Title: A Comprehensive Approach To Relief Of Digestive Symptoms In Cystic Fibrosis: CARDS-CF
Funder: Department of Health and Social Care

Abstract: Background: Cystic fibrosis (CF) is a life-limiting disorder, affecting >10,000 people in the UK. It is autosomal recessive, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Although CF is a multi-system disease, the effects on the lung and the gut are most important. In the lung there is failure of mucociliary clearance, infection and bronchiectasis. In the gut, pancreatic insufficiency causes maldigestion and impaired nutrition which is treated with pancreatic enzyme replacement therapy (PERT). PERT is burdensome, requiring multiple capsules with each meal. In spite of PERT, gastrointestinal (GI) symptoms are universal in CF and severe gut complications occur. Two thirds of people with CF miss school or work because of GI symptoms. Recently, new CFTR modulator drugs have been introduced which treat the underlying defect of CF. The effects of CFTR modulators on the lung are well known but not the effects on the gut. Some patients taking modulators have stopped PERT without ill-effects. A James Lind Alliance (JLA) Priority Setting Partnership in CF, led by our group, identified the top ten questions for clinical research in CF. The following question is priority number 2: &ldquo;How can we relieve gastrointestinal (GI) symptoms, such as stomach pain, bloating and nausea in people with CF?&rdquo; Aims and objectives: To provide key resources for researchers undertaking clinical research in the GI problems of CF including: A patient reported outcome measure (PROM) An epidemiological study of the effects of CFTR modulator drugs on PERT requirements and severe GI complications The first steps in a core outcome set. Development work plan: Workstream 1. Develop an app-based PROM for daily monitoring of gastrointestinal symptoms. We will validate this PROM in a future Programme Grant for Applied Research (PGfAR). Workstream 2. Conduct a study examining trends over a 10 year period in PERT usage and distal intestinal obstruction syndrome (DIOS), in the US and the UK CF registries. This will elucidate the reasons for differing incidence of DIOS in the US vs. the UK and will evaluate the effects of CFTR modulator drugs on PERT usage and DIOS incidence. In a future PGfAR we will conduct a similar study of potent, new CFTR modulators. Workstream 3. Complete a systematic review of outcome measures used in studies of gastrointestinal symptoms and complications in CF to inform development of our PROM and a core outcome set. We will complete the core outcome set work in a future PGfAR. Timelines for delivery: The planned work will take 2 years. After a year, we will submit an application for a PGfAR. If awarded, the programme development grant will run seamlessly into the PGfAR. Anticipated impact and dissemination: We will publish our systematic review and registry study and this will accelerate clinical research in the GI problems of CF. The PROM and core outcome set, which we will develop in our PGfAR, will facilitate clinically relevant research, in a neglected area of CF science, which has been identified as a priority by the patient community.

Lay abstract: Background: Cystic fibrosis (CF) is a genetic condition which may shorten life. People with CF have sticky mucus and lung infections. They may not make digestive enzymes and most require enzyme capsules. Despite treatment, most patients have tummy symptoms and miss school or work. Some develop complications like bowel obstruction. Treatments have improved and people with CF live longer. New drugs, called modulators, treat the underlying problem of CF. We know how modulators affect the lungs but not the gut. Some patients taking modulators have stopped enzyme capsules without ill-effects. Compared to the lungs, there is less research on gut problems in CF. A recent consultation, involving doctors, CF patients and family members (over 600 participants), prioritised this research question: &ldquo;How can we relieve gastrointestinal (GI) symptoms, such as stomach pain, bloating and nausea in people with CF?&rdquo; Aims and objectives: Before we can answer this, we need to know which symptoms are most important to CF patients. We want to work with patients to develop a &ldquo;patient reported outcome measure&rdquo; or PROM, for gut symptoms. We will study why some gut complications of CF are more common in the UK than the US. We will find out if modulator drugs reduce gut complications or allow some patients to stop enzymes. We plan to agree a list of outcomes (such as tests and questionnaires) to be used in every trial of gut treatments in CF. This is called a core outcome set. Development work plan: Workstream 1. Develop our PROM with patients and test it using an app. In a future grant, we will test the reliability and accuracy of the PROM. Workstream 2. We will compare severe gut complications in the US and the UK over the last decade. We will see if modulators had any effect on complications or enzyme use. For our next grant we will repeat this for the newest modulators. Workstream 3. We will read all the scientific papers describing tests and questionnaires for gut trials in CF. We will publish this as a summary (called a systematic review). This will help us develop our core outcome set as part of our next grant. Patient and public involvement: We are addressing a question prioritised by over 300 people with CF and their families in our James Lind Alliance. Our team includes a person with CF and expertise in developing apps. We will work closely with the CF community to develop our PROM and our core outcome set. Impact and dissemination: This work will take 2 years. We will share our findings with the patient community, through an online event. We tell CF teams around the world about our results through conferences and scientific journals.

Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: CONGENITAL DISORDERS