Micro Glucagon During Exercise in Type 1 Diabetes

Study Overview
=================
Brief Summary
-----------------
This proof-of-principle study to assess effects of different doses (mini and micro) of subcutaneous glucagon analog Dasiglucagon (Zealand Pharma, Copenhagen, Denmark) on the change in blood glucose concentration during moderate-intensity exercise in people with T1D.

Detailed Description
-----------------
People with type 1 diabetes (T1D) are recommended to engage in regular exercise for a variety of health and fitness reasons. However, moderate-intensity exercise is associated with an increased risk of hypoglycaemia in people with T1D. Current guidelines are to reduce insulin dose and/or increase carbohydrate consumption in the context of the exercise bout. However, despite the many advances in insulin formulations and delivery devices, hypoglycaemia remains a significant risk. Mini-dose glucagon taken before an exercise bout has been shown to be an effective non-caloric strategy to prevent exercise-induced hypoglycaemia. However, even the reduced doses (150-200 µg) used in previous studies might still be rather high translating into potential side-effects (i.e. hyperglycaemia, gastrointestinal symptoms, etc.). Lower doses (below 100 µg, micro-glucagon) may be sufficiently effective to counteract hypoglycaemia risk associated with exercise and associated with better tolerance. Moreover, there is little information on the effects of subcutaneous glucagon on glycogen stores and changes in exercise metabolism. Greater understanding of exercise-associated metabolism following mini- and micro-dose glucagon using techniques such as magnetic resonance spectroscopy (MRS), continuous glucose monitoring (CGM), stable isotope tracers, and indirect calorimetry may result in novel approaches to improve blood glucose management in people with T1D. Utilising these techniques may also further our understanding of the optimal glucagon dosing (timing and amount) during exercise to manage hypoglycaemia and reduce the risk of adverse events. Proof-of-principle study to assess effects of different doses (mini and micro) of subcutaneous glucagon analog Dasiglucagon (Zealand Pharma, Copenhagen, Denmark) on the change in blood glucose concentration during moderate-intensity exercise in people with T1D. Secondly, to investigate exercise-metabolism following Dasiglucagon injection using 3 tesla magnetic resonance spectroscopy (MRS) and indirect calorimetry. Third, to assess participant experience of Dasiglucagon during exercise and the incidence of adverse events.

Official Title
-----------------
Subcutaneous Dasiglucagon Use During Exercise In People With Type 1 Diabetes: Effects On Plasma Glucose And Exercise Metabolism

Conditions
-----------------
Type 1 Diabetes, Hypoglycemia

Intervention / Treatment
-----------------
* Drug: Micro-glucagon
* Drug: Mini-glucagon


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: T1D for >1 year Male aged 18-45 years old HbA1c <8.0% (64 mmol/mol) based on analysis from the central laboratory unit of Bern University Hospital Regular physical activity (defined as meeting 150 min moderate-intensity exercise per week) Using either continuous subcutaneous insulin infusion or multiple daily injections Written informed consent Exclusion Criteria: Physical or psychological disease likely to interfere with the normal conduct of the study and interpretation of the results as judged by the investigator Current treatment with drugs known to interfere with metabolism e.g. systemic corticosteroids, statins, SGLT2 inhibitors, GLP1 agonists Relevant diabetic complications as judged by the investigator Body mass index 30 kg/m2 Uncontrolled hypertension (>180/100 mmHg)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Time to hypoglycaemia during 60 minutes of aerobic exercise in individuals with type 1 diabetes using mini and micro doses of Dasiglucagon compared to no Dasiglucagon
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Micro-dose glucagon<br>80 µg (micro-dose) subcutaneous Dasiglucagon 5 min before the start of exercise | Drug: Micro-glucagon<br>* Administration of 80 µg (micro-dose) subcutaneous Dasiglucagon 5 min before the start of exercise<br>* Other names: Dasiglucagon;|
| Experimental: Mini-dose glucagon<br>150 µg mini-dose of subcutaneous Dasiglucagon 5 min before exercise the start of exercise | Drug: Mini-glucagon<br>* Administration of 150 µg (mini-dose) subcutaneous Dasiglucagon 5 min before the start of exercise<br>* Other names: Dasiglucagon;|
| No Intervention: No treatment<br>No treatment before the start of exercise | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to hypoglycaemia | Time (in minutes) to hypoglycaemia (plasma glucose <3.9mmol/l) during 60 minutes of aerobic exercise in individuals with type 1 diabetes using mini and micro doses of Dasiglucagon compared to no Dasiglucagon | 60 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in glycaemia during exercise | Change in blood glucose concentration, calculated based on the participants' glucose at the start of exercise and the last value measured at the end of exercise. If the exercise is stopped early because of hypoglycaemia, the last exercise glucose value will be used for analysis | 60 minutes | 
| Glucose during exercise | Mean glucose concentration and area under the glucose curve during exercise | 60 minutes | 
| Glucagon during exercise | Mean glucagon concentration and area under the glucagon curve during exercise | 60 minutes | 
| Time in target | Time in target glycaemic range (4-10 mmol/L) in the recovery period and overnight | 24 hours | 
| Time in target during exercise | Time in target glycaemic range (4-10 mmol/L) during exercise | 60 minutes | 
| Hypoglycaemia | Incidence of hypoglycaemia (≤3.9 mmol/L for 15 min or more) during the 24 hour post exercise recovery period | 24 hours | 
| Glycogen content | Change in skeletal muscle and hepatic glycogen following exercise | 4 hours | 
| Any adverse events | Adverse symptoms following glucagon/placebo use | 24 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
type 1 diabetes, glucagon, hypoglycemia, exercise, glycogen