Glucagon Deficiency, Hypoglycemia, Hypoglycemia Unawareness, Insulin Hypoglycemia, Type 1 Diabetes, Type 1 Diabetes Mellitus With Hypoglycemia
Conditions
Keywords
Type 1 diabetes, Hypoglycaemia, Hypoglycemia, Glucagon, Insulin, Low carbohydrate diet, Stable isotope
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.
Interventions
PROCEDUREStepped 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.
DEVICEInsulin 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.
DEVICEContinuous 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.
OTHERLow carbohydrate diet
30-40g of carbohydrate per main meal portion.
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.
PROCEDUREStable 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.
Sponsors
University of Edinburgh
NHS Lothian
The Leona M. and Harry B. Helmsley Charitable Trust
Tandem Diabetes Care, Inc.
DexCom, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Participants will be divided into two groups using stratified sampling to match for age, sex and BMI.
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Change in Plasma Glucagon Levels (Pmol/L) Measured During Normoglycaemic and Hypoglycaemia | Clamp 1 at baseline and clamp 2 at 8 months | The delta glucagon concentration (pmol/L) from plateau 1 (normoglycaemia- 5.0 mmol/L) to plateau 3 (hypoglycaemia- 2.5 mmol/L). The physiological response in health would be for an increase in glucagon secretion from normo- to hypoglycaemia. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time in Glycaemic Range (3.9-10mmol/L) | Baseline (study entry), midpoint at 4 months and endpoint at 8 months | Percentage time spent in target glycaemic range. |
| Time Spent Above the Target Glycaemic Range (>10mmol/L) | Baseline (study entry), midpoint at 4 months and endpoint at 8 months | Percentage of time spent above the target glycaemic range |
| The Change in Plasma Cortisol (ng/mL) Levels Measured During Normoglycaemic and Hypoglycaemia | Clamp 1 at baseline and clamp 2 at 8 months | Delta cortisol from P1 (5.0 mmol/L) to P3 (2.5 mmol/L) |
| The Change in Plasma Adrenaline (pg/mL) Levels Measured During Normoglycaemic and Hypoglycaemia | Clamp 1 at baseline and clamp 2 at 8 months | Delta adrenaline from plateau 1 (5mmol/L) to plateau 3 (2.5 mmol/L) |
| The Change in Plasma Noradrenaline (pg/mL) Levels Measured During Normoglycaemic and Hypoglycaemia | Clamp 1 at baseline and clamp 2 at 8 months | The change in noradrenaline concentration from plateau 1 (5 mmol/L) to plateau 3 (2.5 mmol/L). |
| Endogenous Glucose Production | Clamp 1 at baseline and clamp 2 at 8 months | The change in the glucose rate of appearance from plateau 1 (5mmol/L) to plateau 3 (2.5 mmol/L) |
| HbA1c | Baseline (study entry) endpoint (8 months) | Delta HbA1c from baseline to study endpoint. |
| Change in Quality of Life at Trial Entry and End. | Baseline (study entry) endpoint (8 months) | Measured using the EQ5D-5L- -VAS. Number on scale of 0-100 to assess wellbeing on that day. 100 being the most well. |
| Change in Emotional Distress Related to Diabetes at Trial Entry and End. | Baseline (study entry) endpoint (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. Data presented is the DDS total score. |
| Change in Fear of Hypoglycaemic | Baseline (study entry) endpoint (8 months) | Measured using the Hypoglycaemia Fear Survey (HFS)- this survey consists of two subscales- Baseline (study entry) endpoint (8 months) Behaviour and Worry. There are 28 items in the survey that the participant ranks from Never (0) to Almost Always (4). Higher scores indicate fear of hypoglycaemia. In the Behaviour subscale the lowest possible score in 0 and the highest possible score is 60. In the Worry subscale the lowest possible score is 0 and the highest is 72. Participants will complete this questionnaire at study entry and study end. |
| Change in Confidence of Managing Hypoglycaemia | Baseline (study entry) endpoint (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. Higher scores mean more confidence. 'Not confident' at lower end of scale scored as 1 and 'very confident' at top of the scale scored as 4. Min score is 9 and max score is 36. |
| Hypoglycaemia Awareness | Clamp 1 - study entry, clamp 2 - 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. Higher scores mean more hypoglycaemia symptoms. The lowest possible score is 0 and the highest possible score is 119. |
