Diabetes Mellitus, Type 1
Conditions
Keywords
T1D, Type 1 Diabetes, Mini-dose Glucagon, Adults, Exercise, Hypoglycemia
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.
Interventions
Glucagon (150 µg) 5 minutes before the start of exercise (SQ-abdomen).
OTHERGlucose Tabs
Dextrose tabs orally (20 grams) 5 minutes before the start of exercise and at 30 minutes of exercise (total 40 grams).
OTHERBasal Insulin Reduction
Basal insulin reduction to 50% 5 minutes before the start of exercise.
Sponsors
Xeris Pharmaceuticals
Jaeb Center for Health Research
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
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) 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes all patients who completed the crossover trial. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Glucagon Injection | Lost to Follow-up | 1 |
| Glucose Tabs | Lost to Follow-up | 1 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 30 years |
| Body Mass Index (BMI) | 24 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| HbA1c | 6.8 % |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 9 Participants |
| Type 1 Diabetes Duration, Continuous | 22 years |
| VO2Max | 42 mL/kg/min |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 15 |
Outcome results
Primary
Glycemic Response During Exercise and Early Recovery
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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Control | Glycemic Response During Exercise and Early Recovery | Plasma Glucose Concentration (End Early Recovery) | 90 mg/dL | Standard Deviation 34 |
| Control | Glycemic Response During Exercise and Early Recovery | Plasma Glucose Concentration (End of Exercise) | 86 mg/dL | Standard Deviation 30 |
| Basal Insulin Reduction | Glycemic Response During Exercise and Early Recovery | Plasma Glucose Concentration (End of Exercise) | 85 mg/dL | Standard Deviation 25 |
| Basal Insulin Reduction | Glycemic Response During Exercise and Early Recovery | Plasma Glucose Concentration (End Early Recovery) | 92 mg/dL | Standard Deviation 34 |
| Glucose Tabs | Glycemic Response During Exercise and Early Recovery | Plasma Glucose Concentration (End of Exercise) | 174 mg/dL | Standard Deviation 59 |
| Glucose Tabs | Glycemic Response During Exercise and Early Recovery | Plasma Glucose Concentration (End Early Recovery) | 222 mg/dL | Standard Deviation 66 |
| G-Pen Mini™ (Glucagon Injection) | Glycemic Response During Exercise and Early Recovery | Plasma Glucose Concentration (End Early Recovery) | 163 mg/dL | Standard Deviation 49 |
| G-Pen Mini™ (Glucagon Injection) | Glycemic Response During Exercise and Early Recovery | Plasma Glucose Concentration (End of Exercise) | 161 mg/dL | Standard Deviation 39 |
Comparison: 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.p-value: <0.001Mixed Models Analysis
Secondary
CGM Metrics During Late Recovery - Coefficient of Variation
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
Population: Included data were limited to periods with at least 12 hours of CGM data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control | CGM Metrics During Late Recovery - Coefficient of Variation | 32 percentage |
| Basal Insulin Reduction | CGM Metrics During Late Recovery - Coefficient of Variation | 35 percentage |
| Glucose Tabs | CGM Metrics During Late Recovery - Coefficient of Variation | 36 percentage |
| G-Pen Mini™ (Glucagon Injection) | CGM Metrics During Late Recovery - Coefficient of Variation | 33 percentage |
p-value: 0.69Mixed Models Analysis
Secondary
CGM Metrics During Late Recovery - Mean Glucose
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
Population: Included data were limited to periods with at least 12 hours of CGM data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control | CGM Metrics During Late Recovery - Mean Glucose | 129 mg/dL |
| Basal Insulin Reduction | CGM Metrics During Late Recovery - Mean Glucose | 139 mg/dL |
| Glucose Tabs | CGM Metrics During Late Recovery - Mean Glucose | 130 mg/dL |
| G-Pen Mini™ (Glucagon Injection) | CGM Metrics During Late Recovery - Mean Glucose | 147 mg/dL |
p-value: 0.16Mixed Models Analysis
Secondary
CGM Metrics During Late Recovery - Peak Glucose
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
Population: Included data were limited to periods with at least 12 hours of CGM data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control | CGM Metrics During Late Recovery - Peak Glucose | 241 mg/dL |
| Basal Insulin Reduction | CGM Metrics During Late Recovery - Peak Glucose | 239 mg/dL |
| Glucose Tabs | CGM Metrics During Late Recovery - Peak Glucose | 267 mg/dL |
| G-Pen Mini™ (Glucagon Injection) | CGM Metrics During Late Recovery - Peak Glucose | 269 mg/dL |
p-value: 0.43Mixed Models Analysis
Secondary
CGM Metrics During Late Recovery - Time > 180 mg/dL
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
Population: Included data were limited to periods with at least 12 hours of CGM data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | CGM Metrics During Late Recovery - Time > 180 mg/dL | 16 percentage | Standard Deviation 13 |
| Basal Insulin Reduction | CGM Metrics During Late Recovery - Time > 180 mg/dL | 21 percentage | Standard Deviation 12 |
| Glucose Tabs | CGM Metrics During Late Recovery - Time > 180 mg/dL | 23 percentage | Standard Deviation 20 |
| G-Pen Mini™ (Glucagon Injection) | CGM Metrics During Late Recovery - Time > 180 mg/dL | 26 percentage | Standard Deviation 16 |
p-value: 0.24Mixed Models Analysis
Secondary
CGM Metrics During Late Recovery - Time > 250 mg/dL
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
Population: Included data were limited to periods with at least 12 hours of CGM data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | CGM Metrics During Late Recovery - Time > 250 mg/dL | 1 percentage | Standard Deviation 2 |
| Basal Insulin Reduction | CGM Metrics During Late Recovery - Time > 250 mg/dL | 4 percentage | Standard Deviation 9 |
| Glucose Tabs | CGM Metrics During Late Recovery - Time > 250 mg/dL | 9 percentage | Standard Deviation 17 |
| G-Pen Mini™ (Glucagon Injection) | CGM Metrics During Late Recovery - Time > 250 mg/dL | 5 percentage | Standard Deviation 7 |
p-value: 0.26Mixed Models Analysis
Secondary
CGM Metrics During Late Recovery - Time < 54 mg/dL
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
Population: Included data were limited to periods with at least 12 hours of CGM data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | CGM Metrics During Late Recovery - Time < 54 mg/dL | 3 percentage | Standard Deviation 3 |
| Basal Insulin Reduction | CGM Metrics During Late Recovery - Time < 54 mg/dL | 3 percentage | Standard Deviation 3 |
| Glucose Tabs | CGM Metrics During Late Recovery - Time < 54 mg/dL | 3 percentage | Standard Deviation 1 |
| G-Pen Mini™ (Glucagon Injection) | CGM Metrics During Late Recovery - Time < 54 mg/dL | 2 percentage | Standard Deviation 2 |
p-value: 0.67Mixed Models Analysis
Secondary
CGM Metrics During Late Recovery - Time < 70 mg/dL
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
Population: Included data were limited to periods with at least 12 hours of CGM data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | CGM Metrics During Late Recovery - Time < 70 mg/dL | 10 percentage | Standard Deviation 9 |
| Basal Insulin Reduction | CGM Metrics During Late Recovery - Time < 70 mg/dL | 8 percentage | Standard Deviation 6 |
| Glucose Tabs | CGM Metrics During Late Recovery - Time < 70 mg/dL | 8 percentage | Standard Deviation 6 |
| G-Pen Mini™ (Glucagon Injection) | CGM Metrics During Late Recovery - Time < 70 mg/dL | 6 percentage | Standard Deviation 4 |
p-value: 0.84Mixed Models Analysis
Secondary
CGM Metrics During Late Recovery - Time in Range (70-180 mg/dL)
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
Population: Included data were limited to periods with at least 12 hours of CGM data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | CGM Metrics During Late Recovery - Time in Range (70-180 mg/dL) | 73 percentage | Standard Deviation 12 |
| Basal Insulin Reduction | CGM Metrics During Late Recovery - Time in Range (70-180 mg/dL) | 71 percentage | Standard Deviation 10 |
| Glucose Tabs | CGM Metrics During Late Recovery - Time in Range (70-180 mg/dL) | 69 percentage | Standard Deviation 20 |
| G-Pen Mini™ (Glucagon Injection) | CGM Metrics During Late Recovery - Time in Range (70-180 mg/dL) | 67 percentage | Standard Deviation 15 |
p-value: 0.63Mixed Models Analysis
Secondary
Continuous Glucose Monitor (CGM) Metrics During Late Recovery - Nadir Glucose
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
Population: Included data were limited to periods with at least 12 hours of CGM data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control | Continuous Glucose Monitor (CGM) Metrics During Late Recovery - Nadir Glucose | 45 mg/dL |
| Basal Insulin Reduction | Continuous Glucose Monitor (CGM) Metrics During Late Recovery - Nadir Glucose | 44 mg/dL |
| Glucose Tabs | Continuous Glucose Monitor (CGM) Metrics During Late Recovery - Nadir Glucose | 49 mg/dL |
| G-Pen Mini™ (Glucagon Injection) | Continuous Glucose Monitor (CGM) Metrics During Late Recovery - Nadir Glucose | 51 mg/dL |
p-value: 0.99Mixed Models Analysis
Secondary
Number of Participants With Hyperglycemia (≥250 mg/dL) During Exercise and Early Recovery
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control | Number of Participants With Hyperglycemia (≥250 mg/dL) During Exercise and Early Recovery | 0 Participants |
| Basal Insulin Reduction | Number of Participants With Hyperglycemia (≥250 mg/dL) During Exercise and Early Recovery | 0 Participants |
| Glucose Tabs | Number of Participants With Hyperglycemia (≥250 mg/dL) During Exercise and Early Recovery | 5 Participants |
| G-Pen Mini™ (Glucagon Injection) | Number of Participants With Hyperglycemia (≥250 mg/dL) During Exercise and Early Recovery | 1 Participants |
p-value: 0.15Mixed Models Analysis
Secondary
Number of Participants With Hypoglycemia (<70 mg/dL) During Exercise and Early Recovery
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control | Number of Participants With Hypoglycemia (<70 mg/dL) During Exercise and Early Recovery | 6 Participants |
| Basal Insulin Reduction | Number of Participants With Hypoglycemia (<70 mg/dL) During Exercise and Early Recovery | 5 Participants |
| Glucose Tabs | Number of Participants With Hypoglycemia (<70 mg/dL) During Exercise and Early Recovery | 0 Participants |
| G-Pen Mini™ (Glucagon Injection) | Number of Participants With Hypoglycemia (<70 mg/dL) During Exercise and Early Recovery | 0 Participants |
p-value: 0.99Mixed Models Analysis