Insulin Hypoglycemia, Severe Hypoglycemia, Type 1 Diabetes Mellitus
Conditions
Keywords
glucagon, hypoglycemia
Brief summary
This is a 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 Novo 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 severe hypoglycemia through IV administration of regular insulin diluted in normal saline. After a hypoglycemic state with plasma glucose \< 54 mg/dL (3 mmol/L) is verified, the subject is administered a dose of G-Pen or Novo Glucagon via subcutaneous injection. Plasma glucose levels are monitored for up to 180 minutes post-dosing, with a value of \>70.0 mg/dL (3.89 mmol/L) or an increase of \> 20 mg/dL (\>1.11 mmol/L) 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 procedures 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
DRUGNovo Glucagon
1 mg subcutaneous injection of Novo Glucagon (glucagon injection)
Sponsors
Empiristat, Inc.
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 non-pregnant females diagnosed with type 1 diabetes (T1D) 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 to 75 years, inclusive. 4. Random serum C-peptide concentration \< 0.6 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 and dated informed consent form (ICF) completed before any trial-related activities occur.
Exclusion criteria
1. Pregnancy 2. Glycated hemoglobin (HbA1c) \> 10% at Screening. 3. Body mass index (BMI) \> 40 kg/m2. 4. Renal insufficiency (serum creatinine greater than 3.0 mg/dL) or end-stage renal disease requiring renal replacement therapy. 5. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) equal to or greater than 3 times the upper limit of normal. 6. Hepatic synthetic insufficiency as defined as a serum albumin of less than 3.0 g/dL. 7. Hematocrit \< 30%. 8. Blood pressure (BP) readings at Screening where systolic blood pressure (SBP) \< 90 or \> 150 mm Hg, and diastolic blood pressure (DBP) \< 50 or \> 100 mm Hg. 9. Clinically significant electrocardiogram (ECG) abnormalities. 10. Use of total insulin dose per day \> 2 U/kg. 11. Inadequate venous access. 12. Congestive heart failure, New York Heart Association (NYHA) class III or IV. 13. History of myocardial infarction, unstable angina, or revascularization within the past 6 months. 14. History of a cerebrovascular accident in the past 6 months or with major neurological deficits. 15. Active malignancy within 5 years from Screening, except basal cell or squamous cell skin cancers. Any history of breast cancer or malignant melanoma will be exclusionary. 16. Major surgical operation within 30 days prior to Screening. 17. Current seizure disorder (other than with suspect or documented hypoglycemia). 18. Current bleeding disorder, treatment with warfarin, or platelet count below 50 × 109 per liter. 19. History of pheochromocytoma or disorder with increased risk of pheochromocytoma (multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis, or Von Hippel-Lindau disease). 20. History of insulinoma. 21. 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 and trehalose) in the investigational formulation. 22. History of glycogen storage disease. 23. Subject tests positive for human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) infection (hepatitis B surface antigen positive \[HBsAg+\]) at Screening. 24. Active substance other than tetrahydrocannabinol (THC) or alcohol abuse (more than 21 drinks per week for male subjects or 14 drinks per week for female subject). 25. Administration of glucagon within 7 days of Screening. 26. 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. 27. Any other reason the Investigator deems exclusionary.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Severe Hypoglycemia Rescue | At 30 minutes following administration of study drug | Number of subjects with an increase in plasma glucose concentration from below 54 mg/dL (3 mmol/L) to greater than 70 mg/dL (3.89 mmol/L) or an increase in plasma glucose concentration \> 20 mg/dL (\> 1.11 mmol/L) within 30 minutes after administration of glucagon |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Glucose Response 1 | At 30 minutes following a decision to administer study drug | Number of subjects with an increase in plasma glucose concentration from below 54 mg/dL (3 mmol/L) to greater than 70 mg/dL (3.89 mmol/L) within 30 minutes of a decision to dose |
| Plasma Glucose Response 2 | At 0-30 minutes following a decision to administer study drug | Number of subjects with an increase in plasma glucose concentration \> 20 mg/dL (\> 1.11 mmol/L) after administration of glucagon. |
| Administration Time | At 0-10 minutes from a decision to administer study drug | Mean time (minutes) to administer study drug from a decision to dose |
| Hypoglycemia Resolution | At 0-90 minutes following administration of study drug | Mean time (minutes) to complete resolution of the overall sensation of hypoglycemia from a decision to dose |
Countries
Austria, Canada, United States
Participant flow
Pre-assignment details
132 subjects were randomized, however 1 subject withdrew prior to dosing, therefore 131 subjects received study drug.
