Cystic fibrosis (CF) is the most common inherited condition in the United Kingdom, affecting approximately 10,837 people. It is well recognised that regular exercise is clinically important for people with CF. Exercise function measured by the maximal oxygen consumption during a cardiopulmonary exercise test is often reduced in people with CF and this has been attributed to multiple factors including, altered heart and blood vessel function, muscle function, reduced physical activity levels and poorer sleep quality.

New medicine (modulators) have become available for many people with CF. Modulators appear able to reduce sweat chloride concentrations, improve lung function and reduce the frequency of pulmonary exacerbations in people with CF. Little evidence exists to show how they may have changed the fitness and underlying mechanisms responsible for this in people with CF.

This study aims to:

1. determine the exercise function
2. determine the blood vessel function
3. determine body composition
4. determine physical activity and sleep levels in people with CF on modulator therapy compared to a healthy controls group.

CF is the most common inherited condition in the United Kingdom, affecting approximately 10,837 people. CF affects the movement of salt and water across the body which leads to a thick sticky build up of mucus causing problems in the lungs and digestive system. CF also causes problems in other parts of the body for example, the heart, the blood vessels and muscles. This can impact a person with CFs' ability to exercise which can have impact prognosis, quality of life and increase the amount of times someone with CF is admitted to hospital due to a chest infection.

For many people with CF, new medicine (modulators) have lately become accessible bringing big changes to their health. Elexacaftor-tezacaftor-ivacaftor (ETI) is the most recently approved modulator for use in people with specific CF transmembrane conductance regulator gene mutations and is now the most widely used modulator therapy. So far clinical trials have largely looked at lung function, sweat chloride levels and body mass index. The wider reaching effects of modulator therapy on exercise function has not been studied. This study will see if people with CF have blood vessel and exercise dysfunction, abnormal body composition and reduced physical activity and sleep quality when they are taking modulator therapy compared to a healthy group.

The aims of this study are:

1. Determine the aerobic exercise function and mechanisms underlying this in people with CF stable on ETI and whether this is different to healthy age- and sex-matched controls;
2. Determine the peripheral muscle function in people with CF stable on ETI and whether this is different to healthy age- and sex-matched controls;
3. Determine the functional exercise capacity in people with CF stable on ETI and whether this is different to healthy age- and sex-matched controls;
4. Determine the micro- and macrovascular endothelial function in people with CF stable on ETI and whether this is different to healthy age- and sex-matched controls;
5. Determine body composition in people with CF stable on ETI and whether this is different to healthy age- and sex-matched controls;
6. Determine the physical activity levels and sleep duration and quality in people with CF stable on ETI and whether this is different to healthy age- and sex-matched controls

This study will recruit 50 people with CF and 50 healthy age- and sex-matched control participants who are older than 10 years of age. It will ask them to attend the University of Portsmouth for 2 visits. The first visit will last ~3 hours. During this time they will undergo measures on blood vessel function and aerobic exercise function. The second visit will last ~2 hours. During this time they will undergo a body composition scan and a series of muscle function test. At home, participants will wear an accelerometer for 7 days and complete a series of questionnaires.

Inclusion criteria for participants with cystic fibrosis:

• Stable on the modulator therapy, Kaftrio®
• Males and females ≥ 10 years of age
• CF diagnosis based on clinical features, supported by a history of an abnormal sweat test (sweat chloride > 60 mmol·L-1 > 100 mg sweat), where possible, diagnostic genotyping would also be desired
• Can clearly state that they are not pregnant
• No contraindications to performing exercise
• Can understand and cooperate with the study protocol
• No increase in symptoms or weight loss in the preceding 2 weeks

Inclusion criteria for healthy control participants:

• Healthy males and females who are age- and sex-matched to the enrolled individuals with CF
• Can clearly state that they are not pregnant
• No clinical diagnosis of a chronic disease
• Can understand and cooperate with the study protocol
• No contraindications to performing exhaustive exercise

Exclusion criteria for participants with cystic fibrosis:

• Any non-pulmonary conditions that may impair exercise ability, such as musculoskeletal disorders and cardiovascular disease.
• Unstable co-morbid asthma (daily pulmonary function variability of >20%)
• Is pregnant during the initial screening process
• Unable to understand or cooperate with the study protocol due to learning difficulties or otherwise
• Not of a suitable age for testing
• Is a smoker or inhales any other substances
• Are taking vasoactive medications

Exclusion criteria for healthy control participants:

• Any pulmonary, metabolic or cardiovascular conditions
• Any other diagnosed disease
• Any non-pulmonary conditions that may impair exercise ability, such as musculoskeletal disorders and cardiovascular disease
• Is pregnant during the initial screening procedure
• Presents with co-morbidities to performing exhaustive exercise
• Is a smoker or inhales any other substance
• Unable to understand or cooperate with the study protocol due to learning difficulties or otherwise
• Not an age- or sex-match for the CF group
• Are taking vasoactive medications

Participants will be recruited from adult and paediatric CF outpatient clinics within the Southampton CF network.