The Use of Mini-dose Glucagon to Prevent Exercise-induced Hypoglycemia in Type 1 Diabetes

• Sponsor: Jaeb Center for Health Research (Other)
• Overall Status: Completed
• CT.gov ID: NCT02660242
• Collaborator: Xeris Pharmaceuticals (Industry)
• Enrollment: 16
• Locations: 2
• Arms: 4
• Duration (Months): 13.5
• Patients Per Site: 8
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This project focuses on development of new strategy for the prevention of exercise-associated hypoglycemia using mini-dose glucagon.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 1	Drug: G-Pen Mini™ (glucagon injection); Other: Glucose Tabs; Other: Basal Insulin Reduction	Phase 2

Detailed Description

The primary objective of the protocol is to determine if the administration of mini-dose glucagon administered subcutaneously just before exercise produces better glucose stability than no adjustments for moderate intensity exercise in patients with Type 1 Diabetes (T1D). It will also be assessed whether mini-dose glucagon before exercise produces better glucose stability than basal insulin reductions or extra carbohydrate consumption.

This is a randomized, 4-way crossover trial. The trial will include 16 participants who complete the study.

Each participant will undergo four aerobic exercise sessions (in random order), with different strategies for glucose regulation:

• Control Trial: Fasted exercise, no basal insulin reduction

• Strategy 1: Fasted exercise, basal insulin reduction only (50% reduction in basal rate at 60 minutes before exercise, for the duration of the exercise)

• Strategy 2: Fasted exercise, no basal adjustment + pre-exercise glucose tabs (buccal route-40 grams in total )

• Strategy 3: Fasted exercise, no basal adjustment + pre-exercise mini-dose glucagon (sc)

In all 4 sessions, aerobic exercise will be performed in the fasted state (before a standardized meal) for 45 minuets at ~50-55% of the participant's per-determined aerobic capacity. The participant's pump will be blinded during the control trial, strategy 1, and strategy 3 and an injection of saline will be given during the control trial and strategy 1 so that participant is blinded to strategy.

The primary outcome for this study will be the glycemic response during exercise and early recovery.

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Participant)
• Primary Purpose: Prevention
• Official Title: The Use of Mini-dose Glucagon to Prevent Exercise-induced Hypoglycemia in Type 1 Diabetes
• Study Start Date: Jan 1, 2016
• Actual Primary Completion Date: Feb 15, 2017
• Actual Study Completion Date: Feb 15, 2017

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Control No basal insulin adjustment, no carbohydrate intake (until glucose drops <70 mg/dL).
Active Comparator: Basal insulin reduction Basal insulin reduction to 50% five minutes before the start of exercise.	Other: Basal Insulin Reduction; Basal insulin reduction to 50% 5 minutes before the start of exercise.
Active Comparator: Glucose Tabs Dextrose tabs orally (20 grams) five minutes before the start of exercise and at 30 minutes of exercise (total 40 grams).	Other: Glucose Tabs; Dextrose tabs orally (20 grams) 5 minutes before the start of exercise and at 30 minutes of exercise (total 40 grams).; Other Names: over-the-counter oral glucose tablets
Experimental: G-Pen Mini™ (glucagon injection) Glucagon (150 µg) five minutes before the start of exercise (SQ-abdomen).	Drug: G-Pen Mini™ (glucagon injection); Glucagon (150 µg) 5 minutes before the start of exercise (SQ-abdomen).; Other Names: mini-dose glucagon

Outcome Measures

Primary Outcome Measures

1. Glycemic Response During Exercise and Early Recovery [0 to 75 minutes following exercise initiation (0, 5, 10, 15, 25, 35, 45, 50, 55, 60, 75 min)]

   Comparison of glycemic response (from blood glucose) during exercise and early recovery between each exercise strategy.

Secondary Outcome Measures

1. Number of Participants With Hypoglycemia (<70 mg/dL) During Exercise and Early Recovery [0 to 75 minutes following exercise initiation]

   Comparison of occurrence of hypoglycemia (<70 mg/dL from blood glucose) during exercise and early recovery between each exercise strategy.

2. Number of Participants With Hyperglycemia (≥250 mg/dL) During Exercise and Early Recovery [0 to 75 minutes following exercise initiation]

   Comparison of occurrence of hyperglycemia (≥250 mg/dL from blood glucose) during exercise and early recovery between each exercise strategy.

3. Continuous Glucose Monitor (CGM) Metrics During Late Recovery - Nadir Glucose [90 min after the standard meal until 1200 noon the day after each exercise session]

   Comparison of nadir glucose from CGM between the exercise strategies.

4. CGM Metrics During Late Recovery - Peak Glucose [90 min after the standard meal until 1200 noon the day after each exercise session]

   Comparison of peak glucose from CGM between the exercise strategies.

5. CGM Metrics During Late Recovery - Mean Glucose [90 min after the standard meal until 1200 noon the day after each exercise session]

   Comparison of mean glucose from CGM between the exercise strategies.

6. CGM Metrics During Late Recovery - Coefficient of Variation [90 min after the standard meal until 1200 noon the day after each exercise session]

   Comparison of the coefficient of variation from CGM between the exercise strategies.

7. CGM Metrics During Late Recovery - Time < 54 mg/dL [90 min after the standard meal until 1200 noon the day after each exercise session]

   Comparison of percentage of time < 54 mg/dL from CGM between the exercise strategies.

8. CGM Metrics During Late Recovery - Time < 70 mg/dL [90 min after the standard meal until 1200 noon the day after each exercise session]

   Comparison of percentage of time < 70 mg/dL from CGM between the exercise strategies.

9. CGM Metrics During Late Recovery - Time in Range (70-180 mg/dL) [90 min after the standard meal until 1200 noon the day after each exercise session]

   Comparison of percentage of time in range (70-180 mg/dL) from CGM between the exercise strategies.

10. CGM Metrics During Late Recovery - Time > 180 mg/dL [90 min after the standard meal until 1200 noon the day after each exercise session]

    Comparison of percentage of time > 180 mg/dL from CGM between the exercise strategies.

11. CGM Metrics During Late Recovery - Time > 250 mg/dL [90 min after the standard meal until 1200 noon the day after each exercise session]

    Comparison of percentage of time > 250 mg/dL from CGM between the exercise strategies.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Clinical diagnosis of presumed autoimmune type 1 diabetes, receiving daily insulin

2. Age 18-<65 years

3. Duration of T1D ≥ 2 years

4. Random C-peptide < 0.6 ng/ml

5. Using continuous subcutaneous insulin infusion (CSII; insulin pump) for at least 6 months, with no plans to discontinue pump use during the study

6. Exercises regularly, i.e. ≥30 minutes moderate or more vigorous aerobic activity X ≥3 times/week

7. Body mass index (BMI) <30 kg/m2

8. Females must meet one of the following criteria:

• Of childbearing potential and not currently pregnant or lactating, and agrees to use an accepted contraceptive regimen as described in the study procedure manual throughout the entire duration of the study; or

• Of non-childbearing potential, defined as a female who has had a hysterectomy or tubal ligation, is clinically considered infertile or is in a menopausal state (at least 1 year without menses)

1. In good general health with no conditions that could influence the outcome of the trial, and in the judgment of the investigator is a good candidate for the study based on review of available medical history, physical examination and clinical laboratory evaluations

2. Willing to adhere to the protocol requirements for the duration of the study

3. Must be enrolled in the T1D Exchange clinic registry or willing to join the registry

Exclusion Criteria:

1. One or more severe hypoglycemic episodes in the past 12 months (as defined by an episode that required third party assistance for treatment)

2. Active diabetic retinopathy (proliferative diabetic retinopathy or vitreous hemorrhage in past 6 months) that could potentially be worsened by exercise protocol

3. Peripheral neuropathy with insensate feet

4. Cardiovascular autonomic neuropathy with inappropriate heart rate response to exercise

5. Use of non-insulin anti-diabetic medications

6. Use of beta-blockers

7. Use of agents that affect hepatic glucose production such as beta adrenergic agonists, xanthine derivatives

8. Use of Pramlintide

9. Currently following a very low calorie or other weight-loss diet

10. Participation in other studies involving administration of an investigational drug or device within 30 days or 5 half-lives, whichever is longer, before screening for the current study or planning to participate in another such study during participation in the current study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Joslin Diabetes Center	Boston	Massachusetts	United States	02215
2	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• Jaeb Center for Health Research
• Xeris Pharmaceuticals

Investigators

• Study Chair: Michael Riddell, PhD, York University
• Study Chair: Michael Rickels, M.D., M.S., University of Pennsylvania
• Study Chair: Howard Wolpert, M.D., Joslin Diabetes Center
• Principal Investigator: Stephanie DuBose, M.P.H, Jaeb Center for Health Research

Study Documents (Full-Text)

• Study Protocol - Apr 14, 2016
• Statistical Analysis Plan - Feb 24, 2017

More Information

Publications

• Brazeau AS, Rabasa-Lhoret R, Strychar I, Mircescu H. Barriers to physical activity among patients with type 1 diabetes. Diabetes Care. 2008 Nov;31(11):2108-9. doi: 10.2337/dc08-0720. Epub 2008 Aug 8.
• Camacho RC, Galassetti P, Davis SN, Wasserman DH. Glucoregulation during and after exercise in health and insulin-dependent diabetes. Exerc Sport Sci Rev. 2005 Jan;33(1):17-23. Review.
• Campbell MD, Walker M, Trenell MI, Jakovljevic DG, Stevenson EJ, Bracken RM, Bain SC, West DJ. Large pre- and postexercise rapid-acting insulin reductions preserve glycemia and prevent early- but not late-onset hypoglycemia in patients with type 1 diabetes. Diabetes Care. 2013 Aug;36(8):2217-24. doi: 10.2337/dc12-2467. Epub 2013 Mar 20.
• Campbell MD, Walker M, Trenell MI, Luzio S, Dunseath G, Tuner D, Bracken RM, Bain SC, Russell M, Stevenson EJ, West DJ. Metabolic implications when employing heavy pre- and post-exercise rapid-acting insulin reductions to prevent hypoglycaemia in type 1 diabetes patients: a randomised clinical trial. PLoS One. 2014 May 23;9(5):e97143. doi: 10.1371/journal.pone.0097143. eCollection 2014.
• Chu L, Hamilton J, Riddell MC. Clinical management of the physically active patient with type 1 diabetes. Phys Sportsmed. 2011 May;39(2):64-77. doi: 10.3810/psm.2011.05.1896. Review.
• Diabetes Research in Children Network (DirecNet) Study Group, Tsalikian E, Kollman C, Tamborlane WB, Beck RW, Fiallo-Scharer R, Fox L, Janz KF, Ruedy KJ, Wilson D, Xing D, Weinzimer SA. Prevention of hypoglycemia during exercise in children with type 1 diabetes by suspending basal insulin. Diabetes Care. 2006 Oct;29(10):2200-4.
• Haymond MW, Schreiner B. Mini-dose glucagon rescue for hypoglycemia in children with type 1 diabetes. Diabetes Care. 2001 Apr;24(4):643-5.
• Oskarsson PR, Lins PE, Wallberg Henriksson H, Adamson UC. Metabolic and hormonal responses to exercise in type 1 diabetic patients during continuous subcutaneous, as compared to continuous intraperitoneal, insulin infusion. Diabetes Metab. 1999 Dec;25(6):491-7.
• Rabasa-Lhoret R, Bourque J, Ducros F, Chiasson JL. Guidelines for premeal insulin dose reduction for postprandial exercise of different intensities and durations in type 1 diabetic subjects treated intensively with a basal-bolus insulin regimen (ultralente-lispro). Diabetes Care. 2001 Apr;24(4):625-30.
• Riddell MC, Bar-Or O, Ayub BV, Calvert RE, Heigenhauser GJ. Glucose ingestion matched with total carbohydrate utilization attenuates hypoglycemia during exercise in adolescents with IDDM. Int J Sport Nutr. 1999 Mar;9(1):24-34.
• Robertson K, Riddell MC, Guinhouya BC, Adolfsson P, Hanas R; International Society for Pediatric and Adolescent Diabetes. ISPAD Clinical Practice Consensus Guidelines 2014. Exercise in children and adolescents with diabetes. Pediatr Diabetes. 2014 Sep;15 Suppl 20:203-23. doi: 10.1111/pedi.12176.
• Stenerson M, Cameron F, Payne SR, Payne SL, Ly TT, Wilson DM, Buckingham BA. The impact of accelerometer use in exercise-associated hypoglycemia prevention in type 1 diabetes. J Diabetes Sci Technol. 2015 Jan;9(1):80-5. doi: 10.1177/1932296814551045. Epub 2014 Sep 17.
• Tanenberg RJ, Newton CA, Drake AJ. Confirmation of hypoglycemia in the "dead-in-bed" syndrome, as captured by a retrospective continuous glucose monitoring system. Endocr Pract. 2010 Mar-Apr;16(2):244-8. doi: 10.4158/EP09260.CR.
• Taplin CE, Cobry E, Messer L, McFann K, Chase HP, Fiallo-Scharer R. Preventing post-exercise nocturnal hypoglycemia in children with type 1 diabetes. J Pediatr. 2010 Nov;157(5):784-8.e1. doi: 10.1016/j.jpeds.2010.06.004. Epub 2010 Jul 21.
• Tsalikian E, Mauras N, Beck RW, Tamborlane WV, Janz KF, Chase HP, Wysocki T, Weinzimer SA, Buckingham BA, Kollman C, Xing D, Ruedy KJ; Diabetes Research In Children Network Direcnet Study Group. Impact of exercise on overnight glycemic control in children with type 1 diabetes mellitus. J Pediatr. 2005 Oct;147(4):528-34.
• West DJ, Morton RD, Bain SC, Stephens JW, Bracken RM. Blood glucose responses to reductions in pre-exercise rapid-acting insulin for 24 h after running in individuals with type 1 diabetes. J Sports Sci. 2010 May;28(7):781-8. doi: 10.1080/02640411003734093.

• Responsible Party: Jaeb Center for Health Research
• ClinicalTrials.gov Identifier: NCT02660242
• Other Study ID Numbers: T1DX Mini-dose Exercise
• First Posted: Jan 21, 2016
• Last Update Posted: Mar 3, 2020
• Last Verified: Feb 1, 2020

• Keywords provided by Jaeb Center for Health Research: T1D; Type 1 Diabetes; Mini-dose Glucagon; Adults; Exercise; Hypoglycemia
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia; Glucagon; Glucagon-Like Peptide 1

Study Results

Participant Flow

Arm/Group Title	MIni-dose Glucagon Crossover Trial
Arm/Group Description	Each participant will undergo four aerobic exercise sessions (in random order) of a) a Control Trial: Fasted exercise, no basal insulin reduction; b) Strategy 1: Fasted exercise, basal insulin reduction only (50% reduction in basal rate five minutes before exercise, for the duration of the exercise); c) Strategy 2: Fasted exercise, no basal adjustment + pre-exercise and mid-exercise glucose tabs (buccal route-40 grams in total); d) Strategy 3: Fasted exercise, no basal adjustment + pre-exercise mini-dose glucagon (sc). Each period includes 0-165 minutes in the lab and the participant continues to wear a continuous glucose monitor during the afternoon, overnight, and through noon the following day.
Period Title: Control
STARTED	16
COMPLETED	16
NOT COMPLETED	0
Period Title: Control
STARTED	16
COMPLETED	16
NOT COMPLETED	0
Period Title: Control
STARTED	16
COMPLETED	15
NOT COMPLETED	1
Period Title: Control
STARTED	16
COMPLETED	15
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	Includes all patients who completed the crossover trial.
Overall Participants	15
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	30
Sex: Female, Male (Count of Participants)
Female	6 40%
Male	9 60%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 13.3%
Not Hispanic or Latino	12 80%
Unknown or Not Reported	1 6.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 6.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	14 93.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Type 1 Diabetes Duration, Continuous (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	22
HbA1c (%) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [%]	6.8
Body Mass Index (BMI) (kg/m^2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m^2]	24
VO2Max (mL/kg/min) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mL/kg/min]	42

Outcome Measures

1. Primary Outcome

Title	Glycemic Response During Exercise and Early Recovery
Description	Comparison of glycemic response (from blood glucose) during exercise and early recovery between each exercise strategy.
Time Frame	0 to 75 minutes following exercise initiation (0, 5, 10, 15, 25, 35, 45, 50, 55, 60, 75 min)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Basal Insulin Reduction	Glucose Tabs	G-Pen Mini™ (Glucagon Injection)
Arm/Group Description	No basal insulin adjustment, no carbohydrate intake (until glucose drops <70 mg/dL).	Basal insulin reduction to 50% 5 minutes before the start of exercise.	Dextrose tabs orally (20 grams) 5 minutes before the start of exercise and at 30 minutes of exercise (total 40 grams).	Glucagon (150 µg) 5 minutes before the start of exercise (SQ-abdomen).
Measure Participants	15	15	15	15
Plasma Glucose Concentration (End of Exercise)	86 (30)	85 (25)	174 (59)	161 (39)
Plasma Glucose Concentration (End Early Recovery)	90 (34)	92 (34)	222 (66)	163 (49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Basal Insulin Reduction, Glucose Tabs, G-Pen Mini™ (Glucagon Injection)
	Comments	The mini-dose glucagon (MDG) condition was compared with each of the conditions. In the event that exercise was terminated early due to glucose <70 mg/dL and the participant was treated for hypoglycemia (or if participant was treated for hypoglycemia during early recovery [prior to the meal]), the nadir glucose value was carried forward through the end of early recovery.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed model w/ repeated measures to account for correlation from cross-over design and multiple measures, adjusting for baseline glucose and period.

2. Secondary Outcome

Title	Number of Participants With Hypoglycemia (<70 mg/dL) During Exercise and Early Recovery
Description	Comparison of occurrence of hypoglycemia (<70 mg/dL from blood glucose) during exercise and early recovery between each exercise strategy.
Time Frame	0 to 75 minutes following exercise initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Basal Insulin Reduction	Glucose Tabs	G-Pen Mini™ (Glucagon Injection)
Arm/Group Description	No basal insulin adjustment, no carbohydrate intake (until glucose drops <70 mg/dL).	Basal insulin reduction to 50% 5 minutes before the start of exercise.	Dextrose tabs orally (20 grams) 5 minutes before the start of exercise and at 30 minutes of exercise (total 40 grams).	Glucagon (150 µg) 5 minutes before the start of exercise (SQ-abdomen).
Measure Participants	15	15	15	15
Count of Participants [Participants]	6 40%	5 NaN	0 NaN	0 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Basal Insulin Reduction, Glucose Tabs, G-Pen Mini™ (Glucagon Injection)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.99
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted for subject effect, exercise session, and baseline blood glucose

3. Secondary Outcome

Title	Number of Participants With Hyperglycemia (≥250 mg/dL) During Exercise and Early Recovery
Description	Comparison of occurrence of hyperglycemia (≥250 mg/dL from blood glucose) during exercise and early recovery between each exercise strategy.
Time Frame	0 to 75 minutes following exercise initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Basal Insulin Reduction	Glucose Tabs	G-Pen Mini™ (Glucagon Injection)
Arm/Group Description	No basal insulin adjustment, no carbohydrate intake (until glucose drops <70 mg/dL).	Basal insulin reduction to 50% 5 minutes before the start of exercise.	Dextrose tabs orally (20 grams) 5 minutes before the start of exercise and at 30 minutes of exercise (total 40 grams).	Glucagon (150 µg) 5 minutes before the start of exercise (SQ-abdomen).
Measure Participants	15	15	15	15
Count of Participants [Participants]	0 0%	0 NaN	5 NaN	1 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Basal Insulin Reduction, Glucose Tabs, G-Pen Mini™ (Glucagon Injection)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.15
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted for subject effect, exercise session, and baseline blood glucose

4. Secondary Outcome

Title	Continuous Glucose Monitor (CGM) Metrics During Late Recovery - Nadir Glucose
Description	Comparison of nadir glucose from CGM between the exercise strategies.
Time Frame	90 min after the standard meal until 1200 noon the day after each exercise session

Outcome Measure Data

Analysis Population Description

Included data were limited to periods with at least 12 hours of CGM data.

Arm/Group Title	Control	Basal Insulin Reduction	Glucose Tabs	G-Pen Mini™ (Glucagon Injection)
Arm/Group Description	No basal insulin adjustment, no carbohydrate intake (until glucose drops <70 mg/dL).	Basal insulin reduction to 50% five minutes before the start of exercise.	Dextrose tabs orally (20 grams) five minutes before the start of exercise and at 30 minutes of exercise (total 40 grams).	Glucagon (150 µg) five minutes before the start of exercise (SQ-abdomen).
Measure Participants	14	13	13	14
Median (Inter-Quartile Range) [mg/dL]	45	44	49	51

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Basal Insulin Reduction, Glucose Tabs, G-Pen Mini™ (Glucagon Injection)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.99
	Comments
	Method	Mixed Models Analysis
	Comments	Accounted for correlation due to cross-over design and adjusted for exercise session

5. Secondary Outcome

Title	CGM Metrics During Late Recovery - Peak Glucose
Description	Comparison of peak glucose from CGM between the exercise strategies.
Time Frame	90 min after the standard meal until 1200 noon the day after each exercise session

Outcome Measure Data

Analysis Population Description

Included data were limited to periods with at least 12 hours of CGM data.

Arm/Group Title	Control	Basal Insulin Reduction	Glucose Tabs	G-Pen Mini™ (Glucagon Injection)
Arm/Group Description	No basal insulin adjustment, no carbohydrate intake (until glucose drops <70 mg/dL).	Basal insulin reduction to 50% 5 minutes before the start of exercise.	Dextrose tabs orally (20 grams) 5 minutes before the start of exercise and at 30 minutes of exercise (total 40 grams).	Glucagon (150 µg) 5 minutes before the start of exercise (SQ-abdomen).
Measure Participants	14	13	13	14
Median (Inter-Quartile Range) [mg/dL]	241	239	267	269

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Basal Insulin Reduction, Glucose Tabs, G-Pen Mini™ (Glucagon Injection)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.43
	Comments
	Method	Mixed Models Analysis
	Comments	Accounted for correlation due to cross-over design and adjusted for exercise session

6. Secondary Outcome

Title	CGM Metrics During Late Recovery - Mean Glucose
Description	Comparison of mean glucose from CGM between the exercise strategies.
Time Frame	90 min after the standard meal until 1200 noon the day after each exercise session

Outcome Measure Data

Analysis Population Description

Included data were limited to periods with at least 12 hours of CGM data.

Arm/Group Title	Control	Basal Insulin Reduction	Glucose Tabs	G-Pen Mini™ (Glucagon Injection)
Arm/Group Description	No basal insulin adjustment, no carbohydrate intake (until glucose drops <70 mg/dL).	Basal insulin reduction to 50% 5 minutes before the start of exercise.	Dextrose tabs orally (20 grams) 5 minutes before the start of exercise and at 30 minutes of exercise (total 40 grams).	Glucagon (150 µg) 5 minutes before the start of exercise (SQ-abdomen).
Measure Participants	14	13	13	14
Median (Inter-Quartile Range) [mg/dL]	129	139	130	147

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Basal Insulin Reduction, Glucose Tabs, G-Pen Mini™ (Glucagon Injection)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.16
	Comments
	Method	Mixed Models Analysis
	Comments	Accounted for correlation due to cross-over design and adjusted for exercise session

7. Secondary Outcome

Title	CGM Metrics During Late Recovery - Coefficient of Variation
Description	Comparison of the coefficient of variation from CGM between the exercise strategies.
Time Frame	90 min after the standard meal until 1200 noon the day after each exercise session

Outcome Measure Data

Analysis Population Description

Included data were limited to periods with at least 12 hours of CGM data

Arm/Group Title	Control	Basal Insulin Reduction	Glucose Tabs	G-Pen Mini™ (Glucagon Injection)
Arm/Group Description	No basal insulin adjustment, no carbohydrate intake (until glucose drops <70 mg/dL).	Basal insulin reduction to 50% 5 minutes before the start of exercise.	Dextrose tabs orally (20 grams) 5 minutes before the start of exercise and at 30 minutes of exercise (total 40 grams).	Glucagon (150 µg) 5 minutes before the start of exercise (SQ-abdomen).
Measure Participants	14	13	13	14
Median (Inter-Quartile Range) [percentage]	32	35	36	33

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Basal Insulin Reduction, Glucose Tabs, G-Pen Mini™ (Glucagon Injection)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.69
	Comments
	Method	Mixed Models Analysis
	Comments	Accounted for correlation due to cross-over design and adjusted for exercise session

8. Secondary Outcome

Title	CGM Metrics During Late Recovery - Time < 54 mg/dL
Description	Comparison of percentage of time < 54 mg/dL from CGM between the exercise strategies.
Time Frame	90 min after the standard meal until 1200 noon the day after each exercise session

Outcome Measure Data

Analysis Population Description

Included data were limited to periods with at least 12 hours of CGM data

Arm/Group Title	Control	Basal Insulin Reduction	Glucose Tabs	G-Pen Mini™ (Glucagon Injection)
Arm/Group Description	No basal insulin adjustment, no carbohydrate intake (until glucose drops <70 mg/dL).	Basal insulin reduction to 50% 5 minutes before the start of exercise.	Dextrose tabs orally (20 grams) 5 minutes before the start of exercise and at 30 minutes of exercise (total 40 grams).	Glucagon (150 µg) 5 minutes before the start of exercise (SQ-abdomen).
Measure Participants	14	13	13	14
Mean (Standard Deviation) [percentage]	3 (3)	3 (3)	3 (1)	2 (2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Basal Insulin Reduction, Glucose Tabs, G-Pen Mini™ (Glucagon Injection)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.67
	Comments
	Method	Mixed Models Analysis
	Comments	Accounted for correlation due to cross-over design and adjusted for exercise session

9. Secondary Outcome

Title	CGM Metrics During Late Recovery - Time < 70 mg/dL
Description	Comparison of percentage of time < 70 mg/dL from CGM between the exercise strategies.
Time Frame	90 min after the standard meal until 1200 noon the day after each exercise session

Outcome Measure Data

Analysis Population Description

Included data were limited to periods with at least 12 hours of CGM data

Arm/Group Title	Control	Basal Insulin Reduction	Glucose Tabs	G-Pen Mini™ (Glucagon Injection)
Arm/Group Description	No basal insulin adjustment, no carbohydrate intake (until glucose drops <70 mg/dL).	Basal insulin reduction to 50% 5 minutes before the start of exercise.	Dextrose tabs orally (20 grams) 5 minutes before the start of exercise and at 30 minutes of exercise (total 40 grams).	Glucagon (150 µg) 5 minutes before the start of exercise (SQ-abdomen).
Measure Participants	14	13	13	14
Mean (Standard Deviation) [percentage]	10 (9)	8 (6)	8 (6)	6 (4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Basal Insulin Reduction, Glucose Tabs, G-Pen Mini™ (Glucagon Injection)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.84
	Comments
	Method	Mixed Models Analysis
	Comments	Accounted for correlation due to cross-over design and adjusted for exercise session

10. Secondary Outcome

Title	CGM Metrics During Late Recovery - Time in Range (70-180 mg/dL)
Description	Comparison of percentage of time in range (70-180 mg/dL) from CGM between the exercise strategies.
Time Frame	90 min after the standard meal until 1200 noon the day after each exercise session

Outcome Measure Data

Analysis Population Description

Included data were limited to periods with at least 12 hours of CGM data

Arm/Group Title	Control	Basal Insulin Reduction	Glucose Tabs	G-Pen Mini™ (Glucagon Injection)
Arm/Group Description	No basal insulin adjustment, no carbohydrate intake (until glucose drops <70 mg/dL).	Basal insulin reduction to 50% 5 minutes before the start of exercise.	Dextrose tabs orally (20 grams) 5 minutes before the start of exercise and at 30 minutes of exercise (total 40 grams).	Glucagon (150 µg) 5 minutes before the start of exercise (SQ-abdomen).
Measure Participants	14	13	13	14
Mean (Standard Deviation) [percentage]	73 (12)	71 (10)	69 (20)	67 (15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Basal Insulin Reduction, Glucose Tabs, G-Pen Mini™ (Glucagon Injection)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments
	Method	Mixed Models Analysis
	Comments	Accounted for correlation due to cross-over design and adjusted for exercise session

11. Secondary Outcome

Title	CGM Metrics During Late Recovery - Time > 180 mg/dL
Description	Comparison of percentage of time > 180 mg/dL from CGM between the exercise strategies.
Time Frame	90 min after the standard meal until 1200 noon the day after each exercise session

Outcome Measure Data

Analysis Population Description

Included data were limited to periods with at least 12 hours of CGM data

Arm/Group Title	Control	Basal Insulin Reduction	Glucose Tabs	G-Pen Mini™ (Glucagon Injection)
Arm/Group Description	No basal insulin adjustment, no carbohydrate intake (until glucose drops <70 mg/dL).	Basal insulin reduction to 50% 5 minutes before the start of exercise.	Dextrose tabs orally (20 grams) 5 minutes before the start of exercise and at 30 minutes of exercise (total 40 grams).	Glucagon (150 µg) 5 minutes before the start of exercise (SQ-abdomen).
Measure Participants	14	13	13	14
Mean (Standard Deviation) [percentage]	16 (13)	21 (12)	23 (20)	26 (16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Basal Insulin Reduction, Glucose Tabs, G-Pen Mini™ (Glucagon Injection)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.24
	Comments
	Method	Mixed Models Analysis
	Comments	Accounted for correlation due to cross-over design and adjusted for exercise session

12. Secondary Outcome

Title	CGM Metrics During Late Recovery - Time > 250 mg/dL
Description	Comparison of percentage of time > 250 mg/dL from CGM between the exercise strategies.
Time Frame	90 min after the standard meal until 1200 noon the day after each exercise session

Outcome Measure Data

Analysis Population Description

Included data were limited to periods with at least 12 hours of CGM data

Arm/Group Title	Control	Basal Insulin Reduction	Glucose Tabs	G-Pen Mini™ (Glucagon Injection)
Arm/Group Description	No basal insulin adjustment, no carbohydrate intake (until glucose drops <70 mg/dL).	Basal insulin reduction to 50% 5 minutes before the start of exercise.	Dextrose tabs orally (20 grams) 5 minutes before the start of exercise and at 30 minutes of exercise (total 40 grams).	Glucagon (150 µg) 5 minutes before the start of exercise (SQ-abdomen).
Measure Participants	14	13	13	14
Mean (Standard Deviation) [percentage]	1 (2)	4 (9)	9 (17)	5 (7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Basal Insulin Reduction, Glucose Tabs, G-Pen Mini™ (Glucagon Injection)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.26
	Comments
	Method	Mixed Models Analysis
	Comments	Accounted for correlation due to cross-over design and adjusted for exercise session

Adverse Events

Time Frame	Adverse Events (AE) were collected 12 hours prior to each exercise session, during each exercise session, and during the day after each exercise session.
Adverse Event Reporting Description	Hypoglycemia, hyperglycemia, injection-related, and exercise-induced events only reported as AEs when criteria below met. Hypoglycemia: event required dextrose or glucagon to treat; Hyperglycemia: evaluation or treatment obtained from a health care provider or event involved Diabetic Ketoacidosis; Injection-related events: treatment was given; Exercise-induced events: subject falls or has signs of heart attack, poor perfusion, angina, pathologic arrhythmia, or other condition not expected
Arm/Group Title	Control		Basal Insulin Reduction		Glucose Tabs		G-Pen Mini™ (Glucagon Injection)
Arm/Group Description	No basal insulin adjustment, no carbohydrate intake (until glucose drops <70 mg/dL).		Basal insulin reduction to 50% 5 minutes before the start of exercise.		Dextrose tabs orally (20 grams) 5 minutes before the start of exercise and at 30 minutes of exercise (total 40 grams).		Glucagon (150 µg) 5 minutes before the start of exercise (SQ-abdomen).
All Cause Mortality
	Control		Basal Insulin Reduction		Glucose Tabs		G-Pen Mini™ (Glucagon Injection)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)
Serious Adverse Events
	Control		Basal Insulin Reduction		Glucose Tabs		G-Pen Mini™ (Glucagon Injection)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Control		Basal Insulin Reduction		Glucose Tabs		G-Pen Mini™ (Glucagon Injection)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.