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

Phase 3

Completed

• Conditions: Type 1 Diabetes Mellitus; Severe Hypoglycemia; Insulin Hypoglycemia
• Interventions: Drug: G-Pen; Drug: Lilly Glucagon

• Registration Number: NCT03439072
• Lead Sponsor: Xeris Pharmaceuticals

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2018-01-23
• Study First Submitted: 2018-02-13
• Study First Submitted QC: 2018-02-13
• Study First Posted: 2018-02-20
• Primary Completion: 2018-04-18
• Study Completion: 2018-05-03
• Results First Submitted: 2019-04-17
• Results First Submitted QC: 2019-05-09
• Results First Posted: 2019-05-30
• Status Verified: 2020-02
• Last Update Submitted: 2020-02-13
• Last Update Posted: 2020-02-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 81

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
G-Pen followed by Lilly Glucagon	Lilly Glucagon	1 mg G-Pen at the first treatment visit followed by 1 mg Lilly Glucagon at the second treatment visit
Lilly Glucagon followed by G-Pen	Lilly Glucagon	1 mg Lilly Glucagon at the first treatment visit followed by 1 mg G-Pen at the second treatment visit
G-Pen followed by Lilly Glucagon	G-Pen	1 mg G-Pen at the first treatment visit followed by 1 mg Lilly Glucagon at the second treatment visit
Lilly Glucagon followed by G-Pen	G-Pen	1 mg Lilly Glucagon at the first treatment visit followed by 1 mg G-Pen at the second treatment visit

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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 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 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
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.
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 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.
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.
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 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 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.

Trial Locations

Locations (6)

ProSciento, Inc.; 🇺🇸 Chula Vista, California, United States

Atlanta Diabetes Associates; 🇺🇸 Atlanta, Georgia, United States

Diablo Clinical Research, Inc.; 🇺🇸 Walnut Creek, California, United States

Rainier Clinical Research Center, Inc.; 🇺🇸 Renton, Washington, United States

LMC ESD, Inc.; 🇨🇦 Toronto, Ontario, Canada

Altasciences Algorithme Pharma; 🇨🇦 Montréal, Quebec, Canada