| Trial Making Test | Clamp 1- study entry, clamp 2 - 8 months | Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Delta score plateau 1 (5 mmol/L) to plateau 3 (2.5 mmol/L) compared between clamp studies. Participants are timed completing the test. Higher scores indicate a longer time to complete the test. |
| Digit Span Test | Clamp 1- study entry, clamp 2 - 8 months | Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Difference in change in score from plateau 1 (5mmol/L) to plateau 3 (2.5 mmol/L) compared between clamp studies. Lower scores mean more errors. Forwards- participant repeats the numbers as read. Backwards- the participant repeats the numbers backwards. |
| Digit Symbol Substitution Test | Clamp 1- study entry, clamp 2 - 8 months | Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Difference in score between plateau 1 (5.0 mmol/L) and plateau 3 (2.5 mmol/L) compared between clamp studies. Given 90 seconds to complete as many items as possible. Higher scores mean more items completed in the allotted time. |
| Time Spent Below the Target Glycaemic Range (<3.9mmol/L) | Baseline (study entry), midpoint at 4 months and endpoint at 8 months | Percentage of time spent below the target glycaemic range |
| Four Choice Reaction Time Test | Clamp 1- study entry, clamp 2 - 8 months | Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Difference in score between plateau 1 (5.0mmol/L) and plateau 3 (2.5 mmol/L) compared between clamp studies. Higher scores mean more time taken to complete the task. |
Countries
United Kingdom
Contacts
PRINCIPAL_INVESTIGATORShareen Forbes, MBChB, PhD
University of Edinburgh
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1 - Standard Care Standard diabetes care. They will undergo 3 periods of blinded continuous glucose monitoring (CGM) lasting 20-days at: baseline, 4 and 8 months. Participants in this group will undergo a hyperinsulinaemic hypoglycaemic clamp study at baseline and 8 months and complete quality of life and diabetes treatment questionnaires.
Stepped hyperinsulinaemic-hypoglycaemic clamp study: Participants will commence a primed insulin infusion at 60mU/m2/min along with a variable rate 20% glucose infusion. Blood glucose monitored (BG) every 5 minutes. The glucose infusion will be altered to achieve BG plateaus of: 5, 3 and 2.5mmol/l. Each lasting 40 minutes. During each plateau blood samples will be taken 3 times for: glucagon, cortisol, adrenaline, noradrenaline, D2 glucose and D5 glycerol. On 2 occasions participants will complete the Edinburgh hypoglycaemia scale and 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 stopped.
Blinded CGM: Allows data on BG to be collected without values altering behaviour. Participants continue to monitor their own BG while wearing the device in the blinded mode.
Stable isotope studies- D2 Glucose and D5 Glycerol: takes place at the same time as the hyperinsulinaemic hypoglycaemic clamp. Participants will receive a priming dose of each stable isotope followed by a continuous infusion for the remainder of the clamp study. | 8 |
| Group 2- Automated Insulin Delivery and Low Carbohydrate Diet Automated insulin delivery system: Tandem t:slim x2 insulin pump with Control IQ and Dexcom G6 continuous glucose monitor (CGM). They will be asked to follow a low-carbohydrate diet (30-40g of carbs/meal). Baseline 20-day period of blinded CGM. Participants in this group will undergo a stepped hypoglycaemic clamp study at baseline and 8 months and complete quality of life and diabetes treatment questionnaires.
Stepped hypoglycaemic clamp study: Participants commence a primed insulin infusion (rate 60mU/m2/min) and a variable rate 20% glucose infusion. Blood glucose (BG) monitored every 5 minutes. Glucose infusion will be altered to achieve BG plateaus of: 5, 3 and 2.5mmol/l. Each lasting 40 minutes. During each plateau blood samples will be taken 3 times for: glucagon, cortisol, adrenaline, noradrenaline, D2 glucose and D5 glycerol. Twice during each plateau participants complete the Edinburgh hypoglycaemia scale and cognitive tests: trail making test, digit span test, digit symbol substitution test and four choice reaction time test.
Insulin pump: Insulin pump with a built-in algorithm automatic insulin adjustment.
CGM: CGM sends data to the insulin pump to allow automatic insulin adjustment.
Low carbohydrate diet: 30-40g of carbs/meal.
Blinded CGM: data on BG collected without values altering behaviour.
Stable isotope studies- D2 Glucose and D5 Glycerol: These studies will take place at the same time as the hypoglycaemic clamp. | 11 |
| Total | 19 |
Baseline characteristics
| Characteristic | Group 1 - Standard Care | Group 2- Automated Insulin Delivery and Low Carbohydrate Diet | Total |
|---|---|---|---|
| Age, Continuous | 35.9 Years STANDARD_DEVIATION 11.3 | 42.9 Years STANDARD_DEVIATION 9.5 | 39.95 Years STANDARD_DEVIATION 10.63 |
| Age Diagnosed (Years) | 7 Years | 20 Years | 16.5 Years |
| BMI | 29.34 kg^m2 STANDARD_DEVIATION 4.1 | 26.18 kg^m2 STANDARD_DEVIATION 2.99 | 27.51 kg^m2 STANDARD_DEVIATION 3.76 |
| CV Glucose | 38.24 Percentage STANDARD_DEVIATION 6.8 | 35.06 Percentage STANDARD_DEVIATION 4.94 | 36.4 Percentage STANDARD_DEVIATION 5.85 |
| HbA1c | 63 mmol/mol | 61 mmol/mol | 63 mmol/mol |
| Insulin Pump User | 4 participants | 3 participants | 7 participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment United Kingdom | 8 participants | 11 participants | 19 participants |
| Sex/Gender, Customized Female | 6 participants | 4 participants | 10 participants |
| Time >10 mmol/L | 25.12 Percentage STANDARD_DEVIATION 11.73 | 33.64 Percentage STANDARD_DEVIATION 12.42 | 30.05 Percentage STANDARD_DEVIATION 12.57 |
| Time >13.9 mmol/L | 21.7 Percentage STANDARD_DEVIATION 8.77 | 15.25 Percentage STANDARD_DEVIATION 13.75 | 17.97 Percentage STANDARD_DEVIATION 12.07 |
| Time <3.0 mmol/L | 0.12 Percentage | 0.13 Percentage | 0.13 Percentage |
| Time <3.9 mmol/L | 0.71 Percentage | 0.65 Percentage | 0.71 Percentage |
| Time in range (3.9-10 mmol/L) | 49.05 Percentage time spent 3.9-10 mmol/L STANDARD_DEVIATION 12.47 | 53.55 Percentage time spent 3.9-10 mmol/L STANDARD_DEVIATION 14.48 | 50.39 Percentage time spent 3.9-10 mmol/L STANDARD_DEVIATION 13.83 |
| Time since diagnosis (Years) | 19.2 Years | 25.5 Years | 24.67 Years |
| Weight | 84.5 Kg STANDARD_DEVIATION 11.9 | 77.33 Kg STANDARD_DEVIATION 7.8 | 80.35 Kg STANDARD_DEVIATION 10.14 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 11 |
| other Total, other adverse events | 0 / 5 | 0 / 11 |
| serious Total, serious adverse events | 0 / 5 | 1 / 11 |
Outcome results
Primary
The Change in Plasma Glucagon Levels (Pmol/L) Measured During Normoglycaemic and Hypoglycaemia
The delta glucagon concentration (pmol/L) from plateau 1 (normoglycaemia- 5.0 mmol/L) to plateau 3 (hypoglycaemia- 2.5 mmol/L). The physiological response in health would be for an increase in glucagon secretion from normo- to hypoglycaemia.
Time frame: Clamp 1 at baseline and clamp 2 at 8 months
Population: Three participants withdrew from group 1 after the 1st clamp study visit. They were excluded from the study analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group 1 - Standard Care | The Change in Plasma Glucagon Levels (Pmol/L) Measured During Normoglycaemic and Hypoglycaemia | Delta Clamp 1 (P3-P1) | 1.34 pmol/L |
| Group 1 - Standard Care | The Change in Plasma Glucagon Levels (Pmol/L) Measured During Normoglycaemic and Hypoglycaemia | Delta Clamp 2 (P3-P1) | 2.26 pmol/L |
| Group 2- Automated insulin delivery and low carbohydrate diet | The Change in Plasma Glucagon Levels (Pmol/L) Measured During Normoglycaemic and Hypoglycaemia | Delta Clamp 1 (P3-P1) | 1.68 pmol/L |
| Group 2- Automated insulin delivery and low carbohydrate diet | The Change in Plasma Glucagon Levels (Pmol/L) Measured During Normoglycaemic and Hypoglycaemia | Delta Clamp 2 (P3-P1) | 0.31 pmol/L |
p-value: >0.99Wilcoxon (Mann-Whitney)
p-value: 0.64Wilcoxon (Mann-Whitney)
Secondary
Change in Confidence of Managing Hypoglycaemia
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. Higher scores mean more confidence. 'Not confident' at lower end of scale scored as 1 and 'very confident' at top of the scale scored as 4. Min score is 9 and max score is 36.
Time frame: Baseline (study entry) endpoint (8 months)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 - Standard Care | Change in Confidence of Managing Hypoglycaemia | Baseline | 27.2 Numerical score | Standard Deviation 5.17 |
| Group 1 - Standard Care | Change in Confidence of Managing Hypoglycaemia | Endpoint | 29.2 Numerical score | Standard Deviation 5.31 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Change in Confidence of Managing Hypoglycaemia | Baseline | 27.64 Numerical score | Standard Deviation 7.63 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Change in Confidence of Managing Hypoglycaemia | Endpoint | 31.27 Numerical score | Standard Deviation 3.9 |
p-value: 0.25Wilcoxon (Mann-Whitney)
p-value: 0.09t-test, 2 sided
Secondary
Change in Emotional Distress Related to Diabetes at Trial Entry and End.
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. Data presented is the DDS total score.
Time frame: Baseline (study entry) endpoint (8 months)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 - Standard Care | Change in Emotional Distress Related to Diabetes at Trial Entry and End. | Baseline | 2.18 Numerical score | Standard Deviation 0.64 |
| Group 1 - Standard Care | Change in Emotional Distress Related to Diabetes at Trial Entry and End. | Endpoint | 1.96 Numerical score | Standard Deviation 0.66 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Change in Emotional Distress Related to Diabetes at Trial Entry and End. | Baseline | 2.2 Numerical score | Standard Deviation 1.15 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Change in Emotional Distress Related to Diabetes at Trial Entry and End. | Endpoint | 1.58 Numerical score | Standard Deviation 0.49 |
p-value: 0.13Wilcoxon (Mann-Whitney)
p-value: 0.03Wilcoxon (Mann-Whitney)
Secondary
Change in Fear of Hypoglycaemic
Measured using the Hypoglycaemia Fear Survey (HFS)- this survey consists of two subscales- Baseline (study entry) endpoint (8 months) Behaviour and Worry. There are 28 items in the survey that the participant ranks from Never (0) to Almost Always (4). Higher scores indicate fear of hypoglycaemia. In the Behaviour subscale the lowest possible score in 0 and the highest possible score is 60. In the Worry subscale the lowest possible score is 0 and the highest is 72. Participants will complete this questionnaire at study entry and study end.
Time frame: Baseline (study entry) endpoint (8 months)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 - Standard Care | Change in Fear of Hypoglycaemic | Behaviour Scale Baseline | 22 Numerical score | Standard Deviation 4.24 |
| Group 1 - Standard Care | Change in Fear of Hypoglycaemic | Behaviour Scale Endpoint | 19.2 Numerical score | Standard Deviation 8.11 |
| Group 1 - Standard Care | Change in Fear of Hypoglycaemic | Worry scale Baseline | 24 Numerical score | Standard Deviation 9.34 |
| Group 1 - Standard Care | Change in Fear of Hypoglycaemic | Worry Scale Endpoint | 21.4 Numerical score | Standard Deviation 15.39 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Change in Fear of Hypoglycaemic | Worry Scale Endpoint | 12.88 Numerical score | Standard Deviation 9.78 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Change in Fear of Hypoglycaemic | Behaviour Scale Baseline | 20.55 Numerical score | Standard Deviation 4.03 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Change in Fear of Hypoglycaemic | Worry scale Baseline | 24.25 Numerical score | Standard Deviation 15.85 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Change in Fear of Hypoglycaemic | Behaviour Scale Endpoint | 18.82 Numerical score | Standard Deviation 4.79 |
Comparison: Behaviour subscalep-value: 0.25Wilcoxon (Mann-Whitney)
Comparison: Worry subscalep-value: 0.63Wilcoxon (Mann-Whitney)
Comparison: Behaviour subscalep-value: 0.35t-test, 2 sided
Comparison: Worry subscalep-value: 0.09t-test, 2 sided
Secondary
Change in Quality of Life at Trial Entry and End.
Measured using the EQ5D-5L- -VAS. Number on scale of 0-100 to assess wellbeing on that day. 100 being the most well.
Time frame: Baseline (study entry) endpoint (8 months)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 - Standard Care | Change in Quality of Life at Trial Entry and End. | Baseline | 81 Number | Standard Deviation 6.52 |
| Group 1 - Standard Care | Change in Quality of Life at Trial Entry and End. | Endpoint | 82 Number | Standard Deviation 11.51 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Change in Quality of Life at Trial Entry and End. | Baseline | 79.36 Number | Standard Deviation 12.33 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Change in Quality of Life at Trial Entry and End. | Endpoint | 80.27 Number | Standard Deviation 9.96 |
p-value: >0.99Wilcoxon (Mann-Whitney)
p-value: 0.82t-test, 2 sided
Secondary
Digit Span Test
Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Difference in change in score from plateau 1 (5mmol/L) to plateau 3 (2.5 mmol/L) compared between clamp studies. Lower scores mean more errors. Forwards- participant repeats the numbers as read. Backwards- the participant repeats the numbers backwards.
Time frame: Clamp 1- study entry, clamp 2 - 8 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group 1 - Standard Care | Digit Span Test | Digit span forwards clamp1 | -1 Correct responses |
| Group 1 - Standard Care | Digit Span Test | Digit span forwards clamp 2 | 0 Correct responses |
| Group 1 - Standard Care | Digit Span Test | Digit span backwards clamp 1 | 0 Correct responses |
| Group 1 - Standard Care | Digit Span Test | Digit span backwards clamp 2 | 0 Correct responses |
| Group 2- Automated insulin delivery and low carbohydrate diet | Digit Span Test | Digit span backwards clamp 2 | 0 Correct responses |
| Group 2- Automated insulin delivery and low carbohydrate diet | Digit Span Test | Digit span forwards clamp1 | -1 Correct responses |
| Group 2- Automated insulin delivery and low carbohydrate diet | Digit Span Test | Digit span backwards clamp 1 | 0 Correct responses |
| Group 2- Automated insulin delivery and low carbohydrate diet | Digit Span Test | Digit span forwards clamp 2 | 0 Correct responses |
Comparison: Digit span forwardsp-value: 0.5Wilcoxon (Mann-Whitney)
Comparison: Digit span backwardsp-value: 0.5Wilcoxon (Mann-Whitney)
Comparison: Digit span forwardsp-value: 0.53Wilcoxon (Mann-Whitney)
p-value: 0.4Wilcoxon (Mann-Whitney)
Secondary
Digit Symbol Substitution Test
Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Difference in score between plateau 1 (5.0 mmol/L) and plateau 3 (2.5 mmol/L) compared between clamp studies. Given 90 seconds to complete as many items as possible. Higher scores mean more items completed in the allotted time.
Time frame: Clamp 1- study entry, clamp 2 - 8 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 - Standard Care | Digit Symbol Substitution Test | Delta score clamp 1 | -4.4 Correct responses | Standard Deviation 5.4 |
| Group 1 - Standard Care | Digit Symbol Substitution Test | Delta score clamp 2 | -6.6 Correct responses | Standard Deviation 13.7 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Digit Symbol Substitution Test | Delta score clamp 1 | 0.82 Correct responses | Standard Deviation 6.56 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Digit Symbol Substitution Test | Delta score clamp 2 | -4.0 Correct responses | Standard Deviation 7.1 |
p-value: 0.88Wilcoxon (Mann-Whitney)
p-value: 0.06t-test, 2 sided
Secondary
Endogenous Glucose Production
The change in the glucose rate of appearance from plateau 1 (5mmol/L) to plateau 3 (2.5 mmol/L)
Time frame: Clamp 1 at baseline and clamp 2 at 8 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 - Standard Care | Endogenous Glucose Production | Delta glucose rate of appearance P3-P1 Clamp 1 | -0.16 mg/kg/minute | Standard Deviation 0.21 |
| Group 1 - Standard Care | Endogenous Glucose Production | Delta glucose rate of appearance P3-P1 Clamp 2 | -0.22 mg/kg/minute | Standard Deviation 0.16 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Endogenous Glucose Production | Delta glucose rate of appearance P3-P1 Clamp 1 | -0.12 mg/kg/minute | Standard Deviation 0.16 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Endogenous Glucose Production | Delta glucose rate of appearance P3-P1 Clamp 2 | -0.8 mg/kg/minute | Standard Deviation 0.16 |
p-value: 0.38Wilcoxon (Mann-Whitney)
p-value: 0.88t-test, 2 sided
Secondary
Four Choice Reaction Time Test
Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Difference in score between plateau 1 (5.0mmol/L) and plateau 3 (2.5 mmol/L) compared between clamp studies. Higher scores mean more time taken to complete the task.
Time frame: Clamp 1- study entry, clamp 2 - 8 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 - Standard Care | Four Choice Reaction Time Test | Clamp 1 | 15.4 Time (ms) | Standard Deviation 7.4 |
| Group 1 - Standard Care | Four Choice Reaction Time Test | Clamp 2 | 52.9 Time (ms) | Standard Deviation 20.43 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Four Choice Reaction Time Test | Clamp 1 | 38.45 Time (ms) | Standard Deviation 63.21 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Four Choice Reaction Time Test | Clamp 2 | 57.78 Time (ms) | Standard Deviation 60.63 |
p-value: 0.38Wilcoxon (Mann-Whitney)
p-value: 0.27t-test, 2 sided
Secondary
HbA1c
Delta HbA1c from baseline to study endpoint.
Time frame: Baseline (study entry) endpoint (8 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1 - Standard Care | HbA1c | 0 mmol/mol |
| Group 2- Automated insulin delivery and low carbohydrate diet | HbA1c | -12 mmol/mol |
p-value: 0.0094Wilcoxon (Mann-Whitney)
Secondary
Hypoglycaemia Awareness
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. Higher scores mean more hypoglycaemia symptoms. The lowest possible score is 0 and the highest possible score is 119.
Time frame: Clamp 1 - study entry, clamp 2 - 8 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group 1 - Standard Care | Hypoglycaemia Awareness | Clamp 1 Plateau 1 | 24 Numerical score |
| Group 1 - Standard Care | Hypoglycaemia Awareness | Clamp 1 Plateau 2 | 35 Numerical score |
| Group 1 - Standard Care | Hypoglycaemia Awareness | Clamp 1 Plateau 3 | 39.64 Numerical score |
| Group 1 - Standard Care | Hypoglycaemia Awareness | Clamp 2 Plateau 1 | 34 Numerical score |
| Group 1 - Standard Care | Hypoglycaemia Awareness | Clamp 2 Plateau 2 | 34 Numerical score |
| Group 1 - Standard Care | Hypoglycaemia Awareness | Clamp 2 Plateau 3 | 46 Numerical score |
| Group 2- Automated insulin delivery and low carbohydrate diet | Hypoglycaemia Awareness | Clamp 2 Plateau 2 | 29 Numerical score |
| Group 2- Automated insulin delivery and low carbohydrate diet | Hypoglycaemia Awareness | Clamp 1 Plateau 1 | 27 Numerical score |
| Group 2- Automated insulin delivery and low carbohydrate diet | Hypoglycaemia Awareness | Clamp 2 Plateau 1 | 28 Numerical score |
| Group 2- Automated insulin delivery and low carbohydrate diet | Hypoglycaemia Awareness | Clamp 1 Plateau 2 | 25 Numerical score |
| Group 2- Automated insulin delivery and low carbohydrate diet | Hypoglycaemia Awareness | Clamp 2 Plateau 3 | 47 Numerical score |
| Group 2- Automated insulin delivery and low carbohydrate diet | Hypoglycaemia Awareness | Clamp 1 Plateau 3 | 34 Numerical score |
p-value: 0.77ANOVA
p-value: 0.37ANOVA
Secondary
The Change in Plasma Adrenaline (pg/mL) Levels Measured During Normoglycaemic and Hypoglycaemia
Delta adrenaline from plateau 1 (5mmol/L) to plateau 3 (2.5 mmol/L)
Time frame: Clamp 1 at baseline and clamp 2 at 8 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group 1 - Standard Care | The Change in Plasma Adrenaline (pg/mL) Levels Measured During Normoglycaemic and Hypoglycaemia | Clamp 1 | 260 Delta pg/mL |
