Maximising Time With a Normal Blood Glucose to Restore the Glucagon Response in Type 1 Diabetes

• ClinicalTrials.gov Identifier: NCT04614168
• Recruitment Status: Recruiting
• First Posted: November 3, 2020
• Last Update Posted: January 14, 2022
• Sponsor: University of Edinburgh
• Collaborators: NHS Lothian; The Leona M. and Harry B. Helmsley Charitable Trust; Tandem Diabetes Care, Inc.; DexCom, Inc.
• Information provided by (Responsible Party): University of Edinburgh

Tracking Information

• First Submitted Date: October 7, 2020
• First Posted Date: November 3, 2020
• Last Update Posted Date: January 14, 2022
• Actual Study Start Date: July 26, 2021
• Estimated Primary Completion Date: March 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 2, 2020)

The change in plasma glucagon levels (pmol/L) measured during normoglycaemic and hypoglycaemia [ Time Frame: 8 months ]

Measured at baseline and each glucose plateau in a stepped hyperinsulinaemic hypoglycaemic clamp study at study start and study end

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 17, 2021)

• Time in glycaemic range (3.9-10mmol/L) [ Time Frame: 8 months ]
  Percentage time spent in target glycaemic range.
• Time spent below the target glycaemic range (<3.9mmol/L) [ Time Frame: 8 months ]
  Percentage of time spent below the target glycaemic range
• Time spent above the target glycaemic range (>10mmol/L) [ Time Frame: 8 months ]
  Percentage of time spent above the target glycaemic range
• The change in plasma cortisol (nmol/L) levels measured during normoglycaemic and hypoglycaemia [ Time Frame: 8 months ]
  Measured at baseline and each glucose plateau in a stepped hyperinsulinaemic hypoglycaemic clamp study at study start and study end
• The change in plasma adrenaline (nmol/L) levels measured during normoglycaemic and hypoglycaemia [ Time Frame: 8 months ]
  Measured at baseline and each glucose plateau in a stepped hyperinsulinaemic hypoglycaemic clamp study at study start and study end
• The change in plasma noradrenaline (nmol/L) levels measured during normoglycaemic and hypoglycaemia [ Time Frame: 8 months ]
  Measured at baseline and each glucose plateau in a stepped hyperinsulinaemic hypoglycaemic clamp study at study start and study end
• Endogenous glucose production [ Time Frame: 8 months ]
  Measured with stable isotope studies using D2 glucose and D5 glycerol
• HbA1c [ Time Frame: 8 months ]
  Difference between baseline and study end
• Change in quality of life at trial entry and end. [ Time Frame: 8 months ]
  Measured using the EQ5D-5L- a quality of life questionnaire comprising of five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension consists of five levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The participant ticks the box most relevant to them at the time of taking the questionnaire. This response is converted into a 1 digit number and the 5 numbers from a domain can be combined to describe the participant's health state. This questionnaire will be completed at trial entry and then at trial end.
• Change in emotional distress related to diabetes at trial entry and end. [ Time Frame: 8 months ]
  Diabetes Distress Scale (DDS-1)- a 28-item self-reporting scale. Each item can be scored from 1 (not a problem) to 6 (a very serious problem). This questionnaire will be completed at study entry and study end.
• Attitude to diabetes technologies [ Time Frame: 8 months ]
  Measured using the Diabetes Technology Questionnaire- a 30 item questionnaire. The participant ranks each item from Very Much (1) to Not at all (5). Participants will complete this questionnaire at study entry and study end. Also assessed using the Diabetes Technology Attitudes Survey- a 5 item questionnaire. The participant ranks each item from Strongly Disagree (1) to Strongly Agree (5).
• Change in fear of hypoglycaemic [ Time Frame: 8 months ]
  Measured using the Hypoglycaemia Fear Survey (HFS)- this survey consists of two subscales- Behaviour and Worry. There are 28 items in the survey that the participant ranks from Never (0) to Almost Always (4). Participants will complete this questionnaire at study entry and study end.
• Change in confidence of managing hypoglycaemia [ Time Frame: 8 months ]
  Measured using the Hypoglycaemic Confidence Scale- this is a 9 item scale. The participant rates each item from Not Confident at All to Very Confident. Participants will complete this questionnaire at study entry and study end.
• Hypoglycaemia awareness [ Time Frame: 8 months ]
  Measured during each clamp study using the Edinburgh Hypoglycaemic Scale- this is a 17 item scale of symptoms of hypoglycaemia. The participant ranks on a scale from Not at all (1) to A Great Deal (7) whether they are experiencing each symptom at the time of the questionnaire being completed.
• Trial Making Test [ Time Frame: 8 months ]
  Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Difference in score between plateaus and at trial entry and end.
• Digit Span Test [ Time Frame: 8 months ]
  Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Difference in score between plateaus and at trial entry and end.
• Digit Symbol Substitution Test [ Time Frame: 8 months ]
  Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Difference in score between plateaus and at trial entry and end.
• Four Choice Reaction Time Test [ Time Frame: 8 months ]
  Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Difference in score between plateaus and at trial entry and end.

