Clinical trial NCT04614168: Maximising Time With a Normal Blood Glucose to Restore the Glucagon Response in Type 1 Diabetes
Official title: Can Maximising Time in Range Using Automated Insulin Delivery and a Low Carbohydrate Diet Restore the Glucagon Response to Hypoglycaemic in Type 1 Diabetes?
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Type 1 Diabetes
Type 1 Diabetes Mellitus With Hypoglycemia
Hypoglycemia
Hypoglycemia Unawareness
Glucagon Deficiency
Insulin Hypoglycemia
Keywords: Type 1 diabetes
Hypoglycaemia
Hypoglycemia
Glucagon
Insulin
Low carbohydrate diet
Stable isotope
Lead sponsor: University of Edinburgh
Sponsor class: OTHER
Collaborators: name: NHS Lothian
name: The Leona M. and Harry B. Helmsley Charitable Trust
name: Tandem Diabetes Care, Inc.
name: DexCom, Inc.
First posted: 2020-11-03
Enrollment: 17
Sex: ALL
Minimum age (years): 21
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be divided into two groups using stratified sampling to match for age, sex and BMI.
Primary purpose: BASIC_SCIENCE

Brief summary: Almost all people who have had type 1 diabetes for 5 years have a defect in secretion of the hormone Glucagon. This hormone is involved in the body's response to low blood glucose (hypoglycaemia). It works by releasing glucose stores from the liver to bring the blood glucose back to normal. This defect therefore increases the risk of severe hypoglycaemia. The reason for this Glucagon defect in people with Type 1 diabetes is currently unknown.

This study aims to look at the Glucagon response to hypoglycaemia in 24 people with type 1 diabetes to ascertain whether tight blood glucose control over a period of time improves this response. The investigators aim to achieve good blood glucose control using new generation Automated Insulin Delivery systems (AIDs). This system is made of: an insulin pump, a continuous glucose monitor (CGM) and an algorithm that allows adjustment of insulin delivery based on the blood glucose readings from the CGM. This is the most up to date technology that there is in the management of type 1 diabetes. However, people using this technology often still have problems with high blood glucose after eating. To ensure a very good blood glucose control participants will also follow a low carbohydrate diet to prevent this blood glucose rise after meals.

The Glucagon response to low blood glucose will be measured at zero and eight months using the hyperinsulinaemic hypoglycaemic clamp technique.

Detailed description: This is a feasibility pilot study involving 24 participants with type 1 diabetes. Participants will be recruited from the local type 1 diabetes clinic and insulin pump waiting list. Each participant will enter the trial for a period of 8 months. The investigators aim to test if maximising time in glycaemic range (blood glucose 3.9-10 mmol/L) will restore the glucagon response to insulin-induced hypoglycaemia.

After signing informed consent participants will be screened for eligibility against the inclusion and exclusion criteria.

Those who are eligible will have an initial 20-day period of baseline blood glucose data collection. This will be achieved using a blinded continuous glucose monitoring (CGM) device. Participants will continue on their pre-trial diabetes care during this period and will be required to monitor their own blood glucose as normal.

The participants will be split into two groups using stratified sampling to match for: age, gender and BMI.

Group 1 will be the control group. Participants in this group will continue on standard diabetes care for the duration of the trial. Participants will be required to undertake two further periods of blinded CGM monitoring at 4 and 8 months.

Group 2 will be the intervention group. Participants in this group will be placed on the automated insulin delivery (AID) system and asked to follow a low carbohydrate diet of 30-40g of carbohydrate per main meal portion. The AID system will consist of: a Tandem t:slim X2 insulin pump with control IQ technology and a Dexcom G6 continuous glucose monitor. After receiving training on the use of the devices these participants will enter a 2 week study run-in period to become accustomed to the devices and so that device settings can be optimised. As a safety measure these participants will be asked to measure blood ketones at least once daily throughout the trial. Study staff will monitor the data from the participants study devices throughout the trial and adjust settings as required to maximise time in glycaemic range.

At the beginning and end of the trial all participants will undergo a hyperinsulinaemic hypoglycaemic clamp study to measure their counterregulatory hormone response to hypoglycaemic. Participants will also undergo cognitive tests and assessment of hypoglycaemic awareness during each clamp study.

Eligibility criteria: Inclusion Criteria:

* Participants with Type 1 diabetes with C-peptide levels less than 200pmol/L.
* Type 1 diabetes for 5 years or more.
* HbA1c greater than or equal to 53 mol/mol.
* Normal renal function.
* Normal thyroid function.
* Gold Score 4-7 (indicating impaired awareness of hypoglycaemia)
* Willingness to monitor blood ketones daily.
* Use of freestyle libre device is permitted at study entry and may be continued in participants in group 1

Exclusion Criteria:

* Current use of a non-approved closed loop / AID system or those on a predictive low glucose suspend insulin pump.
* Proliferative retinopathy
* Regular use of real time CGM in the preceding 3 months.
* History of Diabetic ketoacidosis in the preceding 6 months.
* Severe hypoglycaemic episode requiring external assistance in the preceding 6 months.
* Inability to safely use technology used in this study (e.g. impaired vision, memory or dexterity that prevents safe operation of CGM or insulin pump.)
* Inability to support the technology requirements for the study (e.g. unable to upload study device at home)
* History of Haemophilia, Cystic Fibrosis, pancreatic disease or complete pancreatectomy, ischaemic heart disease, epilepsy or hypoglycaemia induced seizure
* History of severe reaction or allergy to adhesive necessary to this study.
* Unable to adhere to study timetable.
* Unable to give informed consent.
* Pregnancy. We will perform a pregnancy test on all eligible participants at baseline.
* Concurrent use of any non-insulin glucose-lowering agent (including GLP-1 agonists, Symlin, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas. These may lower insulin requirements and predispose to diabetic ketoacidosis.
* Concurrent use of medication that may affect blood glucose such as SSRIs
* A condition, which in the opinion of the investigator, would put the patient or study at risk
* HbA1c greater than or equal to 75 mmol/mol

Primary outcomes:
measure: The change in plasma glucagon levels (pmol/L) measured during normoglycaemic and hypoglycaemia
timeFrame: 8 months
Secondary outcomes:
measure: Time in glycaemic range (3.9-10mmol/L)
timeFrame: 8 months
measure: Time spent below the target glycaemic range (<3.9mmol/L)
timeFrame: 8 months
measure: Time spent above the target glycaemic range (>10mmol/L)
timeFrame: 8 months
measure: The change in plasma cortisol (nmol/L) levels measured during normoglycaemic and hypoglycaemia
timeFrame: 8 months
measure: The change in plasma adrenaline (nmol/L) levels measured during normoglycaemic and hypoglycaemia
timeFrame: 8 months
measure: The change in plasma noradrenaline (nmol/L) levels measured during normoglycaemic and hypoglycaemia
timeFrame: 8 months
measure: Endogenous glucose production
timeFrame: 8 months
measure: HbA1c
timeFrame: 8 months
measure: Change in quality of life at trial entry and end.
timeFrame: 8 months
measure: Change in emotional distress related to diabetes at trial entry and end.
timeFrame: 8 months
measure: Attitude to diabetes technologies
timeFrame: 8 months
measure: Change in fear of hypoglycaemic
timeFrame: 8 months
measure: Change in confidence of managing hypoglycaemia
timeFrame: 8 months
measure: Hypoglycaemia awareness
timeFrame: 8 months
measure: Trial Making Test
timeFrame: 8 months
measure: Digit Span Test
timeFrame: 8 months
measure: Digit Symbol Substitution Test
timeFrame: 8 months
measure: Four Choice Reaction Time Test
timeFrame: 8 months
Other outcomes:
Locations:
city: Edinburgh
country: United Kingdom
facility: Edinburgh Royal Infirmary/University of Edinburgh
Study officials:
affiliation: University of Edinburgh
name: Shareen Forbes, MBChB, PhD
role: PRINCIPAL_INVESTIGATOR
References: