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

• ClinicalTrials.gov Identifier: NCT02882737
• Recruitment Status: Completed
• First Posted: August 30, 2016
• Last Update Posted: July 24, 2017
• Sponsor: Hvidovre University Hospital
• Collaborator: Technical University of Denmark
• Information provided by (Responsible Party): Isabelle Steineck, Hvidovre University Hospital

Tracking Information

• First Submitted Date: August 17, 2016
• First Posted Date: August 30, 2016
• Last Update Posted Date: July 24, 2017
• Study Start Date: September 2016
• Actual Primary Completion Date: July 11, 2017 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: August 29, 2016): 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. [ Time Frame: 2 hours ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 29, 2016)

• The time-to-peak value after glucagon injection. [ Time Frame: 2 hours ]
• Duration of the glucagon effect; equal to the time point from glucagon injection to when plasma glucose is below baseline. [ Time Frame: 2 hours ]
• The glycaemic effect, calculated as the total area under the curve (tAUC) after each glucagon injection. [ Time Frame: 2 hours ]
• Changes in plasma ketone bodies after each glucagon injection. [ Time Frame: 2 hours ]
• Changes in plasma lactic acid after each glucagon injection [ Time Frame: 2 hours ]
• Changes in plasma glucagon after each glucagon injection [ Time Frame: 2 hours ]
• Changes in serum free fatty acid (FFA) after each glucagon injection [ Time Frame: 2 hours ]
• Changes in serum triglycerides after each glucagon injection [ Time Frame: 2 hours ]
• Number of events of hypoglycemia (plasma glucose ≤3.9 mmol/l) in the three study days. [ Time Frame: 3 hours ]
• Number of re-events of hypoglycemia (plasma glucose ≤3.9 mmol/l) 30 minutes after first event in the three study groups. [ Time Frame: 30 minutes ]
• Number of rebound hyperglycemia (plasma glucose ≥10.0 mmol/l). [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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 [ Time Frame: 6 hours ]
• MARD for the two sensor sites (CGMarm and CGMabdomen) from day 1- 7 with the Bayer Contour Link as the reference value. [ Time Frame: 7 days ]
• The rate-of change (ROC) of the two sensors. [ Time Frame: 6 hours ]
• The rate-of change (ROC) of plasma glucose measured by the YSI 2300 STAT PLUS. [ Time Frame: 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.) [ Time Frame: 7 days ]
• The sensors' sensitivity and specificity to detect a hypoglycemic event. [ Time Frame: 7 days ]
• The point accuracy of both sensors with the Clarke error grid analysis [ Time Frame: 7 days ]
• The pressure induced sensor attenuation (PISA) by using a recent fault detection algorithm that can detect non-physiologic anomalous low sensor readings. [ Time Frame: 7 days ]
• The fused data from the two sensors. [ Time Frame: 7 days ]
  Fused data will be compared with data from individual sensors

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Single (Participant); Primary Purpose: Prevention
• Condition: Type 1 Diabetes Mellitus

Intervention

• Drug: Glucagon before exercise
• Drug: Glucagon after exercise
• Drug: Glucagon after resting

Study Arms

• Experimental: Exercise and glucagon before exercise

  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.

  Intervention: Drug: Glucagon before exercise
• Active Comparator: Exercise and glucagon after exercise

  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.

  Intervention: Drug: Glucagon after exercise
• Active Comparator: Resting and glucagon after resting

  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.

  Intervention: Drug: Glucagon after resting

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 29, 2016): 14
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: July 11, 2017
• Actual Primary Completion Date: July 11, 2017 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 64 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Denmark

Administrative Information

• NCT Number: NCT02882737
• Other Study ID Numbers: 16016762
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Data are processed and merged into at least two scientific articles published in international peer-reviewed scientific journal. Positive, negative and inconclusive results will be published as soon as scientifically justifiable. The study protocol will be published at www.clinicaltrial.gov. The results from the study will within 1 year be published on EudraCT. The sponsor will contact the Danish Health and Medicines Authority within 90 days after the study is ended and to inform them that the study has ended

• Current Responsible Party: Isabelle Steineck, Hvidovre University Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Hvidovre University Hospital
• Original Study Sponsor: Same as current
• Collaborators: Technical University of Denmark

Investigators

• Principal Investigator: Isabelle Steineck, MD; Hvidovre Hospital department of endocrinology

• PRS Account: Hvidovre University Hospital
• Verification Date: September 2016