FreeStyle Libre Plus Bluetooth Transmitter Adjunct: Can This Improve Glucose Accuracy and Reduce Burden of Hypoglycaemia

Study Overview
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Brief Summary
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Advanced glucose monitoring systems have revolutionized diabetes care and enabled people with diabetes to achieve better diabetes control with reduced risk of hypoglycaemia. Continuous glucose monitoring (CGM) systems provide real-time glucose monitoring and alarms when glucose approaches extreme readings (hypoglycaemia and hyperglycaemia) or when the change in glucose is rapid. All available CGM systems, except Dexcom G6, require daily calibrations with capillary glucose readings in order to attain accuracy of glucose readings. Decom G6 system is not widely accessible and only available in certain countries. Flash glucose monitoring systems (Flash) provide glucose readings when users actively scan their sensors. FreeStyle Libre (FSL) is the only Flash glucose monitoring system currently available in market. FSL is factory calibrated and sensors are ready to use after placement and initiation. The two main differences between Flash and CGM are user interaction and the alarm facility. While CGM provide real-time glucose readings, Flash is user-dependent for actively scanning and understanding the readings. Moreover, CGM systems provide alarms for low or high glucose and for rapid glucose changes, while Flash does not routinely provide alarms. This is particularly relevant when patients have impaired or lost hypoglycaemia awareness. CGM systems are costlier compared to Flash, which has contributed to the wider adoption of FSL. Several Bluetooth adjuncts have been introduced to market for FSL. These devices attach to Libre sensor and connect to the user's mobile phone via Bluetooth. This enables continuous and real-time feed of glucose readings from the sensor to patient's mobile phone, which enables a wide range of customizable alarms for high and low glucose levels and for rapid glucose changes. This setup also enables calibration of Libre sensor with capillary glucose which, anecdotally, has been reported to improve sensor accuracy. None of these adjuncts have been validated clinically. FSL with Bluetooth adjunct such as MiaoMiao remain cheaper than current CGM options and could be more accessible in some countries than CGM. However, without robust evidence to support effectiveness and safety of such setup it is not possible to recommend this. The Objective of this study is to determine whether FSL with Bluetooth Adjunct is superior to FSL alone in accuracy and reduction of hypoglycaemia burden.

Detailed Description
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Study design: Open-label, crossover, single center, randomized controlled trial of FreeStyle Libre with MiaoMiao Bluetooth transmitter adjunct with calibrations (FSL-M) compared to FreeStyle Libre alone (FSL-A) in people with T1DM. Protocol summary: Following informed written consent, subjects will be randomized to either FSL-M group using FSL with Miaomio and Tomato App premium version, or FSL-A with Libre Link app (stage 1). Subjects will spend 8 weeks in the assigned group followed by 2 weeks washout then subjects will switch over to the other group for further 8 weeks (stage 2). While in FSL-M, subjects will be asked to calibrate FSL with daily capillary glucose values using Contour Plus, or on days 1, 2, 4, 8, 13 of sensor life. Alarms for low glucose (<3.9mmol/L, <70mg/dL) and high glucose (>13.9mmol/L, 250mg/dL) will be set in Tomato App. 7-point capillary glucose profiles will be carried out by subjects in both groups on days 2/3, 5/6, 9/10, 13/14 of each sensor life to enable paired comparison with sensor values. Subjects will have routine labs at randomization, end of stage 1, and end of stage 2. All subjects will be asked to complete the following questionnaires: GOLD, Problem Areas in Diabetes (PAID) and Diabetes Quality of Life (DQOL) at randomization, at end of stage1 and end of stage 2. The group randomized to FSL-M at stage 1 will have qualitative interview at randomization, end of stage 1 and end of stage 2. All adverse events will be collected including, but not limited to, all hypoglycaemia, diabetic ketoacidosis, hospital admissions for any reason, and device related skin reaction for the duration of the study in all subjects in both groups. Data analysis will be carried out on glucose data retrieved from Libre view web-platform and Tomato App downloads in addition to Contour Plus meter downloads.

Official Title
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Crossover Randomized Controlled Trial of FreeStyle Libre Plus Bluetooth Transmitter Compared to FreeStyle Libre Alone in People With Type 1 Diabetes Mellitus. Can This Improve Accuracy and Reduce Burden of Hypoglycaemia

Conditions
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Type1 Diabetes Mellitus

Intervention / Treatment
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* Combination Product: FreeStyle Libre with MiaoMiao
* Device: FreeStyle Libre alone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: T1DM for 12 months or more Age >21 years old Established user of FreeStyle Libre for ≥3 months HbA1C <12% (108mmol/mol) Able to check glucose with finger prick several times a day Exclusion Criteria: Pregnancy or plans for pregnancy over the duration of the study Breast feeding Renal impairment with eGFR <30ml/minute/1.73m2 Significant anaemia (males Hb<110g/L, females Hb <100g/L) Active malignancy Significant vision impairment Any significant illness- decision will be made by the PI or Co-I Not able to attend study visits Not able or not willing to participate in all study components Not able or not willing to give written informed consent

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized crossover study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FSL-M<br>FreeStyle Libre + MiaoMiao Bluetooth adjunct with mobile application | Combination Product: FreeStyle Libre with MiaoMiao<br>* Use of FreeStyle Libre with MiaoMiao Bluetooth adjunct and mobile device application to enable calibration and alarms<br>* Other names: FSL-M;|
| Active Comparator: FSL-A<br>FreeStyle Libre alone | Device: FreeStyle Libre alone<br>* Use of standard FreeStyle Libre with Libre Link app and mobile phone scanning<br>* Other names: FSL-A;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean absolute relative difference (MARD) | Comparing difference between glucose readings from the sensor in comparison to reference paired capillary glucose readings. This is to enable assessing accuracy of the intervention with FSL and MiaoMiao | 9 months | 
| Percentage time below 3.0mmol/L (54mg/dL) | This is to enable evaluating burden of hypoglycaemia. Analysis will be done on sensor glucose data | 9 months | 
| Percentage time in range 4-10mmol/L | This is to enable effect on time spent in normoglycaemia. Analysis will be done on sensor glucose data | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage time <4mmol/L (72mg/dL) | to evaluate general hypoglycaemia | 9 months | 
| Percentage time >10mmol/L | To evaluate hyperglycaemia | 9 months | 
| Change in HbA1C | To evaluate for any change in overall diabetes control | 9 months | 
| Rate of hypoglycaemia | number of episodes of hypoglycaemia | 9 months | 
| Rate of severe hypoglycaemia | number of episodes of severe hypoglycamia | 9 months | 
| Rate of device-related complications | This is specific for Libe and/or MiaoMiao | 9 months | 
| Change in dose of insulin | This will compare before and at end of each phase total daily insulin dose | 9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hytpoglycemia, FreeStyle Libre, Flash Glucose Monitoring, MiaoMiao, Time in Range