Hypoglycemia
Conditions
Keywords
Hypoglycemia, Glucagon, Artificial Pancreas
Brief summary
The purpose of the study is to assess the safety, speed of absorption, and onset of action of G-Pump™ (glucagon infusion) at three subcutaneous doses as compared to Novo GlucaGen®, all delivered via an OmniPod® infusion pump to patients with type 1 diabetes.
Interventions
DRUGNovo Nordisk GlucaGen®
single subcutaneous infusion doses at 0.3 μg/kg, 1.2 μg/kg and 2.0 μg/kg
single subcutaneous infusion doses at 0.3 μg/kg, 1.2 μg/kg and 2.0 μg/kg
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Emissary International LLC
Xeris Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Males or females diagnosed with type 1 diabetes mellitus for at least 24 months * Current usage of subcutaneous insulin pump treatment * Age 18-65 years * C-peptide level \< 0.5 ng/ml * Willingness to follow all study procedures, including attending all clinic visits * Subject has provided informed consent and has signed and dated an informed consent form before any trial-related activities
Exclusion criteria
* Pregnant and/ or Lactating: For women of childbearing potential: there is a requirement for a negative urine pregnancy test and for agreement to use contraception during the study and for at least 1 month after participating in the study. * HbA1c \>10.0% * Renal insufficiency (serum creatinine of 1.2 mg/dL or greater) * Serum ALT or AST equal to or greater than 3 times the upper limit of normal; hepatic synthetic insufficiency as defined as a serum albumin of less than 3.0 g/dL; or serum bilirubin of over 2.0. * Hematocrit of less than or equal to 34% * Congestive heart failure, NYHA class II, III or IV * History of coronary artery disease * Active foot ulceration * History of a cerebrovascular accident * Active alcohol abuse or substance abuse * Active malignancy, except basal cell or squamous cell skin cancers * Major surgical operation within 30 days prior to screening * Seizure disorder * Current administration of oral or parenteral corticosteroids * Use of an investigational drug within 30 days prior to screening * Bleeding disorder, treatment with warfarin, or platelet count below 50,000 * Proliferative or severe non-proliferative retinopathy * Gastroparesis * Personal or family history of pheochromocytoma or disorder with increased risk of pheochromocytoma (MEN 2, neurofibromatosis, or Von Hippel-Lindau disease) * Insulinoma * Allergies to glucagon or glucagon-like products, or any history of significant hypersensitivity to glucagon or any related products. * Glycogen storage disease * Any concurrent illness, other than diabetes, that is not controlled by a stable therapeutic regimen * Whole blood donation of 1 pint (500 mL) within 8 weeks prior to Screening. * Any reason the principal investigator deems exclusionary
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach 50% of Maximum Glucose Concentration (Glucose T50%-Early) | 0 to 150 minutes post-dosing | The onset of action was assessed by determining the time in minutes required to achieve 50% of the maximum plasma concentration of glucose following each dose of glucagon. |
| Time to Reach 50% of Maximum Glucagon Concentration (Glucagon T50%-Early) | 0 to 150 minutes post-dosing | The speed of absorption was assessed by determining the time in minutes required to achieve 50% of the maximum plasma concentration of glucagon following each dose of glucagon. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Glucagon Tmax | From 0 to 150 minutes post-dosing | Time to maximum plasma concentration of glucagon |
| Glucose Tmax | From 0 to 150 minutes post-dosing | Time to maximum plasma concentration of glucose |
| Glucagon AUC | From 0 to 150 minutes post-dosing | Area under the plasma concentration time curve for glucagon |
| Glucagon Cmax | From 0 to 150 minutes post-dosing | Maximum plasma concentration of glucagon |
| Infusion Site Discomfort Score at 10 Minutes | At 10 minutes post-dosing | Infusion site discomfort was assessed by the subjects using a 100 mm Visual Analog Scale (VAS) questionnaire at 10 minutes following the initiation of dosing. Subjects were asked to draw a vertical line across the horizontal scale to indicate their current level of discomfort from 0 = no discomfort to 100 = worst possible discomfort. The distance in mm from the left hand anchor to the the first point where the subject's mark crossed the horizontal scale was measured and reported as the infusion site discomfort score. |
| Infusion Site Discomfort Score at 30 Minutes | At 30 minutes post-dosing | Infusion site discomfort was assessed by the subject using a 100 mm Visual Analog Scale (VAS) questionnaire at 30 minutes following the initiation of dosing. Subjects were asked to draw a vertical line across the horizontal scale to indicate their current level of discomfort from 0 = no discomfort to 100 = worst possible discomfort. The distance in mm from the left hand anchor to the the first point where the subject's mark crossed the horizontal scale was measured and reported as the infusion site discomfort score. |
| Glucose AUC | From 0 to 150 minutes post-dosing | Area under the plasma concentration time curve for glucose |
| Glucose Cmax | From 0 to 150 minutes post-dosing | Maximum plasma concentration of glucose |
Countries
United States
Participant flow
Recruitment details
A total of 19 adults ages 18-65 years with type 1 diabetes were recruited over a period of 4 months to receive treatment at a public university hospital.
