible non-users of CFTR modulators that are otherwise representative of the CFTR modulator user group the year that the CFTR modulator exposure was commenced.
Determine the effect of CFTR modulators on the incidence of DIOS and use of PERT: population level controlled interrupted time series (ITS) [2 years]
This will investigate the effect of CFTR modulator intervention on the rate on PERT use and DIOS incidence. ITS will explore proportion of DIOS events at population level in the CFTR modulator population and the propensity score defined comparator population. ITS will explore proportion of overall PERT usage (user/non user), and the proportion of individuals with a reduction in weight standardised PERT dose (decrease/no decrease).
Determine the effect of CFTR modulators on the incidence of DIOS and use of PERT: patient-level time series [2 years]
This will focus on patient level associations to complement the registry level findings. Associations in the incidence of PERT usage and DIOS events from 2012 in individuals taking CFTR modulators, compared to propensity matched controls will be explored. DIOS events: Multilevel Poisson Regression model for count data by year, incidence rate ratio (frequency of DIOS events). Adjusted analysis for main covariates. PERT use: Multilevel linear regression for continuous data, multilevel logistic regression for dichotomised data. Adjusted for main covariates.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

All patients with CF of any genotype on the UK and US cystic fibrosis registries from the period 2007 - 2018.

Exclusion Criteria:

Patients whose CFTR modulator status is unknown or only have one year of CFTR data recorded on the registry will be excluded from the analysis of the effects of CFTR modulators. This is to account for the fact that DIOS data is annualised on the registries, therefore there is no certainty at what time of year DIOS was diagnosed in relation to commencing CFTR modulator therapy.