| Group 1 - Standard Care | The Change in Plasma Adrenaline (pg/mL) Levels Measured During Normoglycaemic and Hypoglycaemia | Clamp 2 | 413 Delta pg/mL |
| Group 2- Automated insulin delivery and low carbohydrate diet | The Change in Plasma Adrenaline (pg/mL) Levels Measured During Normoglycaemic and Hypoglycaemia | Clamp 2 | 252.5 Delta pg/mL |
| Group 2- Automated insulin delivery and low carbohydrate diet | The Change in Plasma Adrenaline (pg/mL) Levels Measured During Normoglycaemic and Hypoglycaemia | Clamp 1 | 187 Delta pg/mL |
p-value: 0.63Wilcoxon (Mann-Whitney)
p-value: 0.36Wilcoxon (Mann-Whitney)
Secondary
The Change in Plasma Cortisol (ng/mL) Levels Measured During Normoglycaemic and Hypoglycaemia
Delta cortisol from P1 (5.0 mmol/L) to P3 (2.5 mmol/L)
Time frame: Clamp 1 at baseline and clamp 2 at 8 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 - Standard Care | The Change in Plasma Cortisol (ng/mL) Levels Measured During Normoglycaemic and Hypoglycaemia | Delta P3-P1 Clamp 1 | 146 ng/mL | Standard Error 126 |
| Group 1 - Standard Care | The Change in Plasma Cortisol (ng/mL) Levels Measured During Normoglycaemic and Hypoglycaemia | Delta P3-P1 Clamp 2 | 195.2 ng/mL | Standard Error 115.9 |
| Group 2- Automated insulin delivery and low carbohydrate diet | The Change in Plasma Cortisol (ng/mL) Levels Measured During Normoglycaemic and Hypoglycaemia | Delta P3-P1 Clamp 1 | 72.52 ng/mL | Standard Error 91.48 |
| Group 2- Automated insulin delivery and low carbohydrate diet | The Change in Plasma Cortisol (ng/mL) Levels Measured During Normoglycaemic and Hypoglycaemia | Delta P3-P1 Clamp 2 | 11.31 ng/mL | Standard Error 37.14 |
p-value: 0.13Wilcoxon (Mann-Whitney)
p-value: 0.01Wilcoxon (Mann-Whitney)
Secondary
The Change in Plasma Noradrenaline (pg/mL) Levels Measured During Normoglycaemic and Hypoglycaemia
The change in noradrenaline concentration from plateau 1 (5 mmol/L) to plateau 3 (2.5 mmol/L).
Time frame: Clamp 1 at baseline and clamp 2 at 8 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group 1 - Standard Care | The Change in Plasma Noradrenaline (pg/mL) Levels Measured During Normoglycaemic and Hypoglycaemia | Delta noradrenaline (P3-P1) Clamp 1 | 49 pg/mL |
| Group 1 - Standard Care | The Change in Plasma Noradrenaline (pg/mL) Levels Measured During Normoglycaemic and Hypoglycaemia | Delta noradrenaline (P3-P1) Clamp 2 | -43 pg/mL |
| Group 2- Automated insulin delivery and low carbohydrate diet | The Change in Plasma Noradrenaline (pg/mL) Levels Measured During Normoglycaemic and Hypoglycaemia | Delta noradrenaline (P3-P1) Clamp 1 | -10.56 pg/mL |
| Group 2- Automated insulin delivery and low carbohydrate diet | The Change in Plasma Noradrenaline (pg/mL) Levels Measured During Normoglycaemic and Hypoglycaemia | Delta noradrenaline (P3-P1) Clamp 2 | 90.5 pg/mL |
p-value: 0.44Wilcoxon (Mann-Whitney)
p-value: 0.02Wilcoxon (Mann-Whitney)
Secondary
Time in Glycaemic Range (3.9-10mmol/L)
Percentage time spent in target glycaemic range.
