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

• G-Pen (Drug), also known as glucagon: 1 mg subcutaneous injection of G-Pen (glucagon injection) administered via auto-injector
• Lilly Glucagon (Drug), also known as GEK: 1 mg subcutaneous injection of Lilly Glucagon (glucagon injection \[RNDA Origin\])

Primary outcomes

• 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 outcomes

• 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
• 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 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.
• 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

Sex: All, ages: 18 Years to 75 Years

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.

Participant flow

Outcome results

• Number of Subjects With a Positive Glucose Response (Primary), Count of participants, Participants: G-Pen 76; Lilly Glucagon 78
• Time for Positive Glucose Response (Secondary), Mean, minutes: G-Pen 12.17 +/- 3.604; Lilly Glucagon 8.58 +/- 2.026
• Number of Subjects With a Positive Response for the Combination Endpoint: Positive Glucose Response/Positive Glucose Increase (Secondary), Count of participants, Participants: G-Pen 76; Lilly Glucagon 78
• Number of Subjects With a Positive Glucose Increase (Secondary), Count of participants, Participants: G-Pen 76; Lilly Glucagon 78
• Time for Positive Glucose Increase (Secondary), Mean, minutes: G-Pen 11.36 +/- 3.345; Lilly Glucagon 8.02 +/- 1.856
• Number of Subjects With a Positive Response for the Combination Endpoint: Positive Glucose Response/Relief of Neuroglycopenic Symptoms (Secondary), Count of participants, Participants: G-Pen 76; Lilly Glucagon 78
• Number of Subjects With Relief of Neuroglycopenic Symptoms (Secondary), Count of participants, Participants: G-Pen 74; Lilly Glucagon 77
• Time to Resolution of Autonomic Symptoms (Secondary), Mean, minutes: G-Pen 13.8 +/- 10.89; Lilly Glucagon 12.0 +/- 7.44
• Time to Resolution of Neuroglycopenic Symptoms (Secondary), Mean, minutes: G-Pen 14.2 +/- 15.12; Lilly Glucagon 12.2 +/- 8.85
• Time to Resolution of the Feeling of Hypoglycemia (Secondary), Mean, minutes: G-Pen 11.6 +/- 6.45; Lilly Glucagon 13.1 +/- 7.86
• Glucose AUC (Secondary), Mean, mg∙min/dL: G-Pen 33686.04 +/- 5300.204; Lilly Glucagon 33538.60 +/- 5705.219
• Glucose Cmax (Secondary), Mean, mg/dL: G-Pen 238.32 +/- 45.626; Lilly Glucagon 228.11 +/- 46.567
• Glucose Tmax (Secondary), Mean, minutes: G-Pen 125.67 +/- 33.513; Lilly Glucagon 113.89 +/- 31.908
• Glucagon Preparation and Administration Time (Secondary), Mean, seconds: G-Pen 27.3 +/- 19.66; Lilly Glucagon 97.2 +/- 45.06

Adverse events

Time frame: Adverse events were collected for up to 9 weeks, from the time of consent through the follow-up visit.

Other adverse events by term

• Results publication: Christiansen MP, Cummins M, Prestrelski S, Close NC, Nguyen A, Junaidi K. Comparison of a ready-to-use liquid glucagon injection administered by autoinjector to glucagon emergency kit for the symptomatic relief of severe hypoglycemia: two randomized crossover non-inferiority studies. BMJ Open Diabetes Res Care. 2021 Oct;9(1):e002137. doi: 10.1136/bmjdrc-2021-002137. PMID 34620618

• Study Protocol (PDF, 2018-01-29)
• Statistical Analysis Plan (PDF, 2018-05-03)