Insulin Hypoglycemia, Severe Hypoglycemia, Type 1 Diabetes Mellitus
Conditions
Keywords
glucagon, hypoglycemia
Brief summary
This is a non-inferiority, multi-center, randomized, controlled, single-blind, two-way crossover efficacy and safety study in subjects with Type 1 diabetes mellitus. The study involves two daytime clinical research center (CRC) visits with random assignment to receive G-Pen™ glucagon 1 mg during one period and Lilly Glucagon 1 mg during the other. Each daytime visit is preceded by an overnight stay in the CRC. In the morning of the inpatient study visit, the subject is brought into a state of hypoglycemia through IV administration of regular insulin diluted in normal saline. After a hypoglycemic state with plasma glucose \< 50 mg/dL is verified, the subject is administered a dose of G-Pen or Lilly Glucagon via subcutaneous injection. Plasma glucose levels are monitored for up to 180 minutes post-dosing, with a value of \>70.0 mg/dL within 30 minutes of glucagon administration indicating a positive response. After 3 hours, the subject is given a meal and discharged when medically stable. After a wash-out period of 7 to 28 days, subjects return to the CRC, and the procedure are repeated with each subject crossed over to the other treatment. A follow-up visit as a safety check is conducted 2-7 days following administration of the final dose of study drug.
Interventions
DRUGG-Pen
1 mg subcutaneous injection of G-Pen (glucagon injection) administered via auto-injector
DRUGLilly Glucagon
1 mg subcutaneous injection of Lilly Glucagon (glucagon injection \[RNDA Origin\])
Sponsors
SGS S.A.
Integrated Medical Development
Xeris Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Males and females diagnosed with type 1 diabetes mellitus for at least 24 months. 2. Current usage of daily insulin treatment that includes having an assigned correction factor for managing hyperglycemia. 3. Age 18-75 years, inclusive. 4. Random serum C-peptide concentration \< 0.5 ng/mL. 5. Willingness to follow all study procedures, including attending all clinic visits. 6. Subject has provided informed consent as evidenced by a signed/dated informed consent form completed before any trial-related activities occur.
Exclusion criteria
1. Pregnancy: For women of childbearing potential, there is a requirement for a negative urine pregnancy test and for agreement to use contraception throughout the study and for 7 days after the last dose of study glucagon. Acceptable contraception includes birth control pill / patch / vaginal ring, Depo-Provera, Norplant, an IUD, the double barrier method (the woman uses a diaphragm and spermicide and the man uses a condom), or abstinence. 2. Breastfeeding: Nursing mothers will be allowed into the study. However, breast feeding during the during inpatient study visits and for 48 hours after each dose of study drug is not allowed. 3. HbA1c \>9.0% at Screening. 4. BMI \> 40 kg/m2. 5. Renal insufficiency (serum creatinine greater than 3.0 mg/dL) or end-stage renal disease. requiring renal replacement therapy. 6. Serum ALT or AST equal to or greater than 3 times the upper limit of normal. 7. Hepatic synthetic insufficiency as defined as a serum albumin of less than 3.0 g/dL. 8. Hematocrit of less than or equal to 30%. 9. BP readings at Screening where SBP \<90 or \>150 mm Hg, and DBP \<50 or \>100 mm Hg. 10. Clinically significant ECG abnormalities. 11. Use of \> 2.0 U/kg total insulin dose per day. 12. Inadequate venous access. 13. Congestive heart failure, NYHA class III or IV. 14. History of myocardial infarction, unstable angina, or revascularization within the past 6 months. 15. History of a cerebrovascular accident in past 6 months or with major neurological deficits. 16. Active malignancy within 5 years from Screening, except basal cell or squamous cell skin cancers. History of breast cancer or malignant melanoma will be exclusionary. 17. Major surgical operation within 30 days prior to Screening. 18. Current seizure disorder (other than with suspect or documented hypoglycemia). 19. Current bleeding disorder, treatment with warfarin, or platelet count below 50 x 10e9 per liter. 20. History of pheochromocytoma or disorder with increased risk of pheochromocytoma (MEN 2, neurofibromatosis, or Von Hippel-Lindau disease). 21. History of insulinoma. 22. History of allergies to glucagon or glucagon-like products, or any history of significant hypersensitivity to glucagon or any related products or to any of the excipients (DMSO & trehalose) in the investigational formulation. 23. History of glycogen storage disease. 24. Subject tests positive for HIV, HCV or HBV infection (HBsAg+) at Screening. 25. Active substance or alcohol abuse (more than 21 drinks/wk. for males or 14 drinks/wk. for females). Subjects reporting active marijuana use or testing positive for tetrahydrocannabinol (THC) via rapid urine test will be allowed to participate in the study at the discretion of the Investigator. 26. Administration of glucagon within 28 days of Screening. 27. 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 and during participation in the current study. 28. Any reason the Investigator deems exclusionary.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With a Positive Glucose Response | 0 to 30 minutes post dose | Increase in plasma glucose concentration from below 50.0 mg/dL to greater than 70.0 mg/dL within 30 minutes after receiving glucagon |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With a Positive Response for the Combination Endpoint: Positive Glucose Response/Positive Glucose Increase | 0 to 30 minutes post dose | A positive response for this endpoint is a return of plasma glucose to \> 70 mg/dL or an increase in plasma glucose by ≥20 mg/dL within 30 minutes after receiving glucagon |
| Number of Subjects With a Positive Glucose Increase | 0 to 30 minutes post dose | Increase in plasma glucose by ≥ 20.0 mg/dL within 30 minutes after receiving glucagon |
| Time for Positive Glucose Increase | 0 to 180 minutes post dose | Time from administration of glucagon for plasma glucose to increase by ≥20 mg/dL from baseline |
| Number of Subjects With a Positive Response for the Combination Endpoint: Positive Glucose Response/Relief of Neuroglycopenic Symptoms | 0 to 30 minutes post dose | A positive response for this endpoint is a return of plasma glucose to \> 70 mg/dL or clearance of all neuroglycopenic symptoms of hypoglycemia within 30 minutes after receiving glucagon. Four symptoms were assessed: dizziness, blurred vision, difficulty in thinking and faintness. |
| Number of Subjects With Relief of Neuroglycopenic Symptoms | 0 to 30 minutes post dose | Clearance of all neuroglycopenic symptoms of hypoglycemia within 30 minutes after receiving glucagon. Four symptoms were assessed: dizziness, blurred vision, difficulty in thinking and faintness. |
| Time to Resolution of Autonomic Symptoms | 0 to 180 minutes post dose | Time from administration of glucagon to complete resolution of 4 autonomic symptoms of hypoglycemia. Symptoms included: sweating, tremor, palpitations and feeling of nervousness. |
| Time for Positive Glucose Response | 0 to 180 minutes post dose | Time from administration of glucagon for plasma glucose to rise from below 50.0 mg/dL to above 70.0 mg/dL |
| Time to Resolution of the Feeling of Hypoglycemia | 0 to 180 minutes post dose | Time from administration of glucagon to resolution of the overall sensation of hypoglycemia. Subjects were asked to answer yes/no to the question, Do you feel hypoglycemic? The time point as which the subject first answered no was considered the time of resolution. |
| Glucose AUC | 0 to 180 minutes post dose - Blood samples for assessment of blood glucose concentration were collected every 5 minutes post-dose to 90 minutes, and then at 120, 150 and 180 minutes post dose. | Area under the curve for plasma glucose. |
| Glucose Cmax | 0 to 180 minutes post dose - Blood samples for assessment of blood glucose concentration were collected every 5 minutes post-dose to 90 minutes, and then at 120, 150 and 180 minutes post dose. | Maximum concentration of plasma glucose. |
| Glucose Tmax | 0 to 180 minutes post dose | Time to maximum concentration of plasma glucose. Blood samples for assessment of blood glucose concentration were collected every 5 minutes post-dose to 90 minutes, and then at 120, 150 and 180 minutes post dose. |
| Glucagon Preparation and Administration Time | 0 to 5 minutes pre-dose | Time required to prepare and inject glucagon as measured between a decision to dose and completion of the injection |
| Time to Resolution of Neuroglycopenic Symptoms | 0 to 180 minutes post dose | Time from administration of glucagon to complete resolution of 4 neuroglycopenic symptoms of hypoglycemia. Four symptoms were assessed: dizziness, blurred vision, difficulty in thinking and faintness. |
Countries
Canada, United States
Participant flow
Recruitment details
The recruitment period began 08 Jan 2018 and ran through 02 Apr 2018. Subjects were screened for study eligibility at one of the six clinical sites up to 30 days prior to randomization.