Pre-assignment details
A total of 30 subjects were screened for study inclusion. The 19 subjects who met all eligibility criteria were randomized and assigned to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Xeris G-Pump Glucagon First, Followed by GlucaGen Subjects who received G-Pump (glucagon infusion) at the first treatment visit and GlucaGen at the second treatment visit. | 13 |
| GlucaGen First, Followed by Xeris G-Pump Subjects who received GlucaGen at the first treatment visit and G-Pump (glucagon infusion) at the second treatment visit. | 6 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Xeris G-Pump Glucagon First, Followed by GlucaGen | GlucaGen First, Followed by Xeris G-Pump | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 6 Participants | 19 Participants |
| Age, Continuous | 36.7 years STANDARD_DEVIATION 9.54 | 32.2 years STANDARD_DEVIATION 8.38 | 35.3 years STANDARD_DEVIATION 9.21 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 5 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 6 Participants | 19 Participants |
| Region of Enrollment United States | 13 participants | 6 participants | 19 participants |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 12 Participants |
| Sex: Female, Male Male | 5 Participants | 2 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 19 | 12 / 18 |
| serious Total, serious adverse events | 0 / 19 | 0 / 18 |
Outcome results
Primary
Time to Reach 50% of Maximum Glucagon Concentration (Glucagon T50%-Early)
The speed of absorption was assessed by determining the time in minutes required to achieve 50% of the maximum plasma concentration of glucagon following each dose of glucagon.
Time frame: 0 to 150 minutes post-dosing
Population: All randomized, evaluable subjects. Two subjects not evaluable for response to GlucaGen due to dosing errors were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.3 μg/kg G-Pump | Time to Reach 50% of Maximum Glucagon Concentration (Glucagon T50%-Early) | 12.2 minutes | Standard Deviation 10.51 |
| 1.2 μg/kg G-Pump | Time to Reach 50% of Maximum Glucagon Concentration (Glucagon T50%-Early) | 12.4 minutes | Standard Deviation 5.07 |
| 2.0 μg/kg G-Pump | Time to Reach 50% of Maximum Glucagon Concentration (Glucagon T50%-Early) | 13.9 minutes | Standard Deviation 4.65 |
| 0.3μg/kg GlucaGen | Time to Reach 50% of Maximum Glucagon Concentration (Glucagon T50%-Early) | 7.6 minutes | Standard Deviation 3.51 |
| 1.2 μg/kg GlucaGen | Time to Reach 50% of Maximum Glucagon Concentration (Glucagon T50%-Early) | 10.5 minutes | Standard Deviation 4.46 |
| 2.0 μg/kg GlucaGen | Time to Reach 50% of Maximum Glucagon Concentration (Glucagon T50%-Early) | 11.0 minutes | Standard Deviation 3.09 |
p-value: 0.2390% CI: [0.88, 2.12]Mixed Models Analysis
p-value: 0.0990% CI: [1.01, 1.65]Mixed Models Analysis
p-value: 0.0290% CI: [1.11, 1.67]Mixed Models Analysis
Primary
Time to Reach 50% of Maximum Glucose Concentration (Glucose T50%-Early)
The onset of action was assessed by determining the time in minutes required to achieve 50% of the maximum plasma concentration of glucose following each dose of glucagon.
