G-Pen™ Compared to Lilly Glucagon for Hypoglycemia Rescue in Adults With Type 1 Diabetes

G-Pen™ (Glucagon Injection) Compared to Lilly Glucagon (Glucagon for Injection [RDNA Origin]) for Induced Hypoglycemia Rescue in Adults With T1D: a Phase 3 B Multi-Centered, Randomized, Controlled, Single Blind, 2-Way Crossover Study to Evaluate Efficacy and Safety

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.

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.