Pre-assignment details
A total of 81 eligible subjects were randomized to treatment. However, two subjects withdrew consent prior to dosing, so the number of subjects exposed to study treatment was 79.
Participants by arm
| Arm | Count |
|---|---|
| All Randomized Subjects A total of 81 subjects met eligibility requirements and were randomized to study treatment. | 81 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | All Randomized Subjects |
|---|---|
| Age, Continuous | 38.2 years STANDARD_DEVIATION 14.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 75 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 71 Participants |
| Region of Enrollment North America | 81 participants |
| Sex: Female, Male Female | 37 Participants |
| Sex: Female, Male Male | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 76 | 0 / 78 |
| other Total, other adverse events | 46 / 76 | 34 / 78 |
| serious Total, serious adverse events | 0 / 76 | 0 / 78 |
Outcome results
Primary
Number of Subjects With a Positive Glucose Response
Increase in plasma glucose concentration from below 50.0 mg/dL to greater than 70.0 mg/dL within 30 minutes after receiving glucagon
Time frame: 0 to 30 minutes post dose
Population: Intent to treat analysis population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| G-Pen | Number of Subjects With a Positive Glucose Response | 76 Participants |
| Lilly Glucagon | Number of Subjects With a Positive Glucose Response | 78 Participants |
Secondary
Glucagon Preparation and Administration Time
Time required to prepare and inject glucagon as measured between a decision to dose and completion of the injection
Time frame: 0 to 5 minutes pre-dose
Population: Intent to treat analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen | Glucagon Preparation and Administration Time | 27.3 seconds | Standard Deviation 19.66 |
| Lilly Glucagon | Glucagon Preparation and Administration Time | 97.2 seconds | Standard Deviation 45.06 |
Secondary
Glucose AUC
Area under the curve for plasma glucose.
Time frame: 0 to 180 minutes post dose - Blood samples for assessment of blood glucose concentration were collected every 5 minutes post-dose to 90 minutes, and then at 120, 150 and 180 minutes post dose.
Population: Intent to treat analysis population. Due to missing data AUC was only evaluable in 67 subjects per arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen | Glucose AUC | 33686.04 mg∙min/dL | Standard Deviation 5300.204 |
| Lilly Glucagon | Glucose AUC | 33538.60 mg∙min/dL | Standard Deviation 5705.219 |
Secondary
Glucose Cmax
Maximum concentration of plasma glucose.
Time frame: 0 to 180 minutes post dose - Blood samples for assessment of blood glucose concentration were collected every 5 minutes post-dose to 90 minutes, and then at 120, 150 and 180 minutes post dose.
Population: Intent to treat analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen | Glucose Cmax | 238.32 mg/dL | Standard Deviation 45.626 |
| Lilly Glucagon | Glucose Cmax | 228.11 mg/dL | Standard Deviation 46.567 |
Secondary
Glucose Tmax
Time to maximum concentration of plasma glucose. Blood samples for assessment of blood glucose concentration were collected every 5 minutes post-dose to 90 minutes, and then at 120, 150 and 180 minutes post dose.
Time frame: 0 to 180 minutes post dose
Population: Intent to treat analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen | Glucose Tmax | 125.67 minutes | Standard Deviation 33.513 |
| Lilly Glucagon | Glucose Tmax | 113.89 minutes | Standard Deviation 31.908 |
Secondary
Number of Subjects With a Positive Glucose Increase
Increase in plasma glucose by ≥ 20.0 mg/dL within 30 minutes after receiving glucagon
Time frame: 0 to 30 minutes post dose
Population: Intent to treat analysis population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| G-Pen | Number of Subjects With a Positive Glucose Increase | 76 Participants |
| Lilly Glucagon | Number of Subjects With a Positive Glucose Increase | 78 Participants |
Secondary
Number of Subjects With a Positive Response for the Combination Endpoint: Positive Glucose Response/Positive Glucose Increase
A positive response for this endpoint is a return of plasma glucose to \> 70 mg/dL or an increase in plasma glucose by ≥20 mg/dL within 30 minutes after receiving glucagon
Time frame: 0 to 30 minutes post dose
Population: Intent to treat analysis population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| G-Pen | Number of Subjects With a Positive Response for the Combination Endpoint: Positive Glucose Response/Positive Glucose Increase | 76 Participants |
| Lilly Glucagon | Number of Subjects With a Positive Response for the Combination Endpoint: Positive Glucose Response/Positive Glucose Increase | 78 Participants |
Secondary
Number of Subjects With a Positive Response for the Combination Endpoint: Positive Glucose Response/Relief of Neuroglycopenic Symptoms
A positive response for this endpoint is a return of plasma glucose to \> 70 mg/dL or clearance of all neuroglycopenic symptoms of hypoglycemia within 30 minutes after receiving glucagon. Four symptoms were assessed: dizziness, blurred vision, difficulty in thinking and faintness.
