Title: Closed-loop for people living with Cystic Fibrosis related diabetes(CL4P-CF)
Funder: Medical Research Council

Abstract: Cystic fibrosis (CF) is a condition mainly affecting the lungs and the digestive system. CF-related diabetes (CFRD) is the most common complication of CF affecting 15-20% of young people and 35-50% of adults who have CF. CFRD occurs when the pancreas, which usually makes insulin and enzymes which help with digestion, gets blocked with mucus and doesn’t work as well. The lack of insulin causes high blood glucose levels (hyperglycaemia) and eventually diabetes._x000D_ People with CFRD have more lung infections, weight loss, worse lung function and are four times more likely to die early than people with CF who don’t have diabetes. Preventing high glucose levels is important as people with CFRD who have high glucose levels are three times more likely to die than those with better glucose control._x000D_ Insulin is used to treat CFRD, either by injections several times a day or using an insulin pump. Insulin can improve bodyweight and lung function, but current insulin treatment is hard work, needing regular checking of glucose levels and adjustment of insulin doses. This adds to the enormous burden of CF self-management which already involves daily physiotherapy, nebulisers, and sometimes antibiotics. People with CF feel that research which will simplify their treatment burden is the top priority._x000D_ A closed-loop system, also called an artificial pancreas, can improve glucose control and reduce the burden of managing diabetes in people with type 1 diabetes. A closed-loop system is made up of three devices which communicate by bluetooth: a small glucose sensor is worn on the arm/abdomen which continuously measures glucose levels, an insulin pump delivers insulin just under the skin, and a computer algorithm on a smartphone App continuously and automatically adjusts the amount of insulin given by the pump, depending on the glucose levels. People wear the closed-loop devices all the time to allow the system to automatically manage their diabetes. _x000D_ The CL4P-CF study (Closed-Loop For People living with Cystic Fibrosis) aims to find out if closed-loop systems can improve glucose control and quality-of-life compared to standard insulin treatment (insulin injections or insulin pump) in young people (=16 years) and adults with CFRD. We will recruit 128 people from five UK centres. We will randomly allocate participants (like the flip of a coin) to either use the closed-loop system (closed-loop group) or to carry on with their normal insulin treatment (control group) for 26 weeks. Both groups will wear a glucose sensor. All study visits can be done by telephone/email/video to reduce the study burden and face-to-face contact in people at-risk for complications of Covid-19._x000D_ We will compare glucose control based on the data from the glucose sensor between the closed-loop and control groups. We will also compare bodyweight, lung function and the number of lung infections between the two groups. We will ask participants about their health and quality-of-life with questionnaires and interviews and we will collect information to compare the costs of both treatments._x000D_ People living with CFRD and their families have helped design CL4P-CF. The research team includes someone with CFRD who is not a researcher. A patient and public group will help to manage the trial and share the results with people with CF. The CL4P-CF trial will test a new therapy which may improve health and reduce treatment burden and could change the recommendations for managing CFRD.

Lay abstract: Background: Improved therapies for cystic fibrosis (CF) have dramatically increased life-expectancy, resulting in a rise in the prevalence of CF-related diabetes (CFRD). CFRD is associated with weight loss, increased frequency of lung infections, reduced lung function and increased risk of early death. Treatment with insulin can improve bodyweight and may improve lung function, but multiple daily injections and glucose monitoring add to the enormous burden of CF self-management. Closed-loop systems which automatically control insulin delivery in response to real-time glucose levels have the potential to improve glucose control and reduce the burden of managing diabetes._x000D_ _x000D_ Aims: This study addresses the important question of closed-loop insulin delivery in adolescents and adults with CFRD. The aim of the study is to evaluate closed-loop therapy compared to standard care with continuous glucose monitoring (CGM) in adolescents and adults with CFRD in terms of the effect on glucose control, bodyweight, lung function and metabolic parameters. We will also evaluate safety, acceptability, impact on health-related quality of life and other psychosocial aspects and costs._x000D_ _x000D_ Methods: This open-label, multicentre, randomised, two-arm parallel study will contrast closed-loop therapy and standard care with CGM in adolescents (aged 16 years and over) and adults with CFRD over a period of 26 weeks. We will use the CamAPS FX closed-loop system comprising Dana insulin pump, Dexcom G6 CGM, and an Android smartphone App running the Cambridge closed-loop algorithm. All study visits can be undertaken remotely by telephone/email/video-link to minimise study-related burden and reduce face-to-face contact in this at-risk population for Covid-19._x000D_ _x000D_ In total 128 participants with CFRD from five UK centres will be randomised to 26 weeks of closed-loop therapy or to 26 weeks of standard care with CGM (64 participants per group). The study will compare biomedical and psychosocial outcomes of the two interventions. The difference in time spent with glucose in target range (3.9 to 10.0 mmol/L) between the closed-loop group and standard care group will be the primary endpoint. Biomedical outcomes will include glucose and insulin metrics (HbA1c, glucose variability, time above and below target range and C-peptide), body mass index, frequency of pulmonary exacerbations and change in lung function (measured by forced expiratory volume in 1 second [FEV1]). These outcomes will be complemented by health-related quality of life and psychosocial impact assessed by validated generic and CF-specific questionnaires, and semi-structured interviews. Safety outcomes will be reported for both groups. We will collect cost data to allow health economic analysis of each treatment strategy._x000D_ _x000D_ Timelines for delivery: The first participant will be recruited 6 months after the study start date, once setup is complete. The final participant will be recruited by 18 months and will complete the study by 25 months. Data analysis will be completed by 28 months._x000D_ _x000D_ Impact and dissemination: The project will provide evidence for clinical guidance which will inform services for adolescents and adults with CFRD nationally (NHS) and internationally. We will publish the trial results in peer-reviewed international scientific journals and will share the findings with people with CF, healthcare providers and relevant stakeholders.

Research activity codes: 6.3 MEDICAL DEVICES
Health categories: CONGENITAL DISORDERS;METABOLIC AND ENDOCRINE