Clinical trial NCT02882737: The Impact of Subcutaneous Glucagon Before, During and After Exercise a Study in Patients With Type 1 Diabetes Mellitus
Official title: The Impact of Subcutaneous Glucagon Before, During and After Exercise a Study in Patients With Type 1 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Type 1 Diabetes Mellitus
Lead sponsor: Hvidovre University Hospital
Sponsor class: OTHER
Collaborators: name: Technical University of Denmark
First posted: 2016-08-30
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: PREVENTION

Brief summary: 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:

1. To compare the increase in plasma glucose after 200µg glucagon given either after exercise or after resting for 45 minutes.
2. 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.
3. 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: 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:

1. Screening day
2. Run-in period
3. 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: 2 hours
Secondary outcomes:
measure: The time-to-peak value after glucagon injection.
timeFrame: 2 hours
measure: Duration of the glucagon effect; equal to the time point from glucagon injection to when plasma glucose is below baseline.
timeFrame: 2 hours
measure: The glycaemic effect, calculated as the total area under the curve (tAUC) after each glucagon injection.
timeFrame: 2 hours
measure: Changes in plasma ketone bodies after each glucagon injection.
timeFrame: 2 hours
measure: Changes in plasma lactic acid after each glucagon injection
timeFrame: 2 hours
measure: Changes in plasma glucagon after each glucagon injection
timeFrame: 2 hours
measure: Changes in serum free fatty acid (FFA) after each glucagon injection
timeFrame: 2 hours
measure: Changes in serum triglycerides after each glucagon injection
timeFrame: 2 hours
measure: Number of events of hypoglycemia (plasma glucose ≤3.9 mmol/l) in the three study days.
timeFrame: 3 hours
measure: Number of re-events of hypoglycemia (plasma glucose ≤3.9 mmol/l) 30 minutes after first event in the three study groups.
timeFrame: 30 minutes
measure: Number of rebound hyperglycemia (plasma glucose ≥10.0 mmol/l).
timeFrame: 4 hours
measure: 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.
timeFrame: 4 days
measure: Mean absolute relative difference (MARD) during the study visits between the two sensor sites with the YSI 2300 STAT PLUS as the reference value.
timeFrame: 6 hours
measure: 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.
timeFrame: 6 hours
measure: 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.
timeFrame: 6 hours
measure: 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
timeFrame: 6 hours
measure: MARD for the two sensor sites (CGMarm and CGMabdomen) from day 1- 7 with the Bayer Contour Link as the reference value.
timeFrame: 7 days
measure: The rate-of change (ROC) of the two sensors.
timeFrame: 6 hours
measure: The rate-of change (ROC) of plasma glucose measured by the YSI 2300 STAT PLUS.
timeFrame: 6 hours
measure: 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.)
timeFrame: 7 days
measure: The sensors' sensitivity and specificity to detect a hypoglycemic event.
timeFrame: 7 days
measure: The point accuracy of both sensors with the Clarke error grid analysis
timeFrame: 7 days
measure: The pressure induced sensor attenuation (PISA) by using a recent fault detection algorithm that can detect non-physiologic anomalous low sensor readings.
timeFrame: 7 days
measure: The fused data from the two sensors.
timeFrame: 7 days
Other outcomes:
Locations:
city: Hvidovre
country: Denmark
facility: Isabelle Steineck
Study officials:
affiliation: Hvidovre Hospital department of endocrinology
name: Isabelle Steineck, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Steineck IIK, Ranjan A, Schmidt S, Clausen TR, Holst JJ, Norgaard K. Preserved glucose response to low-dose glucagon after exercise in insulin-pump-treated individuals with type 1 diabetes: a randomised crossover study. Diabetologia. 2019 Apr;62(4):582-592. doi: 10.1007/s00125-018-4807-8. Epub 2019 Jan 14.