Safety and Efficacy of G-Pen Compared to Lilly Glucagon for Hypoglycemia Rescue in Adult Type 1 Diabetics

Study Overview
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Brief Summary
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This is a blinded, randomized crossover study to compare the safety and efficacy of G-Pen (glucagon injection) to Lilly Glucagon (glucagon for injection [rDNA origin]) for hypoglycemia rescue of adult patients with type 1 diabetes.

Detailed Description
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This is a blinded, randomized, Phase 3 comparative efficacy and safety study in adults with type 1 diabetes. Patients will complete screening procedures up to 60 days before randomization to determine eligibility before enrollment to the treatment phase. The procedure for evaluating the efficacy of the G-Pen (glucagon injection) consists of inducing hypoglycemia by intravenous administration of regular insulin diluted in normal saline. Each participant will undergo two episodes of insulin-induced hypoglycemia, and in random order will receive 1 mg G-Pen (glucagon injection) during one episode and 1 mg Lilly Glucagon during the other episode. There will be wash out period of 7-28 days between treatment visits. Blood glucose levels will be monitored post-dosing, with a return of plasma glucose to a concentration > 70 mg/dL within 30 minutes signifying successful hypoglycemia rescue. As a confirmation of efficacy, subjects will complete a questionnaire concerning changes in symptoms of hypoglycemia following treatment with glucagon. Subjects will return for a follow-up safety visit 3-14 days following administration of the final dose of glucagon.

Official Title
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G-Pen (Glucagon Injection) Compared to Lilly Glucagon (Glucagon for Injection [RDNA Origin]) for Induced Hypoglycemia Rescue in Adult Patients With T1DM: A Phase 3, Multi-center, Randomized, Blinded, 2-Way Crossover Study to Evaluate Efficacy and Safety

Conditions
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Hypoglycemia, Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: G-Pen (glucagon injection)
* Drug: Lilly Glucagon (glucagon injection [rDNA origin])


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: diagnosed with type 1 diabetes mellitus for at least 24 months usage of daily insulin treatment random serum C-peptide concentration < 0.5 ng/mL Exclusion Criteria: pregnant or nursing HbA1c >9.0% renal insufficiency hepatic synthetic insufficiency aspartate or alanine aminotransferase > 3 times the upper limit of normal hematocrit less than or equal to 30% use of > 2.0 U/kg total insulin dose per day inadequate bilateral venous access in both arms congestive heart failure, New York Heart Association class II, III or IV active malignancy within 5 years, except basal cell or squamous cell skin cancers history of breast cancer or malignant melanoma major surgical operation within 30 days current seizure disorder. current bleeding disorder, treatment with warfarin, or platelet count below 50,000 history of pheochromocytoma or disorder with increased risk of pheochromocytoma history of insulinoma history of glycogen storage disease. positive for HIV, hepatitis C virus or active hepatitis B virus infection whole blood donation of 1 pint (500 mL) within 8 weeks active substance or alcohol abuse administration of glucagon within 28 days participation in other studies involving an investigational drug or device within 30 days

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: G-Pen first, then Lilly Glucagon<br>A single 1 mg subcutaneous (SC) injection of G-Pen (glucagon injection) with a 7-28 day wash-out, followed by a single 1 mg SC injection of Lilly Glucagon (glucagon injection [rDNA origin]) | Drug: G-Pen (glucagon injection)<br>* 1 mg of pre-mixed liquid Xeris glucagon delivered via auto-injector<br>* Other names: glucagon;Drug: Lilly Glucagon (glucagon injection [rDNA origin])<br>* 1 mg of Lilly glucagon reconstituted from lyophilized powder<br>* Other names: glucagon;|
| Other: Lilly Glucagon first, then G-Pen<br>A single 1 mg SC injection of Lilly Glucagon (glucagon injection [rDNA origin]) with a 7-28 day wash-out, followed by a single 1 mg SC injection of G-Pen (glucagon injection) | Drug: G-Pen (glucagon injection)<br>* 1 mg of pre-mixed liquid Xeris glucagon delivered via auto-injector<br>* Other names: glucagon;Drug: Lilly Glucagon (glucagon injection [rDNA origin])<br>* 1 mg of Lilly glucagon reconstituted from lyophilized powder<br>* Other names: glucagon;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hypoglycemia Rescue: Intent-to-Treat Population | Number of subjects with an increase in plasma glucose concentration from below 50 mg/dL to greater than 70 mg/dL within 30 minutes after administration of glucagon | At 30 minutes following administration of study drug | 
| Hypoglycemia Rescue: Per Protocol Population | Number of subjects with an increase in plasma glucose concentration from below 50 mg/dL to greater than 70 mg/dL within 30 minutes after administration of glucagon | At 30 minutes following administration of study drug | 
| Hypoglycemia Rescue: Alternate Glucose Response Definition | Number of subjects with either an increase in plasma glucose concentration from below 50 mg/dL to greater than 70 mg/dL or an increase in from baseline in plasma glucose concentration of at least 20 mg/dL within 30 minutes after administration of glucagon | At 30 minutes following administration of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Glucose Area Under the Curve (AUC) | Pharmacodynamic endpoint of plasma glucose AUC from baseline to 90 minutes following administration of glucagon | At -5, 0, 10, 20, 30, 45, 60, and 90 minutes following administration of glucagon | 
| Plasma Glucose Maximum Concentration (Cmax) | Pharmacodynamic endpoint of plasma glucose Cmax from baseline to 4 hours following administration of glucagon | At -5, 0, 10, 20, 30, 45, 60, 90, 120, 180 and 240 minutes following administration of glucagon | 
| Plasma Glucose Time to Maximum Concentration (Tmax) | Pharmacodynamic endpoint of plasma glucose Tmax from baseline to 4 hours following administration of glucagon | At -5, 0, 10, 20, 30, 45, 60, 90, 120, 180 and 240 minutes following administration of glucagon | 
| Plasma Glucose Time to Concentration > 70 mg/dL | Pharmacodynamic endpoint of time to achieve a plasma glucose concentration > 70 mg/dL following administration of glucagon | At -5, 0, 10, 20, 30, 45, 60, 90, 120, 180 and 240 minutes following administration of glucagon | 
| Time to Resolution of Hypoglycemia Symptoms | Time to resolution of mean autonomic, mean neuroglycopenic and mean total hypoglycemia symptom scores from baseline through 90 minutes following administration of glucagon. | At 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 and 90 minutes following administration of glucagon | 
| Global Assessment of Hypoglycemia | Time to resolution of the overall sensation of hypoglycemia following administration of glucagon | At 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 and 90 minutes following administration of glucagon |