Time frame: 0 to 30 minutes post dose
Population: Intent to treat analysis population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| G-Pen | Number of Subjects With a Positive Response for the Combination Endpoint: Positive Glucose Response/Relief of Neuroglycopenic Symptoms | 76 Participants |
| Lilly Glucagon | Number of Subjects With a Positive Response for the Combination Endpoint: Positive Glucose Response/Relief of Neuroglycopenic Symptoms | 78 Participants |
Secondary
Number of Subjects With Relief of Neuroglycopenic Symptoms
Clearance of all neuroglycopenic symptoms of hypoglycemia within 30 minutes after receiving glucagon. Four symptoms were assessed: dizziness, blurred vision, difficulty in thinking and faintness.
Time frame: 0 to 30 minutes post dose
Population: Intent to treat analysis population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| G-Pen | Number of Subjects With Relief of Neuroglycopenic Symptoms | 74 Participants |
| Lilly Glucagon | Number of Subjects With Relief of Neuroglycopenic Symptoms | 77 Participants |
Secondary
Time for Positive Glucose Increase
Time from administration of glucagon for plasma glucose to increase by ≥20 mg/dL from baseline
Time frame: 0 to 180 minutes post dose
Population: Intent to treat analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen | Time for Positive Glucose Increase | 11.36 minutes | Standard Deviation 3.345 |
| Lilly Glucagon | Time for Positive Glucose Increase | 8.02 minutes | Standard Deviation 1.856 |
Secondary
Time for Positive Glucose Response
Time from administration of glucagon for plasma glucose to rise from below 50.0 mg/dL to above 70.0 mg/dL
Time frame: 0 to 180 minutes post dose
Population: Intent-to treat analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen | Time for Positive Glucose Response | 12.17 minutes | Standard Deviation 3.604 |
| Lilly Glucagon | Time for Positive Glucose Response | 8.58 minutes | Standard Deviation 2.026 |
Secondary
Time to Resolution of Autonomic Symptoms
Time from administration of glucagon to complete resolution of 4 autonomic symptoms of hypoglycemia. Symptoms included: sweating, tremor, palpitations and feeling of nervousness.
Time frame: 0 to 180 minutes post dose
Population: Intent to treat analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen | Time to Resolution of Autonomic Symptoms | 13.8 minutes | Standard Deviation 10.89 |
| Lilly Glucagon | Time to Resolution of Autonomic Symptoms | 12.0 minutes | Standard Deviation 7.44 |
Secondary
Time to Resolution of Neuroglycopenic Symptoms
Time from administration of glucagon to complete resolution of 4 neuroglycopenic symptoms of hypoglycemia. Four symptoms were assessed: dizziness, blurred vision, difficulty in thinking and faintness.
Time frame: 0 to 180 minutes post dose
Population: Intent to treat analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen | Time to Resolution of Neuroglycopenic Symptoms | 14.2 minutes | Standard Deviation 15.12 |
| Lilly Glucagon | Time to Resolution of Neuroglycopenic Symptoms | 12.2 minutes | Standard Deviation 8.85 |
Secondary
Time to Resolution of the Feeling of Hypoglycemia
Time from administration of glucagon to resolution of the overall sensation of hypoglycemia. Subjects were asked to answer yes/no to the question, Do you feel hypoglycemic? The time point as which the subject first answered no was considered the time of resolution.
Time frame: 0 to 180 minutes post dose
Population: Intent to treat analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen | Time to Resolution of the Feeling of Hypoglycemia | 11.6 minutes | Standard Deviation 6.45 |
| Lilly Glucagon | Time to Resolution of the Feeling of Hypoglycemia | 13.1 minutes | Standard Deviation 7.86 |