Maximising Time With a Normal Blood Glucose to Restore the Glucagon Response in Type 1 Diabetes
NCT ID: NCT04614168
Last Updated: 2025-12-17
Study Results
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View full resultsBasic Information
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ACTIVE_NOT_RECRUITING
NA
24 participants
INTERVENTIONAL
2021-07-26
2025-12-26
Brief Summary
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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
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
BASIC_SCIENCE
NONE
Study Groups
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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.
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.
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.
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.
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.
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.
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.
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.
Low carbohydrate diet
30-40g of carbohydrate per main meal portion.
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.
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.
Interventions
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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.
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.
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.
Low carbohydrate diet
30-40g of carbohydrate per main meal portion.
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.
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.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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
21 Years
65 Years
ALL
No
Sponsors
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NHS Lothian
OTHER_GOV
The Leona M. and Harry B. Helmsley Charitable Trust
OTHER
Tandem Diabetes Care, Inc.
INDUSTRY
DexCom, Inc.
INDUSTRY
University of Edinburgh
OTHER
Responsible Party
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Principal Investigators
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Shareen Forbes, MBChB, PhD
Role: PRINCIPAL_INVESTIGATOR
University of Edinburgh
Locations
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Edinburgh Royal Infirmary/University of Edinburgh
Edinburgh, , United Kingdom
Countries
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References
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Baxter F, Baillie N, Forbes S. Study protocol: a randomised controlled proof-of-concept real-world study - does maximising time in range using hybrid closed loop insulin delivery and a low carbohydrate diet restore the glucagon response to hypoglycaemia in adults with type 1 diabetes? BMJ Open. 2022 Dec 20;12(12):e054958. doi: 10.1136/bmjopen-2021-054958.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Other Identifiers
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AC19163
Identifier Type: -
Identifier Source: org_study_id