Time frame: 0 to 150 minutes post-dosing
Population: All randomized, evaluable subjects. Two subjects not evaluable for response to GlucaGen due to dosing errors were excluded from the analysis. In addition, subjects with no increase in glucose concentration post-dosing (i.e., maximum concentration was at time zero) were not evaluable for response and consequently were not included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.3 μg/kg G-Pump | Time to Reach 50% of Maximum Glucose Concentration (Glucose T50%-Early) | 17.2 minutes | Standard Deviation 8.76 |
| 1.2 μg/kg G-Pump | Time to Reach 50% of Maximum Glucose Concentration (Glucose T50%-Early) | 21.9 minutes | Standard Deviation 18.44 |
| 2.0 μg/kg G-Pump | Time to Reach 50% of Maximum Glucose Concentration (Glucose T50%-Early) | 21.3 minutes | Standard Deviation 16.52 |
| 0.3μg/kg GlucaGen | Time to Reach 50% of Maximum Glucose Concentration (Glucose T50%-Early) | 7.6 minutes | Standard Deviation 9.45 |
| 1.2 μg/kg GlucaGen | Time to Reach 50% of Maximum Glucose Concentration (Glucose T50%-Early) | 14.5 minutes | Standard Deviation 15.36 |
| 2.0 μg/kg GlucaGen | Time to Reach 50% of Maximum Glucose Concentration (Glucose T50%-Early) | 22.8 minutes | Standard Deviation 6.51 |
p-value: 0.2390% CI: [0.74, 5.75]Mixed Models Analysis
p-value: 0.5290% CI: [0.69, 2.28]Mixed Models Analysis
p-value: 0.4990% CI: [0.59, 1.25]Mixed Models Analysis
Secondary
Glucagon AUC
Area under the plasma concentration time curve for glucagon
Time frame: From 0 to 150 minutes post-dosing
Population: All randomized, evaluable subjects. Two subjects not evaluable for response to GlucaGen due to dosing errors were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.3 μg/kg G-Pump | Glucagon AUC | 12104 (pg/dl)*minutes | Standard Deviation 3944 |
| 1.2 μg/kg G-Pump | Glucagon AUC | 21177 (pg/dl)*minutes | Standard Deviation 6139 |
| 2.0 μg/kg G-Pump | Glucagon AUC | 27595 (pg/dl)*minutes | Standard Deviation 14530 |
| 0.3μg/kg GlucaGen | Glucagon AUC | 11070 (pg/dl)*minutes | Standard Deviation 3032 |
| 1.2 μg/kg GlucaGen | Glucagon AUC | 15781 (pg/dl)*minutes | Standard Deviation 7874 |
| 2.0 μg/kg GlucaGen | Glucagon AUC | 27355 (pg/dl)*minutes | Standard Deviation 10757 |
p-value: 0.6190% CI: [0.87, 1.3]Mixed Models Analysis
p-value: 0.2290% CI: [0.94, 1.5]Mixed Models Analysis
p-value: 0.2690% CI: [0.66, 1.09]Mixed Models Analysis
Secondary
Glucagon Cmax
Maximum plasma concentration of glucagon
Time frame: From 0 to 150 minutes post-dosing
Population: All randomized, evaluable subjects. Two subjects not evaluable for response to GlucaGen due to dosing errors were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.3 μg/kg G-Pump | Glucagon Cmax | 168.1 pg/dl | Standard Deviation 57.66 |
| 1.2 μg/kg G-Pump | Glucagon Cmax | 328.2 pg/dl | Standard Deviation 127.9 |
| 2.0 μg/kg G-Pump | Glucagon Cmax | 440.6 pg/dl | Standard Deviation 310.9 |
| 0.3μg/kg GlucaGen | Glucagon Cmax | 140.2 pg/dl | Standard Deviation 53.69 |
| 1.2 μg/kg GlucaGen | Glucagon Cmax | 229.3 pg/dl | Standard Deviation 161.6 |
| 2.0 μg/kg GlucaGen | Glucagon Cmax | 446.9 pg/dl | Standard Deviation 220.4 |
p-value: 0.1590% CI: [0.97, 1.64]Mixed Models Analysis
p-value: 0.2490% CI: [0.9, 1.84]Mixed Models Analysis
p-value: 0.3190% CI: [0.6, 1.14]Mixed Models Analysis
Secondary
Glucagon Tmax
Time to maximum plasma concentration of glucagon
Time frame: From 0 to 150 minutes post-dosing
Population: All randomized, evaluable subjects. Two subjects not evaluable for response to GlucaGen due to dosing errors were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.3 μg/kg G-Pump | Glucagon Tmax | 24.5 minutes | Standard Deviation 23.42 |
| 1.2 μg/kg G-Pump | Glucagon Tmax | 27.3 minutes | Standard Deviation 12.93 |
| 2.0 μg/kg G-Pump | Glucagon Tmax | 31.9 minutes | Standard Deviation 15.93 |
| 0.3μg/kg GlucaGen | Glucagon Tmax | 23.3 minutes | Standard Deviation 10.71 |
| 1.2 μg/kg GlucaGen | Glucagon Tmax | 23.9 minutes | Standard Deviation 6.31 |
| 2.0 μg/kg GlucaGen | Glucagon Tmax | 23.9 minutes | Standard Deviation 8.74 |
p-value: 0.790% CI: [0.6, 1.38]Mixed Models Analysis
p-value: 0.1990% CI: [0.94, 1.68]Mixed Models Analysis
p-value: 0.05290% CI: [1.07, 1.98]Mixed Models Analysis
Secondary
Glucose AUC
Area under the plasma concentration time curve for glucose
Time frame: From 0 to 150 minutes post-dosing
Population: All randomized, evaluable subjects. Two subjects not evaluable for response to GlucaGen due to dosing errors were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.3 μg/kg G-Pump | Glucose AUC | 22296 (mg/dl)*minutes | Standard Deviation 7998 |
| 1.2 μg/kg G-Pump | Glucose AUC | 26251 (mg/dl)*minutes | Standard Deviation 7110 |
| 2.0 μg/kg G-Pump | Glucose AUC | 27360 (mg/dl)*minutes | Standard Deviation 8190 |
| 0.3μg/kg GlucaGen | Glucose AUC | 21005 (mg/dl)*minutes | Standard Deviation 7931 |
| 1.2 μg/kg GlucaGen | Glucose AUC | 24079 (mg/dl)*minutes | Standard Deviation 9348 |
| 2.0 μg/kg GlucaGen | Glucose AUC | 25845 (mg/dl)*minutes | Standard Deviation 8624 |
p-value: 0.1990% CI: [0.96, 1.46]Mixed Models Analysis
p-value: 0.2190% CI: [0.95, 1.38]Regression, Cox
p-value: 0.1990% CI: [0.97, 1.31]Mixed Models Analysis
Secondary
Glucose Cmax
Maximum plasma concentration of glucose
Time frame: From 0 to 150 minutes post-dosing
Population: All randomized, evaluable subjects. Two subjects not evaluable for response to GlucaGen due to dosing errors were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.3 μg/kg G-Pump | Glucose Cmax | 177.6 mg/dl | Standard Deviation 43.1 |
| 1.2 μg/kg G-Pump | Glucose Cmax | 198.8 mg/dl | Standard Deviation 49.37 |
| 2.0 μg/kg G-Pump | Glucose Cmax | 212.6 mg/dl | Standard Deviation 57.18 |
| 0.3μg/kg GlucaGen | Glucose Cmax | 162.0 mg/dl | Standard Deviation 51.69 |
| 1.2 μg/kg GlucaGen | Glucose Cmax | 183.3 mg/dl | Standard Deviation 66.15 |
| 2.0 μg/kg GlucaGen | Glucose Cmax | 200.6 mg/dl | Standard Deviation 63.81 |
p-value: 0.0990% CI: [1.01, 1.39]Mixed Models Analysis
p-value: 0.2990% CI: [0.93, 1.35]Mixed Models Analysis
p-value: 0.2490% CI: [0.96, 1.28]Mixed Models Analysis
Secondary
Glucose Tmax
Time to maximum plasma concentration of glucose
Time frame: From 0 to 150 minutes post-dosing
Population: All randomized, evaluable subjects. Two subjects not evaluable for response to GlucaGen due to dosing errors were excluded from the analysis. In addition, subjects with no increase in glucose concentration post-dosing (i.e., maximum concentration was at time zero) were not evaluable for response and consequently were not included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.3 μg/kg G-Pump | Glucose Tmax | 38.2 minutes | Standard Deviation 29.62 |
| 1.2 μg/kg G-Pump | Glucose Tmax | 49.5 minutes | Standard Deviation 41.79 |
| 2.0 μg/kg G-Pump | Glucose Tmax | 49.4 minutes | Standard Deviation 40.59 |
| 0.3μg/kg GlucaGen | Glucose Tmax | 25.9 minutes | Standard Deviation 28.38 |
| 1.2 μg/kg GlucaGen | Glucose Tmax | 31.2 minutes | Standard Deviation 34.75 |
| 2.0 μg/kg GlucaGen | Glucose Tmax | 52.8 minutes | Standard Deviation 20.21 |
p-value: 0.1690% CI: [0.87, 4.66]Mixed Models Analysis
p-value: 0.4890% CI: [0.68, 2.54]Mixed Models Analysis
p-value: 0.2890% CI: [0.57, 1.13]Mixed Models Analysis
Secondary
Infusion Site Discomfort Score at 10 Minutes
Infusion site discomfort was assessed by the subjects using a 100 mm Visual Analog Scale (VAS) questionnaire at 10 minutes following the initiation of dosing. Subjects were asked to draw a vertical line across the horizontal scale to indicate their current level of discomfort from 0 = no discomfort to 100 = worst possible discomfort. The distance in mm from the left hand anchor to the the first point where the subject's mark crossed the horizontal scale was measured and reported as the infusion site discomfort score.
Time frame: At 10 minutes post-dosing
Population: All treated subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.3 μg/kg G-Pump | Infusion Site Discomfort Score at 10 Minutes | 7.8 mm | Standard Deviation 18.9 |
| 1.2 μg/kg G-Pump | Infusion Site Discomfort Score at 10 Minutes | 18.9 mm | Standard Deviation 21.1 |
| 2.0 μg/kg G-Pump | Infusion Site Discomfort Score at 10 Minutes | 22.7 mm | Standard Deviation 25.5 |
| 0.3μg/kg GlucaGen | Infusion Site Discomfort Score at 10 Minutes | 2.2 mm | Standard Deviation 9.2 |
| 1.2 μg/kg GlucaGen | Infusion Site Discomfort Score at 10 Minutes | 0.3 mm | Standard Deviation 1 |
| 2.0 μg/kg GlucaGen | Infusion Site Discomfort Score at 10 Minutes | 0.3 mm | Standard Deviation 0.7 |
p-value: 0.2495% CI: [-17.1, 4.3]Mixed Models Analysis
p-value: 0.000595% CI: [-30.1, -8.7]Mixed Models Analysis
p-value: <0.000195% CI: [-34, -12.6]Mixed Models Analysis
Secondary
Infusion Site Discomfort Score at 30 Minutes
Infusion site discomfort was assessed by the subject using a 100 mm Visual Analog Scale (VAS) questionnaire at 30 minutes following the initiation of dosing. Subjects were asked to draw a vertical line across the horizontal scale to indicate their current level of discomfort from 0 = no discomfort to 100 = worst possible discomfort. The distance in mm from the left hand anchor to the the first point where the subject's mark crossed the horizontal scale was measured and reported as the infusion site discomfort score.
Time frame: At 30 minutes post-dosing
Population: All treated subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.3 μg/kg G-Pump | Infusion Site Discomfort Score at 30 Minutes | 1.9 mm | Standard Deviation 4.8 |
| 1.2 μg/kg G-Pump | Infusion Site Discomfort Score at 30 Minutes | 1.5 mm | Standard Deviation 4 |
| 2.0 μg/kg G-Pump | Infusion Site Discomfort Score at 30 Minutes | 3.8 mm | Standard Deviation 9 |
| 0.3μg/kg GlucaGen | Infusion Site Discomfort Score at 30 Minutes | 0 mm | Standard Deviation 0 |
| 1.2 μg/kg GlucaGen | Infusion Site Discomfort Score at 30 Minutes | 0.7 mm | Standard Deviation 2.6 |
| 2.0 μg/kg GlucaGen | Infusion Site Discomfort Score at 30 Minutes | 0.3 mm | Standard Deviation 1.4 |
p-value: 0.2295% CI: [-5.1, 1.2]Mixed Models Analysis
p-value: 0.5895% CI: [-4, 2.3]Mixed Models Analysis
p-value: 0.0395% CI: [-6.7, -0.4]Mixed Models Analysis