The Impact of Subcutaneous Glucagon Before, During and After Exercise a Study in Patients With Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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This project is part of several studies exploring situations, where glucagon potential has lesser glucose elevating effect. Exercise can be one of these situations as exercise may reduce liver glycogen depots. The investigators aims are: To compare the increase in plasma glucose after 200µg glucagon given either after exercise or after resting for 45 minutes. To determine whether a subcutaneous glucagon injection just before exercise has a greater impact on hepatic glucose production and thereby is superior to an injection after exercise in preventing hypoglycemia during and two hours after exercise. To compare the accuracy of two Dexcom G4 continuous glucose monitors, (CGM) placed at either the abdominal wall or on the upper arm.

Detailed Description
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Design: A randomized placebo-controlled single-blinded study will be conducted. The subjects do not know if they get glucagon or placebo but the investigator know if the subject get glucagon or placebo. Study participants have to complete three study days and serve as their own controls. After participants have given an informed consent, they will go through three steps: Screening day Run-in period Three study days in a random order: Exercise and glucagon injected after cycling/or during cycling in case of hypoglycemia Resting and glucagon after resting Exercise and glucagon subcutaneous before cycling 47-49 hours before the study visits one CGM device is placed on the abdominal wall on the participant at least 7 cm from the site of the insulin pump infusion set. One CGM is placed on the non-dominant upper arm between 10 cm from elbow and 10 cm from shoulder on the posterior/lateral side on the arm. The CGMs will be in place for seven days. The CGM readings on the CGM placed at the abdominal wall are not blinded for the participant. The CGM readings on the CGM placed on the arm is blinded for the participant. In the period from the study visits to 4 days after the study visits the participant will do self-monitoring of blood glucose 8 times a day on standardized times.

Official Title
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The Impact of Subcutaneous Glucagon Before, During and After Exercise a Study in Patients With Type 1 Diabetes Mellitus

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Drug: Glucagon before exercise
* Drug: Glucagon after exercise
* Drug: Glucagon after resting


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 Diabetes ≥ 2 year BMI 20-30 kg/m2 Insulin pump ≥ 1 year. HbA1c < 69 mmol/mol (8.5 %) Hypoglycemia awareness (reported by Gold et al.) Use of carbohydrate counting and the insulin pump bolus calculator for all meals Sedentary or mild physical activity: Less than 150 minutes of moderate-intensity aerobic physical activity throughout the week and less than 75 minutes of vigorous-intensity aerobic physical activity throughout the week . Exclusion Criteria: Allergy or intolerance to lactose or GlucaGen® (Novo Nordisk, Bagsværd, DK) Impaired renal function (eGFR < 60 ml/min/1.73m2) Liver disease with ALAT > 2.5 times the upper limit of the reference interval Use of anti-diabetic medicine (other than insulin), per oral corticosteroids or other drugs affecting glucose metabolism during the study period or within 30 days prior to study start Known or suspected alcohol or drug abuse Other concomitant medical or psychological condition that according to the investigator's assessment makes the patient unsuitable for study participation Females who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods Inability to understand the patient information and to give informed consent Physical or mental incapacity to perform exercise Chronic use or unable to stop acetaminophen (paracetamol) use Allergy to the patch of CGM

