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

• ClinicalTrials.gov Identifier: NCT03815006
• Recruitment Status: Active, not recruiting
• First Posted: January 24, 2019
• Last Update Posted: December 7, 2021
• Sponsor: Manchester University NHS Foundation Trust
• Collaborators: University Hospitals of Derby and Burton NHS Foundation Trust; Cambridge University Hospitals NHS Foundation Trust; Portsmouth Hospitals NHS Trust; University Hospital Birmingham NHS Foundation Trust; Norfolk and Norwich University Hospitals NHS Foundation Trust; University of Manchester; Diabetes UK; Manchester Clinical Trials Unit; BHR Limited; East Suffolk and North Essex NHS Foundation Trust; The Adam Practice
• Information provided by (Responsible Party): Manchester University NHS Foundation Trust

Study Description

Brief Summary:

FreeStyle Libre (FSL) 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 FSL 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 FSL or continue usual finger-stick glucose monitoring in random order. A total of up to 160 participants (aiming for 128 completed participants) aged 16 years and older with T1D on insulin pump therapy or multiple daily injection therapy will be recruited through diabetes clinics in participating centres.

Participants will receive appropriate training to maximise the benefits of FSL 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 FSL, 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 FSL device compared with self-monitoring will also be assessed from a UK NHS perspective.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 1	Device: Free Style Libre	Phase 4

Detailed Description:

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 device with traditional finger-stick glucose monitoring for 24 weeks. Expecting approximately 15% to 20% dropout rate recruitment will aim for 160 participants aiming for 150 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

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 Visit1. In addition, participants in the FSL arm will be asked to complete a additional questionnaire exploring expectations and experience of using FSL during the study. A subset of participants (n=40 aiming for 25 completed questionnaires) in the FSL arm and subset of researchers (n=10) will also be asked to complete additional questionnaires to help with the process evaluation.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 160 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Multi-centre, Randomised, Parallel Design Study to Assess the Efficacy of Flash Glucose Monitoring in Adults With Type 1 Diabetes
• Actual Study Start Date: January 9, 2020
• Estimated Primary Completion Date: February 2, 2022
• Estimated Study Completion Date: February 2, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Free Style Libre device; At the start, a blood sample will be taken for the measurement of HbA1c. Training and education on the use of FSL will be provided by the research team. Participants will be advised to use flash glucose monitoring continuously for the next 24 weeks.	Device: Free Style Libre; FreeStyle Libre (FSL) 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 (T1D).
No Intervention: Self-monitoring of blood glucose; At the start, a blood sample will be taken for the measurement of HbA1c. Masked FSL will be applied for two weeks, during the last two weeks of control period. Education will focus on using fingerstick measurement for treatment optimisation.

Outcome Measures

Primary Outcome Measures :

1. HbA1c Level at 24 weeks [ Time Frame: 24 weeks ]
   The primary outcome is difference in HbA1c between the two groups at 24 weeks.

Secondary Outcome Measures :

1. HbA1c Level at 12 weeks [ Time Frame: 12 weeks ]
   This is the difference in HbA1c between the two groups at 12 weeks
2. Percentage with HbA1c ≤ 53 mmol/mol (7.0%) at 12 weeks [ Time Frame: 12 weeks ]
   This is the comparison between arms of percentage with HbA1c ≤ 53 mmol/mol (7.0%) at 12 weeks
3. Percentage with HbA1c ≤ 53 mmol/mol (7.0%) at 24 weeks [ Time Frame: 24 weeks ]
   This is the comparison between arms of percentage with HbA1c ≤ 53 mmol/mol (7.0%) at 24 weeks
4. Sensor based - Time spent in the target glucose range between 3.9 to 10.0 mmol/l [ Time Frame: 24 weeks ]
   Time spent in the target glucose range between 3.9 to 10.0 mmol/l (70 to 180mg/dl).
5. Sensor based - Time spent below target glucose (<3.9mmol/l) [ Time Frame: 24 weeks ]
   Time spent below target glucose (<3.9mmol/l) (<70mg/dl)
6. Sensor based - Time spent above target glucose (10.0 mmol/l) [ Time Frame: 24 weeks ]
   Time spent above target glucose (10.0 mmol/l) (180 mg/dl)
7. Sensor based - Average glucose levels [ Time Frame: 24 weeks ]
   Average glucose levels
8. Sensor based - Standard deviation glucose levels [ Time Frame: 24 weeks ]
   Standard deviation glucose levels
9. Sensor based - Coefficient of variation glucose levels [ Time Frame: 24 weeks ]
   Coefficient of variation glucose levels
10. Sensor based - time with sensor glucose levels < 3.5 mmol/l [ Time Frame: 24 weeks ]
    The time with sensor glucose levels < 3.5 mmol/l (63 mg/dl)
11. Sensor based - time with sensor glucose levels < 3.5 mmol/l [ Time Frame: 24 weeks ]
    The time with sensor glucose levels < 3.0 (54mg/dl)
12. Sensor based - time with sensor glucose levels < 2.8 mmol/l [ Time Frame: 24 weeks ]
    The time with sensor glucose levels < 2.8 mmol/l (50 mg/dl)
13. Sensor based - time with sensor glucose levels in the significant hyperglycaemia [ Time Frame: 24 weeks ]
    The time with sensor glucose levels in the significant hyperglycaemia (glucose levels > 16.7 mmol/l) (300mg/dl)
14. Sensor based - AUC of glucose below 3.0mmol/l [ Time Frame: 24 weeks ]
    AUC of glucose below 3.0mmol/l (54mg/dl)
15. Total daily average insulin dose [ Time Frame: 24 weeks ]
    Comparison between arms of Total daily average insulin dose
16. Daily average basal insulin dose [ Time Frame: 24 weeks ]
    Comparison between arms of Daily average basal insulin dose
17. Daily average bolus dose [ Time Frame: 24 weeks ]
    Comparison between arms of Daily average bolus dose
18. Average number of boluses of rapid acting insulin [ Time Frame: 24 weeks ]
    Average number of boluses of rapid acting insulin per day
19. Number of Freestyle Libre scans per day [ Time Frame: 24 weeks ]
    Number of Freestyle Libre scans per day in the intervention arm only
20. Frequency of severe hypoglycaemic episodes [ Time Frame: 24 weeks ]
    Frequency of severe hypoglycaemic episodes as defined by American Diabetes Association
21. Frequency of significant ketosis events [ Time Frame: 24 weeks ]
    Frequency of significant ketosis events (plasma ketones >3mmol/l)
22. Nature and severity of other adverse events [ Time Frame: 24 weeks ]
    Nature and severity of other adverse events.
23. Type 1 Diabetes Distress Scale Score [ Time Frame: 24 weeks ]
    Type 1 Diabetes Distress Scale score compared between arms
24. EQ-5D-5L Quality of Life questionnaire Score [ Time Frame: 24 weeks ]
    EQ-5D-5L Quality of Life questionnaire
25. Patient Health Questionnaire Score [ Time Frame: 24 weeks ]
    Patient Health Questionnaire: score of 5-9 would be minimal symptoms. any score large than 20 would be categorised as severe major depression
26. Diabetes fear of injecting and self-testing questionnaire Score [ Time Frame: 24 weeks ]
    Diabetes fear of injecting and self-testing questionnaire: 15 questions, 6 for Fear of Self injecting, 9 for fear of self testing.
27. The revised Diabetes Eating Problem Survey score [ Time Frame: 24 weeks ]
    The revised Diabetes Eating Problem Survey
28. Average number of days of Libre usage per week [ Time Frame: 24 weeks ]
    Average number of days of usage per week
29. Diabetes Treatment Satisfaction Questionnaire score [ Time Frame: 24 weeks ]
    Diabetes Treatment Satisfaction Questionnaire
30. Glucose Monitoring Satisfaction Survey score [ Time Frame: 24 weeks ]
    Glucose Monitoring Satisfaction Survey: 15 questions ranging from 1-5.

