Assessment of the Impact of Real-Time Continuous Glucose Monitoring on People Presenting With Severe Hypoglycaemia

Study Overview
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Brief Summary
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This study aims to assess the impact of real-time continuous glucose monitoring on the frequency, duration, awareness and severity of hypoglycaemia in people with type 1 diabetes and a recent history of severe hypoglycaemia, compared to usual care.

Detailed Description
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Type 1 diabetes (T1DM), which affects 300,000 in the UK, is characterised by autoimmune destruction of the pancreatic beta cells, leading to absolute deficiency of insulin. Management of T1DM requires exogenous insulin administration, aiming for glucose concentrations as close to physiological values as possible. Intensive management of T1DM improves glucose control and reduces the risk of microvascular diabetes complications and cardiovascular disease1. In the UK diabetes consumes more than 10% of the National Health Service budget 2 and in the USA a relatively greater amount is spent on type 1 compared with type 2 diabetes (8.6% of the diabetes budget compared with 5.6% of diabetes prevalence)3. Medication and insulin pump therapy accounts for less than 10% of diabetes expenditure with the majority of costs incurred in the treatment of complications4. Optimal control remains challenging to achieve and intensive insulin treatment increases the risk of severe hypoglycaemia, with lower glucose values also associated with an increased frequency and severity of moderate hypoglycaemia5, 6. Severe hypoglycaemia is defined as any episode of hypoglycaemia requiring the assistance of a third party actively to treat. Hypoglycaemia is associated with morbidity and even mortality, and places a financial burden on health systems. Severe hypoglycaemia costs £13million per year in NHS costs7. Between 4 and 10% of deaths in people with type 1 diabetes are attributed to hypoglycaemia and the risk of severe hypoglycaemia increases 6-fold in people with impaired awareness of hypoglycaemia. Avoidance of hypoglycaemia is associated with restoration of hypoglycaemia awareness and this may be enabled by the use of continuous glucose monitoring. In type 1 diabetes real-time continuous glucose monitoring (CGM) improves overall glucose control in all age groups when used continuously, reduces hypoglycaemia in people with an HbA1c <7.0%, and may reduce severe hypoglycaemia8-10. The predictive Low-Glucose suspend (PLGS) feature in sensor augmented insulin pumps (SAP) automatically reduces insulin delivery when trends in CGM glucose concentrations predict future hypoglycaemia, and significantly reduces hypoglycaemia without rebound hyperglycaemia compared to SAP without PLGS11. In England continuous glucose monitoring is supported by NICE for people with type 1 diabetes who are willing to commit to using it at least 70% of the time and to calibrate it as needed, and who have any of the following despite optimised use of insulin therapy and conventional blood glucose monitoring12: More than 1 episode a year of severe hypoglycaemia with no obvious preventable precipitating cause. Complete loss of awareness of hypoglycaemia. Frequent (more than 2 episodes a week) asymptomatic hypoglycaemia that is causing problems with daily activities. Extreme fear of hypoglycaemia. Hyperglycaemia (HbA1c level of 75 mmol/mol [9%] or higher) that persists despite testing at least 10 times a day Addressing severe hypoglycaemia, reducing the risk of further episodes and acting promptly to optimise hypoglycaemia awareness are critical in people at high risk. Continuous subcutaneous insulin pump therapy is supported for adults and children over 12 with type 1 diabetes in whom attempts to achieve target haemoglobin A1c (HbA1c) with multiple daily injections (MDI) have resulted in disabling hypoglycaemia or HbA1c levels have remained high (8.5% [69 mmol/mol] or above) despite high level care12. This study consists of 3 phases: The main study (SMBG vs RT-CGM for 12 weeks), an optional Extended Phase 1 (RT-CGM for 6 months) and a further optional Extended phase 2 (where participants have the choice to continue on RT-CGM or to be re-randomised onto RT-CGM alone or RT-CGM with CSII).

