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

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Primary Purpose

Status

Completed

Phase

Not Applicable

Locations

Denmark

Study Type

Interventional

Intervention

Glucagon before exercise

Glucagon after exercise

Glucagon after resting

About this trial

This is an interventional prevention trial for Type 1 Diabetes Mellitus

Eligibility Criteria

18 Years - 64 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Isabelle Steineck

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Arm Label

Exercise and glucagon before exercise

Exercise and glucagon after exercise

Resting and glucagon after resting

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

The time-to-peak value after glucagon injection.

Duration of the glucagon effect; equal to the time point from glucagon injection to when plasma glucose is below baseline.

The glycaemic effect, calculated as the total area under the curve (tAUC) after each glucagon injection.

Changes in plasma ketone bodies after each glucagon injection.

Changes in plasma lactic acid after each glucagon injection

Changes in plasma glucagon after each glucagon injection

Changes in serum free fatty acid (FFA) after each glucagon injection

Changes in serum triglycerides after each glucagon injection

Number of events of hypoglycemia (plasma glucose ≤3.9 mmol/l) in the three study days.

Number of re-events of hypoglycemia (plasma glucose ≤3.9 mmol/l) 30 minutes after first event in the three study groups.

Number of rebound hyperglycemia (plasma glucose ≥10.0 mmol/l).

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.

Mean absolute relative difference (MARD) during the study visits between the two sensor sites with the YSI 2300 STAT PLUS as the reference value.

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.

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.

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

MARD for the two sensor sites (CGMarm and CGMabdomen) from day 1- 7 with the Bayer Contour Link as the reference value.

The rate-of change (ROC) of the two sensors.

The rate-of change (ROC) of plasma glucose measured by the YSI 2300 STAT PLUS.

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.)

The sensors' sensitivity and specificity to detect a hypoglycemic event.

The point accuracy of both sensors with the Clarke error grid analysis

The pressure induced sensor attenuation (PISA) by using a recent fault detection algorithm that can detect non-physiologic anomalous low sensor readings.

The fused data from the two sensors.

Fused data will be compared with data from individual sensors

Full Information

NCT ID

NCT02882737

First Posted

August 17, 2016

Last Updated

July 20, 2017

Sponsor

Hvidovre University Hospital

Collaborators

Technical University of Denmark

1. Study Identification

Unique Protocol Identification Number

NCT02882737

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2016

Overall Recruitment Status

Completed

Study Start Date

September 2016 (undefined)

Primary Completion Date

July 11, 2017 (Actual)

Study Completion Date

July 11, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Hvidovre University Hospital

Collaborators

Technical University of Denmark

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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: 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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Type 1 Diabetes Mellitus

7. Study Design

Primary Purpose

Prevention

Study Phase

Not Applicable

Interventional Study Model

Crossover Assignment

Masking

Participant

Allocation

Randomized

Enrollment

14 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Exercise and glucagon before exercise

Arm Type

Experimental

Arm Description

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.

Arm Title

Exercise and glucagon after exercise

Arm Type

Active Comparator

Arm Description

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.

Arm Title

Resting and glucagon after resting

Arm Type

Active Comparator

Arm Description

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 Type

Drug

Intervention Name(s)

Glucagon before exercise

Intervention Type

Drug

Intervention Name(s)

Glucagon after exercise

Intervention Type

Drug

Intervention Name(s)

Glucagon after resting

Primary Outcome Measure Information:

Title

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

Secondary Outcome Measure Information:

Title

The time-to-peak value after glucagon injection.

Time Frame

2 hours

Title

Duration of the glucagon effect; equal to the time point from glucagon injection to when plasma glucose is below baseline.

Time Frame

2 hours

Title

The glycaemic effect, calculated as the total area under the curve (tAUC) after each glucagon injection.

Time Frame

2 hours

Title

Changes in plasma ketone bodies after each glucagon injection.

Time Frame

2 hours

Title

Changes in plasma lactic acid after each glucagon injection

Time Frame

2 hours

Title

Changes in plasma glucagon after each glucagon injection

Time Frame

2 hours

Title

Changes in serum free fatty acid (FFA) after each glucagon injection

Time Frame

2 hours

Title

Changes in serum triglycerides after each glucagon injection

Time Frame

2 hours

Title

Number of events of hypoglycemia (plasma glucose ≤3.9 mmol/l) in the three study days.

Time Frame

3 hours

Title

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

Title

Number of rebound hyperglycemia (plasma glucose ≥10.0 mmol/l).

Time Frame

4 hours

Title

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

Title

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

Title

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

Title

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

Title

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

Title

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

Title

The rate-of change (ROC) of the two sensors.

Time Frame

6 hours

Title

The rate-of change (ROC) of plasma glucose measured by the YSI 2300 STAT PLUS.

Time Frame

6 hours

Title

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

Title

The sensors' sensitivity and specificity to detect a hypoglycemic event.

Time Frame

7 days

Title

The point accuracy of both sensors with the Clarke error grid analysis

Time Frame

7 days

Title

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

Title

The fused data from the two sensors.

Description

Fused data will be compared with data from individual sensors

Time Frame

7 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

64 Years

Accepts Healthy Volunteers

No

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Isabelle Steineck, MD

Organizational Affiliation

Hvidovre Hospital department of endocrinology

Official's Role

Principal Investigator

Facility Information:

Facility Name

Isabelle Steineck

City

Hvidovre

ZIP/Postal Code

2650

Country

Denmark

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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

Citations:

PubMed Identifier

30643924

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.

Results Reference

derived

Type 1 Diabetes Mellitus

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial