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

• ClinicalTrials.gov Identifier: NCT02660242
• Recruitment Status: Completed
• First Posted: January 21, 2016
• Results First Posted: August 7, 2018
• Last Update Posted: March 3, 2020
• Sponsor: Jaeb Center for Health Research
• Collaborator: Xeris Pharmaceuticals
• Information provided by (Responsible Party): Jaeb Center for Health Research

Tracking Information

• First Submitted Date: January 6, 2016
• First Posted Date: January 21, 2016
• Results First Submitted Date: June 6, 2018
• Results First Posted Date: August 7, 2018
• Last Update Posted Date: March 3, 2020
• Study Start Date: January 2016
• Actual Primary Completion Date: February 15, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 11, 2018)

Glycemic Response During Exercise and Early Recovery [ Time Frame: 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.

Original Primary Outcome Measures (submitted: January 18, 2016)

Glycemic response [ Time Frame: 0 to 75 minutes following exercise initiation ]

Comparison of glycemic response during each exercise strategy. Glucose over various time points throughout exercise and early recovery will be assessed. The primary analysis will compare the mini-dose glucagon group (strategy 3) with the control group.

Current Secondary Outcome Measures (submitted: July 11, 2018)

• Number of Participants With Hypoglycemia (<70 mg/dL) During Exercise and Early Recovery [ Time Frame: 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.
• Number of Participants With Hyperglycemia (≥250 mg/dL) During Exercise and Early Recovery [ Time Frame: 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.
• Continuous Glucose Monitor (CGM) Metrics During Late Recovery - Nadir Glucose [ Time Frame: 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.
• CGM Metrics During Late Recovery - Peak Glucose [ Time Frame: 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.
• CGM Metrics During Late Recovery - Mean Glucose [ Time Frame: 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.
• CGM Metrics During Late Recovery - Coefficient of Variation [ Time Frame: 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.
• CGM Metrics During Late Recovery - Time < 54 mg/dL [ Time Frame: 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.
• CGM Metrics During Late Recovery - Time < 70 mg/dL [ Time Frame: 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.
• CGM Metrics During Late Recovery - Time in Range (70-180 mg/dL) [ Time Frame: 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.
• CGM Metrics During Late Recovery - Time > 180 mg/dL [ Time Frame: 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.
• CGM Metrics During Late Recovery - Time > 250 mg/dL [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: January 18, 2016)

• Occurrence of hypoglycemia (<70 mg/dL) [ Time Frame: 0 to 75 minutes following exercise initiation ]
• Occurrence of hyperglycemia (≥270 mg/dL) [ Time Frame: 0 to 165 minutes following exercise initiation ]
• Glucose levels (venous plasma) [ Time Frame: 0 to 165 minutes following exercise initiation ]
• % of time below 70 mg/dL [ Time Frame: From 75 minutes post exercise initiation through noon the following day ]
  (from CGM)
• % of time in range (70-180 mg/dL) [ Time Frame: From 75 minutes post exercise initiation through noon the following day ]
  (from CGM)
• Mean Glucose levels [ Time Frame: From 75 minutes post exercise initiation through noon the following day ]
  (from CGM)
• Occurrence of hypoglycemia (<70 mg/dL) overnight [ Time Frame: From 75 minutes post exercise initiation through noon the following day ]
  (from CGM)
• Nadir Glucose levels [ Time Frame: From 75 minutes post exercise initiation through noon the following day ]
  (from CGM)
• Area above and below curve threshold (i.e. area above or below 70-180 mg/dL) [ Time Frame: From 75 minutes post exercise initiation through noon the following day ]
  (from CGM)
• Carbohydrate intake [ Time Frame: 60 minutes prior to exercise initiation to 75 minutes post exercise initiation ]
  case report form
• Heart Rate [ Time Frame: 0 to 45 minutes following exercise initiation ]
  physiological parameter
• Ratings of perceived exertion [ Time Frame: 0 to 45 minutes following exercise initiation ]
  scale
• Insulin [ Time Frame: From 0 to 165 minutes post exercise initiation ]
  lab
• Glucose counter-regulatory hormones [ Time Frame: From 0 to 165 minutes post exercise initiation ]
  lab
• Inflammatory cytokines [ Time Frame: From 0 to 165 minutes post exercise initiation ]
  lab
• Metabolites [ Time Frame: From 0 to 165 minutes post exercise initiation ]
  lab

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: January 18, 2016)

• Proportion reporting at least one adverse event [ Time Frame: Through study completion, an average of 12 weeks ]
  Adverse events will be tabulated by strategy
• Proportion with an adverse event thought by investigator to be related to strategy [ Time Frame: Through study completion, an average of 12 weeks ]
  Adverse events will be tabulated by strategy
• Proportion who stopped study treatment in response to an adverse event [ Time Frame: Through study completion, an average of 12 weeks ]
  Adverse events will be tabulated by strategy
• Total number of adverse events reported [ Time Frame: Through study completion, an average of 12 weeks ]
  Adverse events will be tabulated by strategy
• Number of serious adverse events reported [ Time Frame: Through study completion, an average of 12 weeks ]
  Adverse events will be tabulated by strategy
• Number of non-serious adverse events reported [ Time Frame: Through study completion, an average of 12 weeks ]
  Adverse events will be tabulated by strategy

Descriptive Information

• Brief Title: The Use of Mini-dose Glucagon to Prevent Exercise-induced Hypoglycemia in Type 1 Diabetes
• Official Title: The Use of Mini-dose Glucagon to Prevent Exercise-induced Hypoglycemia in Type 1 Diabetes
• Brief Summary: This project focuses on development of new strategy for the prevention of exercise-associated hypoglycemia using mini-dose glucagon.

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 Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Single (Participant); Primary Purpose: Prevention
• Condition: Diabetes Mellitus, Type 1

Intervention

• Drug: G-Pen Mini™ (glucagon injection)
  Glucagon (150 µg) 5 minutes before the start of exercise (SQ-abdomen).
  Other Name: mini-dose glucagon
• 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 Name: over-the-counter oral glucose tablets
• Other: Basal Insulin Reduction
  Basal insulin reduction to 50% 5 minutes before the start of exercise.

Study Arms

• 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.
  Intervention: Other: Basal Insulin Reduction
• 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).
  Intervention: Other: Glucose Tabs
• Experimental: G-Pen Mini™ (glucagon injection)
  Glucagon (150 µg) five minutes before the start of exercise (SQ-abdomen).
  Intervention: Drug: G-Pen Mini™ (glucagon injection)

Publications *

• 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.
• 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.
• 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.
• 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. doi: 10.2337/diacare.24.4.625.
• 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.
• 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.
• 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. doi: 10.1016/j.jpeds.2005.04.065.
• 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.
• 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.
• 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.
• 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. doi: 10.1123/ijsn.9.1.24.
• 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. No abstract available.
• 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.
• 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.
• Haymond MW, Schreiner B. Mini-dose glucagon rescue for hypoglycemia in children with type 1 diabetes. Diabetes Care. 2001 Apr;24(4):643-5. doi: 10.2337/diacare.24.4.643.
• 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. doi: 10.2337/dc06-0495.
• Rickels MR, DuBose SN, Toschi E, Beck RW, Verdejo AS, Wolpert H, Cummins MJ, Newswanger B, Riddell MC; T1D Exchange Mini-Dose Glucagon Exercise Study Group. Mini-Dose Glucagon as a Novel Approach to Prevent Exercise-Induced Hypoglycemia in Type 1 Diabetes. Diabetes Care. 2018 Sep;41(9):1909-1916. doi: 10.2337/dc18-0051. Epub 2018 May 18.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 18, 2016): 16
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: February 15, 2017
• Actual Primary Completion Date: February 15, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)
9. 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
10. Willing to adhere to the protocol requirements for the duration of the study
11. 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

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: United States

Administrative Information

• NCT Number: NCT02660242
• Other Study ID Numbers: T1DX Mini-dose Exercise
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Jaeb Center for Health Research
• Original Responsible Party: T1D Exchange Clinic Network Coordinating Center
• Current Study Sponsor: Jaeb Center for Health Research
• Original Study Sponsor: T1D Exchange Clinic Network Coordinating Center
• Collaborators: 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

• PRS Account: Jaeb Center for Health Research
• Verification Date: February 2020