Flash-glucose Monitoring in Sub-optimally Controlled Type 1 Diabetes (FLASH-UK)

An Open-label, Multi-centre, Randomised, Parallel Design Study to Assess the Efficacy of Flash Glucose Monitoring in Adults With Sub-optimally Controlled Type 1 Diabetes.

FreeStyle Libre (FSL2) is a novel glucose monitoring device (Flash glucose monitoring) in the form of a disc worn on the arm for 14 days, and a hand-held reader which is designed to largely replace the recommended 4-10 painful finger-stick blood glucose tests required each day for the self-management of type 1 diabetes. The purpose of this study is to determine whether flash glucose monitoring with FSL2 device will improve HbA1c over 24 weeks compared to self-monitoring of blood glucose in adults and adolescents (16 or older) with sub-optimally controlled (HbA1c 7.5% to 11%) type 1 diabetes.

This is an open-label, multi-centre, randomised, parallel design study, involving a 2-week run-in period, followed by a 24-week study period during which participants will use either FSL2 or continue usual finger-stick glucose monitoring in random order. A total of up to 156

randomised participants from up to 180 recruited aged 16 years and older with T1D on insulin pump therapy or multiple daily injection therapy were recruited through diabetes clinics in participating centres.

Participants will receive appropriate training to maximise the benefits of FSL2 and finger-stick glucose levels in self-management. The primary outcome is the difference in HbA1c between the two groups at 24 weeks. Secondary outcomes are time spent with glucose levels above and below target, as recorded by FSL2, and other flash glucose-based metrics. Impact on quality of life, diabetes distress, mood, needle burden, disordered eating and treatment satisfaction will also be undertaken. Relative cost-effectiveness of FSL2 device compared with self-monitoring will also be assessed from a UK NHS perspective.

Study Design:

An open-label, multi-centre, randomised, parallel study, in adults and adolescents (16 years and older) with type 1 diabetes and sub-optimal glycaemic control (HbA1c 7.5% to 11%), either on insulin pump treatment or multiple daily injections, contrasting flash glucose monitoring using FreeStyle Libre 2 device with traditional finger-stick glucose monitoring for 24 weeks. Expecting approximately 15% to 20% dropout rate recruitment will aim for 180 participants aiming for 156 randomised and 128 completed participants.

Participant Recruitment:

This is a UK multi-centre and recruitment will take place at the following centres:

1. Diabetes Centres within Manchester University Foundation Trust
2. Royal Derby Hospital, Derby
3. Queen Elizabeth Hospital, Birmingham
4. Addenbrookes Hospital, Cambridge
5. Norfolk and Norwich University Hospital, Norwich
6. Queen Alexandra Hospital, Portsmouth
7. Ipswich Hospital
8. The Adam Practice, Dorset

Each centre will aim to recruit between 25 to 30 participants. Additional diabetes centres surrounding above hospitals may act as participant identification centres. Potential participants will be identified by their treating clinicians and invited to contact the research team. They will be sent the study information leaflets and an invitation by post or in-person to join the study by the research team at least one day before the recruitment visit. The study may also be advertised via social media.

After recruitment, consent, subjects will be randomised for 24-weeks home use of flash-glucose monitoring or 24-weeks use finger-stick glucose monitoring.

Study Visits:

The study includes up to 7 visits for participants completing the study. Maximum time in study is 30 weeks. Each study visit can be scheduled with +/- 2 weeks of the planned visit date.

Visit 1: Recruitment Visit and Screening Assessment

Once the participants have agreed to participate in the study, they will be invited for the recruitment visit, and given a participant ID, when the following activities will be performed by the research team:

• written informed consent/assent
• checking inclusion and exclusion criteria
• medical and diabetes history including the presence of diabetes complications and hypoglycaemia burden
• ethnicity, body weight and height measurement; calculation of BMI
• record of current insulin therapy
• urine or blood pregnancy test (females of child-bearing potential)
• record of occupation and educational attainment
• any history of disordered eating or needle phobia
• previous participation in structured education, the status of carb counting, use of bolus calculator

Screening Blood Sampling

Blood samples will be taken to measure HbA1c (measured at the local laboratory if not done within the last two weeks). Renal and Thyroid function will also be evaluated (if not done in last one year). Less than 15 ml of whole blood will be taken from each participant.

Questionnaires at screening

Evaluation of participants' responses in terms of quality of life, diabetes distress, needle burden, disordered eating, depression and diabetes treatment satisfaction using

1. EQ-5DL-5L questionnaire
2. Type 1 Diabetes Distress Scale (DDS),
3. Diabetes fear of injecting and self-testing (D-FISQ) questionnaire,
4. Diabetes Eating Problem Survey (DEPS-R),
5. Diabetes Treatment Satisfaction Questionnaire (DTSQ),
6. Patient Health Questionnaire (PHQ-9) and
7. The Glucose Monitoring Satisfaction Survey (GMSS).
8. Hypoglycaemia burden will be assessed using Clarke questionnaire and Gold score.

Visit 2: Insertion of the blinded glucose monitoring device

Purpose of visit 2 is to insert a blinded glucose monitor (FreeStyle Libre Pro device). The participant will be provided with instructions about using this device for the next two weeks. Visit two may be combined with visit 1.