Participants by arm
| Arm | Count |
|---|---|
| G-Pen, Then Novo Glucagon Participants first received G-Pen 1 mg subcutaneous injection each. After a washout period of 7-28 days, they then received Novo Glucagon 1 mg subcutaneous injection. | 66 |
| Novo Glucagon, Then G-Pen Participants first received Novo Glucagon 1 mg subcutaneous injection each. After a washout period of 7-28 days, they then received G-Pen 1 mg subcutaneous injection. | 66 |
| Total | 132 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Total | Novo Glucagon, Then G-Pen | G-Pen, Then Novo Glucagon |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 3 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 126 Participants | 63 Participants | 63 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 128 Participants | 63 Participants | 65 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 | 6 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 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 | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 123 Participants | 61 Participants | 62 Participants |
| Sex: Female, Male Female | 62 Participants | 33 Participants | 29 Participants |
| Sex: Female, Male Male | 70 Participants | 33 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 127 | 0 / 123 |
| other Total, other adverse events | 67 / 127 | 57 / 123 |
| serious Total, serious adverse events | 0 / 127 | 0 / 123 |
Outcome results
Primary
Severe Hypoglycemia Rescue
Number of subjects with an increase in plasma glucose concentration from below 54 mg/dL (3 mmol/L) to greater than 70 mg/dL (3.89 mmol/L) or an increase in plasma glucose concentration \> 20 mg/dL (\> 1.11 mmol/L) within 30 minutes after administration of glucagon
Time frame: At 30 minutes following administration of study drug
Population: Intent-to-Treat Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| G-Pen | Severe Hypoglycemia Rescue | 127 Participants |
| Novo Glucagon | Severe Hypoglycemia Rescue | 123 Participants |
Secondary
Administration Time
Mean time (minutes) to administer study drug from a decision to dose
Time frame: At 0-10 minutes from a decision to administer study drug
Population: Intent-to-Treat Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen | Administration Time | 0.79 minutes | Standard Deviation 0.53 |
| Novo Glucagon | Administration Time | 1.76 minutes | Standard Deviation 0.678 |
Secondary
Hypoglycemia Resolution
Mean time (minutes) to complete resolution of the overall sensation of hypoglycemia from a decision to dose
Time frame: At 0-90 minutes following administration of study drug
Population: Intent-to-Treat Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen | Hypoglycemia Resolution | 15.69 minutes | Standard Deviation 7.428 |
| Novo Glucagon | Hypoglycemia Resolution | 15.32 minutes | Standard Deviation 8.479 |
Secondary
Plasma Glucose Response 1
Number of subjects with an increase in plasma glucose concentration from below 54 mg/dL (3 mmol/L) to greater than 70 mg/dL (3.89 mmol/L) within 30 minutes of a decision to dose
Time frame: At 30 minutes following a decision to administer study drug
Population: Intent-to-Treat Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| G-Pen | Plasma Glucose Response 1 | 127 Participants |
| Novo Glucagon | Plasma Glucose Response 1 | 123 Participants |
Secondary
Plasma Glucose Response 2
Number of subjects with an increase in plasma glucose concentration \> 20 mg/dL (\> 1.11 mmol/L) after administration of glucagon.
Time frame: At 0-30 minutes following a decision to administer study drug
Population: Intent-to-Treat Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| G-Pen | Plasma Glucose Response 2 | 127 Participants |
| Novo Glucagon | Plasma Glucose Response 2 | 123 Participants |