Original Secondary Outcome Measures (submitted: November 2, 2020)

• Time in glycaemic range (3.9-10mmol/L) [ Time Frame: 8 months ]
  Percentage time spent in target glycaemic range.
• Time spent below the target glycaemic range (<3.9mmol/L) [ Time Frame: 8 months ]
  Percentage of time spent below the target glycaemic range
• Time spent above the target glycaemic range (>10mmol/L) [ Time Frame: 8 months ]
  Percentage of time spent above the target glycaemic range
• The change in plasma cortisol (nmol/L) levels measured during normoglycaemic and hypoglycaemia [ Time Frame: 8 months ]
  Measured at baseline and each glucose plateau in a stepped hyperinsulinaemic hypoglycaemic clamp study at study start and study end
• The change in plasma adrenaline (nmol/L) levels measured during normoglycaemic and hypoglycaemia [ Time Frame: 8 months ]
  Measured at baseline and each glucose plateau in a stepped hyperinsulinaemic hypoglycaemic clamp study at study start and study end
• The change in plasma noradrenaline (nmol/L) levels measured during normoglycaemic and hypoglycaemia [ Time Frame: 8 months ]
  Measured at baseline and each glucose plateau in a stepped hyperinsulinaemic hypoglycaemic clamp study at study start and study end
• Endogenous glucose production [ Time Frame: 8 months ]
  Measured with stable isotope studies using D2 glucose and D5 glycerol
• HbA1c [ Time Frame: 8 months ]
  Difference between baseline and study end
• Change in quality of life at trial entry and end. [ Time Frame: 8 months ]
  Measured using the EQ5D-5L- a quality of life questionnaire comprising of five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension consists of five levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The participant ticks the box most relevant to them at the time of taking the questionnaire. This response is converted into a 1 digit number and the 5 numbers from a domain can be combined to describe the participant's health state. This questionnaire will be completed at trial entry and then at trial end.
• Change in emotional distress related to diabetes at trial entry and end. [ Time Frame: 8 months ]
  Diabetes Distress Scale (DDS-1)- a 28-item self-reporting scale. Each item can be scored from 1 (not a problem) to 6 (a very serious problem). This questionnaire will be completed at study entry and study end.
• Attitude to diabetes technologies [ Time Frame: 8 months ]
  Measured using the Diabetes Technology Questionnaire- a 30 item questionnaire. The participant ranks each item from Very Much (1) to Not at all (5). Participants will complete this questionnaire at study entry and study end.
• Diabetes Treatment Satisfaction [ Time Frame: 8 months ]
  Measured using the Diabetes Technology Attitudes Survey- a 5 item questionnaire. The participant ranks each item from Strongly Disagree (1) to Strongly Agree (5).
• Change in fear of hypoglycaemic [ Time Frame: 8 months ]
  Measured using the Hypoglycaemia Fear Survey (HFS)- this survey consists of two subscales- Behaviour and Worry. There are 28 items in the survey that the participant ranks from Never (0) to Almost Always (4). Participants will complete this questionnaire at study entry and study end.
• Change in confidence of managing hypoglycaemia [ Time Frame: 8 months ]
  Measured using the Hypoglycaemic Confidence Scale- this is a 9 item scale. The participant rates each item from Not Confident at All to Very Confident. Participants will complete this questionnaire at study entry and study end.
• Hypoglycaemia awareness [ Time Frame: 8 months ]
  Measured during each clamp study using the Edinburgh Hypoglycaemic Scale- this is a 17 item scale of symptoms of hypoglycaemia. The participant ranks on a scale from Not at all (1) to A Great Deal (7) whether they are experiencing each symptom at the time of the questionnaire being completed.
• Trial Making Test [ Time Frame: 8 months ]
  Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Difference in score between plateaus and at trial entry and end.
• Digit Span Test [ Time Frame: 8 months ]
  Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Difference in score between plateaus and at trial entry and end.
• Digit Symbol Substitution Test [ Time Frame: 8 months ]
  Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Difference in score between plateaus and at trial entry and end.
• Four Choice Reaction Time Test [ Time Frame: 8 months ]
  Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Difference in score between plateaus and at trial entry and end.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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?

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.

• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Participants will be divided into two groups using stratified sampling to match for age, sex and BMI.