Visit 3: Adherence assessment, randomisation and the start of study treatment

During Visit 3, participant's adherence/tolerance of using the flash-CGM over preceding 14 days will be assessed. To proceed with the study participant should have worn the blinded glucose monitoring device for at least ten days' during the last 14 days of the run-in period. If the participant fails to demonstrate adherence or develops any significant allergy or intolerance to the glucose sensor, the study will be terminated, and the participant will be removed from the study. Participant randomisation for the treatment intervention will take place during visit 3.

Initiation of study treatment The participant will arrive at the clinical facility or clinic at the agreed time. Body weight measurement will be made. Participants will be provided with necessary training on the use of study devices according to randomisation.

Training session Participants randomised to flash-glucose monitoring arm will receive education and training about insertion and initiation of the sensor as well as how to use flash-glucose monitoring data for treatment optimisation. They will be encouraged to download data at home to identify pattern recognition. This session will be conducted by a professional diabetes educator or a member of the study team. Education will be tailored to meet the needs of the individual. Participants randomised to conventional finger-stick glucose monitoring arm will be encouraged to use finger-stick glucose levels to optimise treatment and will receive education about insulin dose adjustments using finger-stick glucose levels. The study will try to mimic real-life conditions by continuing participants pre-study diabetes treatment unchanged and finger-stick glucose testing frequency as determined by the participant as required. Participants in both arms will also receive training on sick day rules and dealing with hypo and hyperglycaemia. Participants will be provided with a paper diary to collect information about insulin doses and carbohydrate intake in the last three days of each study month.

Visit 4: (+4 weeks since randomisation): Review data and treatment optimisation Purpose of this visit is to review data from Flash-glucose monitoring and finger-stick glucose monitoring to further optimise treatment. Study devices will be downloaded. Information about insulin doses and any adverse events will be collected.

Visit 5: (+12 weeks since randomisation): Review data and treatment optimisation

Purpose of this visit is to review data from Flash-glucose monitoring and finger-stick glucose monitoring to further optimise treatment. Study devices will be downloaded. Information about insulin doses, participant diaries and any adverse events will be collected. A blood sample will be collected for HbA1c.

Visit 6: (+22 weeks since randomisation): Finger-stick glucose monitoring arm only

Participants randomised to finger-stick glucose monitoring arm will have an extra visit ten weeks after visit 5 to insert a blinded glucose sensor for data capture.

Visit 7: (+24 weeks since randomisation): End of randomised study treatment

The participant will be invited to attend the research centre approximately 12 weeks after Visit 5. This would be the end of 24 weeks randomised study period. All study devices will be downloaded. Insulin usage data will be recorded and diaries collected. The participant will have a blood test for the HbA1c. Body weight measurement will be made. The participant will be asked to complete the same questionnaires completed at Visit 1. In addition, participants in the FSL2 arm will be asked to complete a additional questionnaire exploring expectations and experience of using FSL2 during the study. A subset of participants (n=40 aiming for 25 completed questionnaires) in the FSL2 arm and subset of researchers (n=10) will also be asked to complete additional questionnaires to help with the process evaluation.

Inclusion Criteria:

• The participant is ≥16 years old
• The participant has type 1 diabetes, as defined by WHO for at least 1 year or is confirmed C-peptide negative if duration of diabetes is < 1 years
• Participant is treated with insulin pump or multiple daily injection for at least 12 weeks and no plans to change treatment modality during next 28 weeks
• The participant is literate in English for safe study conduct
• Screening HbA1c ≥ 7.5% (58.5mmol/mol) and ≤ 11% (97 mmol/mol) based on analysis from local laboratory
• The participant is willing to wear study glucose sensor and scan for glucose levels at regular intervals
• The participant is willing to follow study specific instructions and improve glucose control
• Female participants of child bearing age should be on effective contraception and must have a negative blood or urine pregnancy test at screening.
• The participant adopting a virtual pathway through the trial is able and willing to post study devices, questionnaires and blood collection kits back to the research team or to the laboratory using pre-paid postal services.
• The participant adopting a virtual pathway through the trial has internet connection, appropriate videoconferencing software and supporting devices to undertake video consultations where necessary.

Exclusion Criteria:

Key exclusion criteria:

• Non-type 1 diabetes mellitus including those secondary to chronic disease
• Any other physical disease or people with known severe mental illness (psychotic disorder, bipolar disorder, dementia, substance and alcohol dependence, learning disabilities, depression with active suicidal ideation) which are likely to interfere with the normal conduct of the study and interpretation of the study results as judged by the investigator
• Current users of real-time glucose monitoring sensors or flash-glucose monitoring for more than 4 weeks within last 12 weeks
• Current treatment with drugs known to interfere with glucose metabolism, e.g. systemic corticosteroids, SGLT2 inhibitors, GLP-1 agonists, Pramlinatide, non-selective beta-blockers and MAO inhibitors etc.(patients on stable metformin is not an exclusion)
• Known or suspected allergy against insulin
• Severe visual impairment
• Complete loss of hypoglycaemia awareness
• Significant renal impairment eGFR<30 within previous one year or on dialysis or active retinopathy (defined as presence of maculopathy or proliferative changes) as judged by the investigator
• More than one episode of severe hypoglycaemia as defined by American Diabetes Association (30) in preceding 24 weeks