Eligibility Criteria

• Ages Eligible for Study: 16 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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 literate in English
• 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.

Exclusion Criteria:

Key exclusion criteria:

• Non-type 1 diabetes mellitus including those secondary to chronic disease
• Any other physical or psychological disease likely to interfere with the normal conduct of the study and interpretation of the study results as judged by the investigator
• Untreated hypothyroidism
• 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

Contacts and Locations

Locations

United Kingdom

The Adam Practice

Poole, Dorset, United Kingdom, BH16 5PW

College of Medical and Dental Sciences University of Birmingham

Birmingham, United Kingdom, B152TT

Addenbrooke's Hospital

Cambridge, United Kingdom, CB20QQ

University Hospitals of Derby and Burton NHS Foundation Trust

Derby, United Kingdom, DE223NE

Ipswich Hospital

Ipswich, United Kingdom, IP4 5PD

Manchester University NHS Foundation Trust

Manchester, United Kingdom, M139WL

Norfolk and Norwich University Hospitals NHS Foundation Trust

Norwich, United Kingdom, NR47UY

Queen Alexandra Hospital

Portsmouth, United Kingdom, PO63LY

Sponsors and Collaborators

Manchester University NHS Foundation Trust

University Hospitals of Derby and Burton NHS Foundation Trust

Cambridge University Hospitals NHS Foundation Trust

Portsmouth Hospitals NHS Trust

University Hospital Birmingham NHS Foundation Trust

Norfolk and Norwich University Hospitals NHS Foundation Trust

University of Manchester

Diabetes UK

Manchester Clinical Trials Unit

BHR Limited

East Suffolk and North Essex NHS Foundation Trust

The Adam Practice

More Information

Publications:

Leelarathna L, Wilmot EG. Flash forward: a review of flash glucose monitoring. Diabet Med. 2018 Apr;35(4):472-482. doi: 10.1111/dme.13584. Epub 2018 Feb 27. Review.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Wilmot EG, Evans M, Barnard-Kelly K, Burns M, Cranston I, Elliott RA, Gkountouras G, Kanumilli N, Krishan A, Kotonya C, Lumley S, Narendran P, Neupane S, Rayman G, Sutton C, Taxiarchi VP, Thabit H, Leelarathna L. Flash glucose monitoring with the FreeStyle Libre 2 compared with self-monitoring of blood glucose in suboptimally controlled type 1 diabetes: the FLASH-UK randomised controlled trial protocol. BMJ Open. 2021 Jul 14;11(7):e050713. doi: 10.1136/bmjopen-2021-050713.

• Responsible Party: Manchester University NHS Foundation Trust
• ClinicalTrials.gov Identifier: NCT03815006
• Other Study ID Numbers: B00373
• First Posted: January 24, 2019
• Last Update Posted: December 7, 2021
• Last Verified: December 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Individual participant data that underlie the results reported in the primary study manuscript after deidentification (text, tables, figures, and appendices).
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: Beginning 6 months and ending 3 years following article publication
• Access Criteria: Researchers who provide a methodologically sound proposal not overlapping with any planned secondary publications from the research team.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases