Diabetes Mellitus, Type 1, Hypoglycemia
Conditions
Brief summary
This is a blinded, randomized crossover study to compare the safety and efficacy of G-Pen (glucagon injection) to Lilly Glucagon (glucagon for injection \[rDNA origin\]) for hypoglycemia rescue of adult patients with type 1 diabetes.
Detailed description
This is a blinded, randomized, Phase 3 comparative efficacy and safety study in adults with type 1 diabetes. Patients will complete screening procedures up to 60 days before randomization to determine eligibility before enrollment to the treatment phase. The procedure for evaluating the efficacy of the G-Pen (glucagon injection) consists of inducing hypoglycemia by intravenous administration of regular insulin diluted in normal saline. Each participant will undergo two episodes of insulin-induced hypoglycemia, and in random order will receive 1 mg G-Pen (glucagon injection) during one episode and 1 mg Lilly Glucagon during the other episode. There will be wash out period of 7-28 days between treatment visits. Blood glucose levels will be monitored post-dosing, with a return of plasma glucose to a concentration \> 70 mg/dL within 30 minutes signifying successful hypoglycemia rescue. As a confirmation of efficacy, subjects will complete a questionnaire concerning changes in symptoms of hypoglycemia following treatment with glucagon. Subjects will return for a follow-up safety visit 3-14 days following administration of the final dose of glucagon.
Interventions
DRUGG-Pen (glucagon injection)
1 mg of pre-mixed liquid Xeris glucagon delivered via auto-injector
DRUGLilly Glucagon (glucagon injection [rDNA origin])
1 mg of Lilly glucagon reconstituted from lyophilized powder
Sponsors
Xeris Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* diagnosed with type 1 diabetes mellitus for at least 24 months * usage of daily insulin treatment * random serum C-peptide concentration \< 0.5 ng/mL
Exclusion criteria
* pregnant or nursing * HbA1c \>9.0% * renal insufficiency * hepatic synthetic insufficiency * aspartate or alanine aminotransferase \> 3 times the upper limit of normal * hematocrit less than or equal to 30% * use of \> 2.0 U/kg total insulin dose per day * inadequate bilateral venous access in both arms * congestive heart failure, New York Heart Association class II, III or IV * active malignancy within 5 years, except basal cell or squamous cell skin cancers * history of breast cancer or malignant melanoma * major surgical operation within 30 days * current seizure disorder. * current bleeding disorder, treatment with warfarin, or platelet count below 50,000 * history of pheochromocytoma or disorder with increased risk of pheochromocytoma * history of insulinoma * history of glycogen storage disease. * positive for HIV, hepatitis C virus or active hepatitis B virus infection * whole blood donation of 1 pint (500 mL) within 8 weeks * active substance or alcohol abuse * administration of glucagon within 28 days * participation in other studies involving an investigational drug or device within 30 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hypoglycemia Rescue: Intent-to-Treat Population | At 30 minutes following administration of study drug | Number of subjects with an increase in plasma glucose concentration from below 50 mg/dL to greater than 70 mg/dL within 30 minutes after administration of glucagon |
| Hypoglycemia Rescue: Per Protocol Population | At 30 minutes following administration of study drug | Number of subjects with an increase in plasma glucose concentration from below 50 mg/dL to greater than 70 mg/dL within 30 minutes after administration of glucagon |
| Hypoglycemia Rescue: Alternate Glucose Response Definition | At 30 minutes following administration of study drug | Number of subjects with either an increase in plasma glucose concentration from below 50 mg/dL to greater than 70 mg/dL or an increase in from baseline in plasma glucose concentration of at least 20 mg/dL within 30 minutes after administration of glucagon |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Glucose Time to Concentration > 70 mg/dL | At -5, 0, 10, 20, 30, 45, 60, 90, 120, 180 and 240 minutes following administration of glucagon | Pharmacodynamic endpoint of time to achieve a plasma glucose concentration \> 70 mg/dL following administration of glucagon |
| Plasma Glucose Area Under the Curve (AUC) | At -5, 0, 10, 20, 30, 45, 60, and 90 minutes following administration of glucagon | Pharmacodynamic endpoint of plasma glucose AUC from baseline to 90 minutes following administration of glucagon |
| Global Assessment of Hypoglycemia | At 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 and 90 minutes following administration of glucagon | Time to resolution of the overall sensation of hypoglycemia following administration of glucagon |
| Time to Resolution of Hypoglycemia Symptoms | At 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 and 90 minutes following administration of glucagon | Time to resolution of mean autonomic, mean neuroglycopenic and mean total hypoglycemia symptom scores from baseline through 90 minutes following administration of glucagon. |
| Plasma Glucose Maximum Concentration (Cmax) | At -5, 0, 10, 20, 30, 45, 60, 90, 120, 180 and 240 minutes following administration of glucagon | Pharmacodynamic endpoint of plasma glucose Cmax from baseline to 4 hours following administration of glucagon |
| Plasma Glucose Time to Maximum Concentration (Tmax) | At -5, 0, 10, 20, 30, 45, 60, 90, 120, 180 and 240 minutes following administration of glucagon | Pharmacodynamic endpoint of plasma glucose Tmax from baseline to 4 hours following administration of glucagon |
Countries
Canada, United States
Participant flow
Recruitment details
The recruitment period began 15 March 2017 and ran through 30 June 2017. Subjects were screened for study eligibility at one of the 7 clinical sites up to 60 days prior to randomization.
Pre-assignment details
A total of 6 screened and eligible subjects were not randomized to one of the treatment sequences due to closing of the enrollment period.
Participants by arm
| Arm | Count |
|---|---|
| G-Pen First, Then Lilly Glucagon A single 1 mg subcutaneous (SC) injection of G-Pen™ (glucagon injection) with a 7-28 day wash-out, followed by a single 1 mg SC injection of Lilly Glucagon (glucagon injection \[rDNA origin\])
G-Pen™ (glucagon injection): 1 mg of pre-mixed liquid Xeris glucagon delivered via auto-injector
Lilly Glucagon (glucagon injection \[rDNA origin\]): 1 mg of Lilly glucagon reconstituted from lyophilized powder | 44 |
| Lilly Glucagon First, Then G-Pen A single 1 mg SC injection of Lilly Glucagon (glucagon injection \[rDNA origin\]) with a 7-28 day wash-out, followed by a single 1 mg SC injection of G-Pen™ (glucagon injection)
Lilly Glucagon (glucagon injection \[rDNA origin\]): 1 mg of Lilly glucagon reconstituted from lyophilized powder
G-Pen™ (glucagon injection): 1 mg of pre-mixed liquid Xeris glucagon delivered via auto-injector | 36 |
| Total | 80 |
Baseline characteristics
| Characteristic | G-Pen First, Then Lilly Glucagon | Lilly Glucagon First, Then G-Pen | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 5 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 40 Participants | 31 Participants | 71 Participants |
| Age, Continuous | 42.1 years STANDARD_DEVIATION 15.55 | 45.5 years STANDARD_DEVIATION 14.87 | 43.6 years STANDARD_DEVIATION 15.25 |
| Race/Ethnicity, Customized Race/Ethnicity African American | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Hispanic | 2 Participants | 4 Participants | 6 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Non-Hispanic White | 38 Participants | 29 Participants | 67 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Other | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment North America Canada | 4 Participants | 4 Participants | 8 Participants |
| Region of Enrollment North America United Staates | 40 Participants | 32 Participants | 72 Participants |
| Sex: Female, Male Female | 15 Participants | 15 Participants | 30 Participants |
| Sex: Female, Male Male | 29 Participants | 21 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 78 | 0 / 79 |
| other Total, other adverse events | 24 / 78 | 16 / 79 |
| serious Total, serious adverse events | 0 / 78 | 1 / 79 |
Outcome results
Primary
Hypoglycemia Rescue: Alternate Glucose Response Definition
Number of subjects with either an increase in plasma glucose concentration from below 50 mg/dL to greater than 70 mg/dL or an increase in from baseline in plasma glucose concentration of at least 20 mg/dL within 30 minutes after administration of glucagon
Time frame: At 30 minutes following administration of study drug
Population: Modified intent-to-treat population of all randomized subjects analyzed by actual treatment received
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| G-Pen | Hypoglycemia Rescue: Alternate Glucose Response Definition | 76 Participants |
| Lilly Glucagon | Hypoglycemia Rescue: Alternate Glucose Response Definition | 79 Participants |
Primary
Hypoglycemia Rescue: Intent-to-Treat Population
Number of subjects with an increase in plasma glucose concentration from below 50 mg/dL to greater than 70 mg/dL within 30 minutes after administration of glucagon
Time frame: At 30 minutes following administration of study drug
Population: Modified intent-to-treat population of all randomized subjects analyzed by actual treatment received
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| G-Pen | Hypoglycemia Rescue: Intent-to-Treat Population | 74 Participants |
| Lilly Glucagon | Hypoglycemia Rescue: Intent-to-Treat Population | 79 Participants |
Primary
Hypoglycemia Rescue: Per Protocol Population
Number of subjects with an increase in plasma glucose concentration from below 50 mg/dL to greater than 70 mg/dL within 30 minutes after administration of glucagon
Time frame: At 30 minutes following administration of study drug
Population: All randomized, treated subjects without a major protocol violation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| G-Pen | Hypoglycemia Rescue: Per Protocol Population | 74 Participants |
| Lilly Glucagon | Hypoglycemia Rescue: Per Protocol Population | 78 Participants |
Secondary
Global Assessment of Hypoglycemia
Time to resolution of the overall sensation of hypoglycemia following administration of glucagon
Time frame: At 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 and 90 minutes following administration of glucagon
Population: Modified intent-to-treat population of all randomized subjects analyzed by actual treatment received
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen | Global Assessment of Hypoglycemia | 16.8 minutes | Standard Deviation 10.7 |
| Lilly Glucagon | Global Assessment of Hypoglycemia | 15.7 minutes | Standard Deviation 8.3 |
Secondary
Plasma Glucose Area Under the Curve (AUC)
Pharmacodynamic endpoint of plasma glucose AUC from baseline to 90 minutes following administration of glucagon
Time frame: At -5, 0, 10, 20, 30, 45, 60, and 90 minutes following administration of glucagon
Population: Modified intent-to-treat population of all randomized subjects analyzed by actual treatment received
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen | Plasma Glucose Area Under the Curve (AUC) | 11651.4 mg*min/dL | Standard Deviation 2406.9 |
| Lilly Glucagon | Plasma Glucose Area Under the Curve (AUC) | 12260.4 mg*min/dL | Standard Deviation 2134.2 |
Secondary
Plasma Glucose Maximum Concentration (Cmax)
Pharmacodynamic endpoint of plasma glucose Cmax from baseline to 4 hours following administration of glucagon
Time frame: At -5, 0, 10, 20, 30, 45, 60, 90, 120, 180 and 240 minutes following administration of glucagon
Population: Modified intent-to-treat population of all randomized subjects analyzed by actual treatment received
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen | Plasma Glucose Maximum Concentration (Cmax) | 202.7 mg/dL | Standard Deviation 41.8 |
| Lilly Glucagon | Plasma Glucose Maximum Concentration (Cmax) | 193.5 mg/dL | Standard Deviation 42.2 |
Secondary
Plasma Glucose Time to Concentration > 70 mg/dL
Pharmacodynamic endpoint of time to achieve a plasma glucose concentration \> 70 mg/dL following administration of glucagon
Time frame: At -5, 0, 10, 20, 30, 45, 60, 90, 120, 180 and 240 minutes following administration of glucagon
Population: Modified intent-to-treat population of all randomized subjects analyzed by actual treatment received
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen | Plasma Glucose Time to Concentration > 70 mg/dL | 19.9 minutes | Standard Deviation 8.5 |
| Lilly Glucagon | Plasma Glucose Time to Concentration > 70 mg/dL | 14.2 minutes | Standard Deviation 4.3 |
Secondary
Plasma Glucose Time to Maximum Concentration (Tmax)
Pharmacodynamic endpoint of plasma glucose Tmax from baseline to 4 hours following administration of glucagon
Time frame: At -5, 0, 10, 20, 30, 45, 60, 90, 120, 180 and 240 minutes following administration of glucagon
Population: Modified intent-to-treat population of all randomized subjects analyzed by actual treatment received
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen | Plasma Glucose Time to Maximum Concentration (Tmax) | 111.3 minutes | Standard Deviation 33.5 |
| Lilly Glucagon | Plasma Glucose Time to Maximum Concentration (Tmax) | 100.4 minutes | Standard Deviation 42.7 |
Secondary
Time to Resolution of Hypoglycemia Symptoms
Time to resolution of mean autonomic, mean neuroglycopenic and mean total hypoglycemia symptom scores from baseline through 90 minutes following administration of glucagon.
Time frame: At 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 and 90 minutes following administration of glucagon
Population: Modified intent-to-treat population of all randomized subjects analyzed by actual treatment received
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| G-Pen | Time to Resolution of Hypoglycemia Symptoms | Autonomic Symptoms | 16.0 minutes | Standard Deviation 11.5 |
| G-Pen | Time to Resolution of Hypoglycemia Symptoms | Neuroglycopenic Symptoms | 16.7 minutes | Standard Deviation 10.2 |
| G-Pen | Time to Resolution of Hypoglycemia Symptoms | All Symptoms | 19.8 minutes | Standard Deviation 11.7 |
| Lilly Glucagon | Time to Resolution of Hypoglycemia Symptoms | Autonomic Symptoms | 14.2 minutes | Standard Deviation 9.4 |
| Lilly Glucagon | Time to Resolution of Hypoglycemia Symptoms | Neuroglycopenic Symptoms | 14.3 minutes | Standard Deviation 9 |
| Lilly Glucagon | Time to Resolution of Hypoglycemia Symptoms | All Symptoms | 17.0 minutes | Standard Deviation 8.9 |
Post Hoc
Hypoglycemia Rescue: Glucose or Symptomatic Response Definition
Number of subjects with either an increase in plasma glucose concentration from below 50 mg/dL to greater than 70 mg/dL or resolution of all neuroglycopenic symptoms of hypoglycemia within 30 minutes after administration of glucagon
Time frame: At 30 minutes following administration of study drug
Population: Modified intent-to-treat population of all randomized subjects analyzed by actual treatment received
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| G-Pen | Hypoglycemia Rescue: Glucose or Symptomatic Response Definition | 78 Participants |
| Lilly Glucagon | Hypoglycemia Rescue: Glucose or Symptomatic Response Definition | 79 Participants |