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Trial · Interventional

CompletedNot applicableResults postedRegistry data

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

NCTNCT04614168 (opens ClinicalTrials.gov in a new tab)Other idAC19163
Open at ClinicalTrials.govAsk about this trial

This trial does not test a peptide that PepBank tracks.

  • Measures Glucagon, does not give it. It appears in an outcome measure.

Overview

Status
Completed
Phase
Not applicable
Enrollment
24 participants (actual)
Sponsor
University of Edinburgh · Other
Design
Randomized · Open label (no masking)
Countries
1 country

United Kingdom

Start
26 Jul 2021
Primary completion
22 Sept 2023
Completion
26 Dec 2025
First posted
3 Nov 2020
Last update posted
28 Jan 2026
Conditions
Type 1 Diabetes · Type 1 Diabetes Mellitus With Hypoglycemia · Hypoglycemia · Hypoglycemia Unawareness · Glucagon Deficiency · Insulin Hypoglycemia

Timeline

1 trial · 1 completed · 1 with posted results

  • Completed
  • Ongoing
  • Not yet recruiting
  • Stopped
  • Estimated dates (est.)
  • Results posted
202120222023202420252026
  1. N/A

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

    NCT04614168

    26 Jul 2021 to 26 Dec 2025

Registry summary

Text and fields below are the sponsor's entries at ClinicalTrials.gov, shown as posted.

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.

Interventions

  • Stepped hyperinsulinaemic-hypoglycaemic clamp studyProcedure
  • Insulin pumpDevice
  • Continuous glucose monitorDevice
  • Low carbohydrate dietOther
  • Blinded continuous glucose monitorDevice
  • Stable isotope studies- D2 Glucose and D5 GlycerolProcedure

Arms2

  • 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.

  • 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.

Primary outcomes1

Outcomes the sponsor listed as primary.

  1. The Change in Plasma Glucagon Levels (Pmol/L) Measured During Normoglycaemic and Hypoglycaemia

    Time frame · Clamp 1 at baseline and clamp 2 at 8 months

    Registry description

    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 outcomes(17)

  1. Time in Glycaemic Range (3.9-10mmol/L)

    Time frame · Baseline (study entry), midpoint at 4 months and endpoint at 8 months

    Registry description

    Percentage time spent in target glycaemic range.

  2. Time Spent Below the Target Glycaemic Range (<3.9mmol/L)

    Time frame · Baseline (study entry), midpoint at 4 months and endpoint at 8 months

    Registry description

    Percentage of time spent below the target glycaemic range

  3. Time Spent Above the Target Glycaemic Range (>10mmol/L)

    Time frame · Baseline (study entry), midpoint at 4 months and endpoint at 8 months

    Registry description

    Percentage of time spent above the target glycaemic range

  4. The Change in Plasma Cortisol (ng/mL) Levels Measured During Normoglycaemic and Hypoglycaemia

    Time frame · Clamp 1 at baseline and clamp 2 at 8 months

    Registry description

    Delta cortisol from P1 (5.0 mmol/L) to P3 (2.5 mmol/L)

  5. The Change in Plasma Adrenaline (pg/mL) Levels Measured During Normoglycaemic and Hypoglycaemia

    Time frame · Clamp 1 at baseline and clamp 2 at 8 months

    Registry description

    Delta adrenaline from plateau 1 (5mmol/L) to plateau 3 (2.5 mmol/L)

  6. The Change in Plasma Noradrenaline (pg/mL) Levels Measured During Normoglycaemic and Hypoglycaemia

    Time frame · Clamp 1 at baseline and clamp 2 at 8 months

    Registry description

    The change in noradrenaline concentration from plateau 1 (5 mmol/L) to plateau 3 (2.5 mmol/L).

  7. Endogenous Glucose Production

    Time frame · Clamp 1 at baseline and clamp 2 at 8 months

    Registry description

    The change in the glucose rate of appearance from plateau 1 (5mmol/L) to plateau 3 (2.5 mmol/L)

  8. HbA1c

    Time frame · Baseline (study entry) endpoint (8 months)

    Registry description

    Delta HbA1c from baseline to study endpoint.

  9. Change in Quality of Life at Trial Entry and End.

    Time frame · Baseline (study entry) endpoint (8 months)

    Registry description

    Measured using the EQ5D-5L- -VAS. Number on scale of 0-100 to assess wellbeing on that day. 100 being the most well.

  10. Change in Emotional Distress Related to Diabetes at Trial Entry and End.

    Time frame · Baseline (study entry) endpoint (8 months)

    Registry description

    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.

  11. Change in Fear of Hypoglycaemic

    Time frame · Baseline (study entry) endpoint (8 months)

    Registry description

    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.