Time frame: Baseline (study entry), midpoint at 4 months and endpoint at 8 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 - Standard Care | Time in Glycaemic Range (3.9-10mmol/L) | Baseline | 51.46 Percentage | Standard Deviation 13.63 |
| Group 1 - Standard Care | Time in Glycaemic Range (3.9-10mmol/L) | Midpoint | 44.26 Percentage | Standard Deviation 11.5 |
| Group 1 - Standard Care | Time in Glycaemic Range (3.9-10mmol/L) | Endpoint | 39.64 Percentage | Standard Deviation 20.15 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Time in Glycaemic Range (3.9-10mmol/L) | Baseline | 53.55 Percentage | Standard Deviation 14.48 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Time in Glycaemic Range (3.9-10mmol/L) | Midpoint | 78.01 Percentage | Standard Deviation 6.32 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Time in Glycaemic Range (3.9-10mmol/L) | Endpoint | 76.85 Percentage | Standard Deviation 9.61 |
p-value: 0.37ANOVA
p-value: <0.0001ANOVA
Secondary
Time Spent Above the Target Glycaemic Range (>10mmol/L)
Percentage of time spent above the target glycaemic range
Time frame: Baseline (study entry), midpoint at 4 months and endpoint at 8 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 - Standard Care | Time Spent Above the Target Glycaemic Range (>10mmol/L) | Baseline | 21.94 Percentage | Standard Deviation 13.93 |
| Group 1 - Standard Care | Time Spent Above the Target Glycaemic Range (>10mmol/L) | Midpoint | 21.67 Percentage | Standard Deviation 13.55 |
| Group 1 - Standard Care | Time Spent Above the Target Glycaemic Range (>10mmol/L) | Endpoint | 23.42 Percentage | Standard Deviation 17.23 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Time Spent Above the Target Glycaemic Range (>10mmol/L) | Baseline | 33.64 Percentage | Standard Deviation 12.42 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Time Spent Above the Target Glycaemic Range (>10mmol/L) | Midpoint | 18.93 Percentage | Standard Deviation 4.66 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Time Spent Above the Target Glycaemic Range (>10mmol/L) | Endpoint | 19.06 Percentage | Standard Deviation 5.87 |
p-value: 0.58ANOVA
p-value: 0.01ANOVA
Secondary
Time Spent Below the Target Glycaemic Range (<3.9mmol/L)
Percentage of time spent below the target glycaemic range
Time frame: Baseline (study entry), midpoint at 4 months and endpoint at 8 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 - Standard Care | Time Spent Below the Target Glycaemic Range (<3.9mmol/L) | Baseline | 1.02 Percentage | Standard Deviation 0.62 |
| Group 1 - Standard Care | Time Spent Below the Target Glycaemic Range (<3.9mmol/L) | Midpoint | 2.25 Percentage | Standard Deviation 3.5 |
| Group 1 - Standard Care | Time Spent Below the Target Glycaemic Range (<3.9mmol/L) | Endpoint | 2.18 Percentage | Standard Deviation 3.85 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Time Spent Below the Target Glycaemic Range (<3.9mmol/L) | Baseline | 2.13 Percentage | Standard Deviation 3.17 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Time Spent Below the Target Glycaemic Range (<3.9mmol/L) | Midpoint | 0.94 Percentage | Standard Deviation 0.55 |
| Group 2- Automated insulin delivery and low carbohydrate diet | Time Spent Below the Target Glycaemic Range (<3.9mmol/L) | Endpoint | 0.74 Percentage | Standard Deviation 0.57 |
p-value: 0.2ANOVA
p-value: 0.95ANOVA
Secondary
Trial Making Test
Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Delta score plateau 1 (5 mmol/L) to plateau 3 (2.5 mmol/L) compared between clamp studies. Participants are timed completing the test. Higher scores indicate a longer time to complete the test.
Time frame: Clamp 1- study entry, clamp 2 - 8 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group 1 - Standard Care | Trial Making Test | Trail making A delta clamp 1 | -3.05 Minutes |
| Group 1 - Standard Care | Trial Making Test | Trail making A delta clamp 2 | -2.6 Minutes |
| Group 1 - Standard Care | Trial Making Test | Trail making B delta clamp 1 | 11.5 Minutes |
| Group 1 - Standard Care | Trial Making Test | Trail making B delta clamp 2 | 0.7 Minutes |
| Group 2- Automated insulin delivery and low carbohydrate diet | Trial Making Test | Trail making B delta clamp 2 | -5.6 Minutes |
| Group 2- Automated insulin delivery and low carbohydrate diet | Trial Making Test | Trail making A delta clamp 1 | 0.00 Minutes |
| Group 2- Automated insulin delivery and low carbohydrate diet | Trial Making Test | Trail making B delta clamp 1 | -7.8 Minutes |
| Group 2- Automated insulin delivery and low carbohydrate diet | Trial Making Test | Trail making A delta clamp 2 | -1.9 Minutes |
Comparison: Trail making A delta clamp 1 compared to clamp 2p-value: 0.88Wilcoxon (Mann-Whitney)
Comparison: Trail Making B delta clamp 1 compared to clamp 2p-value: 0.69Wilcoxon (Mann-Whitney)
Comparison: Trail making A delta clamp 1 compared to clamp 2p-value: 0.41Wilcoxon (Mann-Whitney)
Comparison: Trail making B delta clamp 1 compared to clamp 2p-value: 0.49t-test, 2 sided