Official Title
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Assessment of the Impact of Real-Time Continuous Glucose Monitoring on People Presenting With Severe Hypoglycaemia

Conditions
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Diabetes Mellitus, Type 1, Hypoglycemia Unawareness, Hypoglycemia

Intervention / Treatment
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* Device: Dexcom G6 CGM
* Device: Tandem t:slim X2 Insulin Pump


Participation Criteria
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Eligibility Criteria
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PRE-REGISTRATION EVALUATIONS Episode of severe hypoglycaemia Age >18 years Diagnosis of type 1 diabetes INCLUSION CRITERIA Adults over 18 years of age Severe hypoglycaemia requiring ambulance call-out or emergency department attendance within 2 weeks Type 1 diabetes confirmed on the basis of clinical features Type 1 diabetes for greater than 3 years EXCLUSION CRITERIA Use of CGM within the last 6 months (except short periods of diagnostic blinded use under clinic supervision). Prior use of Abbott FreeStyle Libre Device is permitted. Use of pre-mixed insulin No access to smartphone or computer Pregnant or planning pregnancy Breastfeeding Have active malignancy or under investigation for malignancy Severe visual impairment Reduced manual dexterity Unable to participate due to other factors, as assessed by the Chief Investigators WITHDRAWAL CRITERIA Participants will be withdrawn if their ability to give informed consent is impaired. Participants will also be withdrawn, at the chief investigators discretion, if glucose control is negatively impacted by the use of either intervention.

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomised open-label parallel group study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Continuous Glucose Monitoring (CGM)<br>The RT CGM group will receive a Dexcom G6 transmitter and sensors, as well as a structured education refresher focusing on hypoglycaemia avoidance, recognition, and management. | Device: Dexcom G6 CGM<br>* Commercially available Dexcom G6 Continuous Glucose Monitoring<br>|
| No Intervention: Self Monitoring Blood Glucose (SMBG)<br>The SMBG group will additionally undergo blinded CGM at weeks 1 and 2, weeks 4 to 6 and weeks 9 to 12 using the Dexcom G6 system. Participants in this group will be shown how to insert the Dexcom G6 at the first clinic visit and sensors provided so they can do this at home. | |
| Experimental: Continuous Subcutaneous Insulin Infusion (CSII)<br>All participants will be re-consented with the choice to continue using RT-CGM for a further 16 weeks or be re-randomised to either receive the Tandem t:slim X2 insulin pump or RT-CGM. Participants randomised to the Tandem t:slim X2 group will be proficiently trained to safely use the Tandem t:slim X2 insulin pump. All participants (Tandem t:slim X2 and RT-CGM) will be provided with Dexcom G6 real time CGM transmitters and sensors for the 16-week second extension phase. | Device: Dexcom G6 CGM<br>* Commercially available Dexcom G6 Continuous Glucose Monitoring<br>Device: Tandem t:slim X2 Insulin Pump<br>* sensor augmented insulin pump with predictive low glucose suspend<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time spent in hypoglycaemia | Percentage time spent in hypoglycaemia (<3.0mmol/L, 55mg/dL) | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time spent in hypoglycaemia (<3.9mmol/L, 70mg/dL) | Percentage time spent in hypoglycaemia (<3.9mmol/L, 70mg/dL) | 12 weeks | 
| Number of episode of serious hypoglycaemia | defined as a sensor glucose <3.0mmol/L (55mg/dL) for >20 minutes | 12 weeks | 
| time in euglycaemia | % time in euglycaemia (3.9-7.8mmol/L, 70-140mg/dL) | 12 weeks | 
| time spent in target | % time spent in target (3.9-10mmol/L, 70-180mg/dL) | 12 weeks | 
| time spent in hyperglycaemia | % time spent in hyperglycaemia (>10mmol/L, 180mg/dL) | 12 weeks | 
| hypoglycaemic excursions | Number hypoglycaemic excursions | 12 weeks | 
| Severe Hypoglycaemia | Measured via CGM | 12 weeks | 
| Mean Absolute Difference in Glucose (MAD%) | Measured via CGM expressed as a percentage reference value | 12 weeks | 
| Glucose Variability | Measured via CGM | 12 weeks | 
| HbA1C | Measured via venous blood tests | 12 weeks | 
| Ambulance call-out rates | Provided by LAS | 12 weeks | 
| DTSQ | Diabetes Treatment Satisfaction Questionnaire | 12 weeks | 
| CGM Usability | Continuous Glucose Monitoring Usability Questionnaire | 12 weeks | 
| PAID | Problem Area in Diabetes Questionnaire | 12 weeks | 
| Gold Score | Hypoglycaemia awareness (GOLD score) questionnaire | 12 weeks | 
| HFS2 questionnaire | Fear of Hypoglycaemia Survey Score | 12 weeks | 
| Cost effectiveness (measured in pounds sterling) | Cost effectiveness of CGM when compared with SMBG | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Real time continuous glucose monitoring, continuous subcutaneous insulin infusion, self monitoring blood glucose, sensor augmented pump, severe hypoglycaemia, hypounaware