  12. Change in Confidence of Managing Hypoglycaemia

    Time frame · Baseline (study entry) endpoint (8 months)

    Registry description

    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.

  13. Hypoglycaemia Awareness

    Time frame · Clamp 1 - study entry, clamp 2 - 8 months

    Registry description

    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.

  14. Trial Making Test

    Time frame · Clamp 1- study entry, clamp 2 - 8 months

    Registry description

    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.

  15. Digit Span Test

    Time frame · Clamp 1- study entry, clamp 2 - 8 months

    Registry description

    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.

  16. Digit Symbol Substitution Test

    Time frame · Clamp 1- study entry, clamp 2 - 8 months

    Registry description

    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.

  17. Four Choice Reaction Time Test

    Time frame · Clamp 1- study entry, clamp 2 - 8 months

    Registry description

    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.

Posted results

Values are shown as posted at ClinicalTrials.gov, with their units. PepBank has not converted, pooled or compared them.

Primary outcome results

Primary outcomeMedian· Clamp 1 at baseline and clamp 2 at 8 months

The Change in Plasma Glucagon Levels (Pmol/L) Measured During Normoglycaemic and Hypoglycaemia

GroupValue (pmol/L)
Group 1 - Standard Care1.34
Group 2- Automated Insulin Delivery and Low Carbohydrate Diet1.68
Secondary and other outcome results(7)
Secondary outcomeMean· Baseline (study entry), midpoint at 4 months and endpoint at 8 months

Time in Glycaemic Range (3.9-10mmol/L)

GroupValue (Percentage)Spread
Group 1 - Standard Care51.4613.63
Group 2- Automated Insulin Delivery and Low Carbohydrate Diet53.5514.48
Secondary outcomeMean· Baseline (study entry), midpoint at 4 months and endpoint at 8 months

Time Spent Below the Target Glycaemic Range (<3.9mmol/L)

GroupValue (Percentage)Spread
Group 1 - Standard Care1.020.62
Group 2- Automated Insulin Delivery and Low Carbohydrate Diet2.133.17
Secondary outcomeMean· Baseline (study entry), midpoint at 4 months and endpoint at 8 months

Time Spent Above the Target Glycaemic Range (>10mmol/L)

GroupValue (Percentage)Spread
Group 1 - Standard Care21.9413.93
Group 2- Automated Insulin Delivery and Low Carbohydrate Diet33.6412.42
Secondary outcomeMean· Clamp 1 at baseline and clamp 2 at 8 months

The Change in Plasma Cortisol (ng/mL) Levels Measured During Normoglycaemic and Hypoglycaemia

GroupValue (ng/mL)Spread
Group 1 - Standard Care146126
Group 2- Automated Insulin Delivery and Low Carbohydrate Diet72.5291.48
Secondary outcomeMedian· Clamp 1 at baseline and clamp 2 at 8 months

The Change in Plasma Adrenaline (pg/mL) Levels Measured During Normoglycaemic and Hypoglycaemia

GroupValue (Delta pg/mL)
Group 1 - Standard Care260
Group 2- Automated Insulin Delivery and Low Carbohydrate Diet187
Secondary outcomeMedian· Clamp 1 at baseline and clamp 2 at 8 months

The Change in Plasma Noradrenaline (pg/mL) Levels Measured During Normoglycaemic and Hypoglycaemia

GroupValue (pg/mL)
Group 1 - Standard Care49
Group 2- Automated Insulin Delivery and Low Carbohydrate Diet-10.56
Secondary outcomeMean· Clamp 1 at baseline and clamp 2 at 8 months

Endogenous Glucose Production

GroupValue (mg/kg/minute)Spread
Group 1 - Standard Care-0.160.21
Group 2- Automated Insulin Delivery and Low Carbohydrate Diet-0.120.16

Adverse events, as posted

Adverse events as posted: participants affected out of participants at risk, by group
GroupDeathsSerious eventsOther events
Group 1 - Standard CareStandard 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.0 / 50 / 50 / 5
Group 2- Automated Insulin Delivery and Low Carbohydrate DietAutomated 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.0 / 111 / 110 / 11

Each cell reads participants affected / participants at risk, as the registry posted them.

Registry data comes from ClinicalTrials.gov. Study results come from studies, not from the registry. How PepBank works

Studies0

Studies that cite this trial.

No study cites this trial.

Other registry references

References listed at the registry that are not in PepBank. They link to PubMed.

  • DerivedBaxter 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. PMID 36600427

Eligibility

Who could join, as posted.

Sex
All
Age
from 21 Years up to 65 Years
Healthy volunteers
Not accepted
Inclusion and exclusion criteria, as posted
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

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