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exercise and glucagon before exercise<br>120 minutes after breakfast; a single subcutaneous bolus of 200µg glucagon is administered by the primary investigator. However, the patient do, not know whether placebo or a glucagon injection is administered. Exercise: Immediately thereafter, the patient will bicycle for 45 minutes at 50% of the heart rate HR reserve. When exercise is ended a single subcutaneous bolus of 0.2 ml saline is administered and the exercise session will be suspended. Again, the patient do not know whether placebo or a glucagon is administered. | Drug: Glucagon before exercise<br> <br> |
| Active Comparator: Exercise and glucagon after exercise<br>120 minutes after breakfast; a single subcutaneous bolus of 0.2 ml saline is administered by the primary investigator. However, the patient do, not know whether placebo or a glucagon injection is administered. Exercise: Immediately thereafter, the patient will bicycle for 45 minutes at 50% of the heart rate HR reserve. Low-dose glucagon phase: When exercise is ended or when hypoglycemia occurs (≤3.9 mmol/l); a single subcutaneous bolus of 200μg glucagon is administered and the exercise session will be suspended. Again, the patient do not know whether placebo or a glucagon is administered. | Drug: Glucagon after exercise<br> <br> |
| Active Comparator: Resting and glucagon after resting<br>120 minutes after breakfast; a single subcutaneous bolus of 200μg placebo is administered. Resting: After placebo injection the patient will be resting on a hospital bed for 45 minutes. The patient do not know if placebo or glucagon is administered. Low-dose glucagon phase: After 45 minutes of resting or when hypoglycemia occurs, a single subcutaneous bolus of 200μg glucagon is administered. Safety issues: If plasma glucose drops < 2.5 mmol/l at two consecutive measurements with 5 min interval or the patient experiences unbearable symptoms of hypoglycemia even after glucagon administration, 20 g carbohydrate is given orally. If plasma glucose drops< 2.3 mmol/l or doesn't raise sufficient after oral glucose, we will give intravenøs glucose to the patient. The study will then end and a new study day will be planned. | Drug: Glucagon after resting<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary endpoint is peak plasma glucose achieved within 2 hours after the 200 μg subcutaneous glucagon injection. In the primary analysis, the investigators will compare the peak plasma glucose after exercise and after resting. |  | 2 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The time-to-peak value after glucagon injection. |  | 2 hours | 
| Duration of the glucagon effect; equal to the time point from glucagon injection to when plasma glucose is below baseline. |  | 2 hours | 
| The glycaemic effect, calculated as the total area under the curve (tAUC) after each glucagon injection. |  | 2 hours | 
| Changes in plasma ketone bodies after each glucagon injection. |  | 2 hours | 
| Changes in plasma lactic acid after each glucagon injection |  | 2 hours | 
| Changes in plasma glucagon after each glucagon injection |  | 2 hours | 
| Changes in serum free fatty acid (FFA) after each glucagon injection |  | 2 hours | 
| Changes in serum triglycerides after each glucagon injection |  | 2 hours | 
| Number of events of hypoglycemia (plasma glucose ≤3.9 mmol/l) in the three study days. |  | 3 hours | 
| Number of re-events of hypoglycemia (plasma glucose ≤3.9 mmol/l) 30 minutes after first event in the three study groups. |  | 30 minutes | 
| Number of rebound hyperglycemia (plasma glucose ≥10.0 mmol/l). |  | 4 hours | 
| Mean absolute difference (MARD) in the two CGM sites during the four days after the study day using the daily 8 prespecified plasma glucose measurements by Bayer Contour Link as the reference value. |  | 4 days | 
| Mean absolute relative difference (MARD) during the study visits between the two sensor sites with the YSI 2300 STAT PLUS as the reference value. |  | 6 hours | 
| MARD during the hypoglycemia range (≤3.9 mmol/l) of the study visits between the two sensor sites (CGMarm vs. CGMabdomen) with the YSI 2300 STAT PLUS as the reference value. |  | 6 hours | 
| MARD during the euglycemia range (>3.9 mmol/l and < 10.0 mmol/l) of the study visits between the two sensor sites (CGMarm vs. CGMabdomen) with the YSI 2300 STAT PLUS as the reference. |  | 6 hours | 
| MARD during the hyperglycemia range (≥10.0 mmol/l) of the study visits for the two Dexcom G4 sensor sites (CGMarm vs. CGMabdomen) with the YSI 2300 STAT PLUS as the reference value |  | 6 hours | 
| MARD for the two sensor sites (CGMarm and CGMabdomen) from day 1- 7 with the Bayer Contour Link as the reference value. |  | 7 days | 
| The rate-of change (ROC) of the two sensors. |  | 6 hours | 
| The rate-of change (ROC) of plasma glucose measured by the YSI 2300 STAT PLUS. |  | 6 hours | 
| The Precision Absolute Relative Difference (=CGM readings of one system will be subtracted from CGM readings of the other system, and this difference will be divided by the average of the CGM readings of the abdominal sensors.) |  | 7 days | 
| The sensors' sensitivity and specificity to detect a hypoglycemic event. |  | 7 days | 
| The point accuracy of both sensors with the Clarke error grid analysis |  | 7 days | 
| The pressure induced sensor attenuation (PISA) by using a recent fault detection algorithm that can detect non-physiologic anomalous low sensor readings. |  | 7 days | 
| The fused data from the two sensors. | Fused data will be compared with data from individual sensors | 7 days |