Masking: None (Open Label)
Primary Purpose: Basic Science

Condition

• Type 1 Diabetes
• Type 1 Diabetes Mellitus With Hypoglycemia
• Hypoglycemia
• Hypoglycemia Unawareness
• Glucagon Deficiency
• Insulin Hypoglycemia

Intervention

• Procedure: Stepped hyperinsulinaemic-hypoglycaemic clamp study
  Participants will commence on a primed insulin infusion at a constant rate of 60mU/m2/min along with a variable rate 20% glucose infusion. Participants will have their blood glucose monitored every 5 minutes. The glucose infusion will be altered to achieve the desired blood glucose plateaus of: 5mmol/l, 3mmol/l and 2.5mmol/l. Each plateau will be held for 40 minutes. During each plateau blood samples will be taken on three occasions for: glucagon, cortisol, adrenaline, noradrenaline, D2 glucose and D5 glycerol. On two occasions during each plateau participants will complete the Edinburgh hypoglycaemia scale and the following cognitive tests: trail making test, digit span test, digit symbol substitution test and four choice reaction time test. At the end of the clamp study the insulin infusion will be discontinued and the blood glucose will be allowed to rise to the normal range. Participants will consume lunch before leaving the clinical research facility.
• Device: Insulin pump
  Insulin pump with a built-in algorithm that allows it to work with a CGM device to adjust insulin delivery based on CGM readings.
  Other Name: Tandem t:slim x2 with Control IQ technology
• Device: Continuous glucose monitor
  Continuous glucose monitoring device that sends data to the insulin pump to allow the algorithm to adjust insulin delivery. Participants are able to see the glucose data from the device when it is used in open mode.
  Other Name: Dexcom G6
• Other: Low carbohydrate diet
  30-40g of carbohydrate per main meal portion.
• Device: Blinded continuous glucose monitor
  Allows data on blood glucose to be collected without values altering the behaviour of the participant. Participants have to continue to monitor their own blood glucose while wearing the device in the blinded mode.
  Other Name: Dexcom G6
• Procedure: Stable isotope studies- D2 Glucose and D5 Glycerol
  These studies will take place at the same time as the hyperinsulinaemic hypoglycaemic clamp studies. Participants will receive a priming dose of each stable isotope followed by a continuous infusion for the remainder of the clamp study.

Study Arms

• Active Comparator: Group 1 - Standard Care
  This group will continue on their standard diabetes care. They will be required to undergo three periods of blinded continuous glucose monitoring each lasting 20-days at: baseline, 4 months and 8 months. Participants in this group will undergo a hyperinsulinaemic hypoglycaemic clamp study at baseline and 8 months. They will also complete quality of life and diabetes treatment questionnaires at baseline and 8 months.
  Interventions:

  • Procedure: Stepped hyperinsulinaemic-hypoglycaemic clamp study
  • Device: Blinded continuous glucose monitor
  • Procedure: Stable isotope studies- D2 Glucose and D5 Glycerol
• Experimental: Group 2- Automated insulin delivery and low carbohydrate diet
  This group will be placed on an automated insulin delivery system: Tandem t:slim x2 insulin pump with Control IQ technology and Dexcom G6 continuous glucose monitor. They will also be asked to follow a low-carbohydrate diet of 30-40g of carbohydrate per main meal. At baseline they will have a 20-day period of blinded continuous glucose monitoring. Participants in this group will undergo a stepped hyperinsulinaemic hypoglycaemic clamp study at baseline and 8 months. They will also complete quality of life and diabetes treatment questionnaires at baseline and 8 months.
  Interventions:

  • Procedure: Stepped hyperinsulinaemic-hypoglycaemic clamp study
  • Device: Insulin pump
  • Device: Continuous glucose monitor
  • Other: Low carbohydrate diet
  • Device: Blinded continuous glucose monitor
  • Procedure: Stable isotope studies- D2 Glucose and D5 Glycerol

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 2, 2020): 24
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 2023
• Estimated Primary Completion Date: March 2023 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 21 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Shareen Forbes, MBChB, PhD; + 44 (0)131 2426741; shareen.forbes@ed.ac.uk

Contact: Faye Baxter, MBChB; fbaxter@ed.ac.uk

• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT04614168
• Other Study ID Numbers: AC19163
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University of Edinburgh
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Edinburgh
• Original Study Sponsor: Same as current

Collaborators

• NHS Lothian
• The Leona M. and Harry B. Helmsley Charitable Trust
• Tandem Diabetes Care, Inc.
• DexCom, Inc.

Investigators

• Principal Investigator: Shareen Forbes, MBChB, PhD; University of Edinburgh

• PRS Account: University of Edinburgh
• Verification Date: January 2022