A Trial to Evaluate the Immunogenicity of Dasiglucagon and GlucaGen in Patients With Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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The trial's objective is to evaluate the immunogenicity of repeated single doses of dasiglucagon* and GlucaGen following subcutaneous (SC) administration in patients with type 1 diabetes mellitus (T1DM) and further to evaluate the safety and tolerability of dasiglucagon and GlucaGen. *dasiglucagon is the proposed International Nonproprietary Name (pINN) for ZP4207

Detailed Description
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Patients with T1DM were randomly assigned in a 1:1 ratio to receive 3 SC injections of either dasiglucagon (0.6 mg) or GlucaGen (1 mg), with 1 week between doses. Patients were followed for 15 weeks from the day of the first dose to assess the immune response. Patients with previous exogenic glucagon exposure were not excluded from the trial, but the information on previous glucagon administration was recorded to enable subgroup analyses. It was expected that 112 patients in total would be randomly assigned to treatment groups and treated. A total of 90 patients were expected to complete the trial (45 in each treatment arm). To qualify as completed, the patient had to be dosed according to the procedure described in the protocol and to have blood drawn for the antidrug antibody analyses as scheduled.

Official Title
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A Phase 3, Randomized, Double-Blind, Parallel Group Safety Trial to Evaluate the Immunogenicity of Dasiglucagon and GlucaGen® Administered Subcutaneously in Patients With Type 1 Diabetes Mellitus (T1DM)

Conditions
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Hypoglycemia, Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: dasiglucagon
* Drug: GlucaGen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent obtained before any trial-related activities (trial-related activities are any procedure that would not have been performed during normal management of the patient) Availability for the entire trial period Age between 18 and 70 years, both inclusive Male or female patients with T1DM for at least 1 year. Diagnostic criteria as defined by the American Diabetes Association Hemoglobin A1c (HbA1c) <10% Stable anti-diabetic treatment for at least 1 month (e.g. within 10% insulin dose adjustment) Exclusion Criteria: Previous administration of dasiglucagon (previously referred to as ZP4207) Known or suspected allergy to trial medication(s) or related products History of anaphylaxis or symptoms of severe systemic allergy (such as angioedema) Previous participation (randomization) in this trial Females who are pregnant according to a positive pregnancy test, actively attempting to get pregnant, or are lactating Patients on a closed loop artificial pancreas Receipt of any investigational drug within 3 months prior to screening Active malignancy within the last 5 years Congestive heart failure, New York Heart Association class II-IV Inadequately treated blood pressure as defined as systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥90 mmHg at screening Current bleeding disorder, including use of anticoagulant treatment Known presence or history of pheochromocytoma (i.e. adrenal gland tumor) or insulinoma (i.e. insulin-secreting pancreas tumor) Known or suspected HIV infection Use of a systemic beta-blocker drug, indomethacin, warfarin or anticholinergic drugs in the previous 28 days before Day 1 of this trial Use of systemic corticosteroids, anti-inflammatory biological agents, kinase inhibitors or other immune modulating agents within the last 3 months prior to screening Donation of blood or plasma in the past month, or in excess of 500 mL within 12 weeks prior to screening A positive result in the alcohol and/or urine drug screen at the screening visit. Significant history of alcoholism or drug abuse as judged by the investigator or consuming more than 24 g alcohol per day for men, or more than 12 g alcohol per day for women. Surgery or trauma with significant blood loss within the last 2 months prior to screening Use of prescription or non-prescription medications known to cause QT prolongation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dasiglucagon (ZP4207)<br>Repeated single fixed doses (s.c.injection) of dasiglucagon | Drug: dasiglucagon<br>* Glucagon Analog<br>* Other names: ZP4207;|
| Experimental: GlucaGen<br>Repeated single fixed doses (s.c.injection) of GlucaGen | Drug: GlucaGen<br>* Native Glucagon<br>* Other names: GlucaGen HypoKit;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With ADA | Percentage of the combined results of treatment-induced ADA-positive patients and treatment-boosted ADA-positive patients out of the total number of evaluable patients. ADA = antidrug antibodies. | 104 days after the first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Treatment-induced ADA | Percentage of the total number of evaluable patients that were ADA negative at baseline and ADA positive after drug administration out of the total number of evaluable patients. ADA = antidrug antibodies | 104 days after the first dose | 
| Percentage of Patients With Treatment-boosted ADA | Percentage of baseline ADA-positive patients with significant increases (≥5-fold) in ADA titre after drug administration out of the total number of evaluable patients. ADA = antidrug antibodies | 104 days after the first dose | 
| Characterization of ADA Response - Neutralizing Activity | Percentage of ADA positive patients with ADA neutralizing activity. ADA = antidrug antibodies. | 104 days after the first dose | 
| Characterization of ADA Response - Titer of Neutralizing Activity | Titre of neutralizing activity of ADA positive patients. ADA = antidrug antibodies. | 104 days after the first dose | 
| Characterization of ADA Response - Cross-reactivity | Percentage of ADA positive patients with cross-reactivity towards endogenous glucagon. ADA = antidrug antibodies. | 104 days after the first dose | 
| Characterization of ADA Response - Timing | The timing of detected ADA response. ADA = antidrug antibodies. | 104 days after the first dose | 
| Characterization of ADA Response - Duration | The Duration of detected ADA response. ADA = antidrug antibodies. | 104 days after the first dose | 
| Pharmacokinetics - Area Under the Plasma Concentration Curve | Area under the plasma concentration curve (AUC) 0-30 minutes at visit 2 and 4 (days 0 and 14). Plasma PK concentrations were measured before dosing and at 5, 10 and 30 minutes after dosing. | 0-30 minutes | 
| Pharmacokinetics - Area Under the Plasma Concentration Curve | Area under the plasma concentration curve (AUC) 0-90 minutes at visit 2 and 4 (days 0 and 14). Plasma PK concentrations were measured before dosing and at 5, 10, 30, 60 and 90 minutes after dosing. | 0-90 minutes | 
| Pharmacokinetics - Maximum Plasma Concentration | Maximum plasma concentration (Cmax) at visit 2 and 4 (days 0 and 14). Plasma PK concentrations were measured before dosing and at 5, 10, 30, 60 and 90 minutes after dosing. | 90 minutes | 
| Pharmacokinetics - Time to Maximum Plasma Concentration | Time to maximum plasma concentration (Tmax) at visit 2 and 4 (days 0 and 14). Plasma PK concentrations were measured before dosing and at 5, 10, 30, 60 and 90 minutes after dosing. | 90 minutes | 
| Pharmacodynamics - Area Under the Effect Curve | Plasma glucose profiles, area under the effect curve (AUE) 0-30 minutes at visit 2 and 4 (days 0 and 14). Plasma glucose concentrations were measured before dosing and at 5, 10 and 30 minutes after dosing. | 0-30 minutes | 
| Pharmacodynamics - Area Under the Effect Curve | Plasma glucose profiles, area under the effect curve (AUE) 0-90 minutes at visit 2 and 4 (days 0 and 14). Plasma glucose concentrations were measured before dosing and at 5, 10, 30, 60 and 90 minutes after dosing. | 0-90 minutes | 
| Pharmacodynamics - Change From Baseline Plasma Glucose | Change from baseline plasma glucose to maximum plasma glucose (CEmax) at visit 2 and 4 (days 0 and 14). Plasma glucose concentrations were measured before dosing and at 5, 10, 30, 60 and 90 minutes after dosing. | 90 minutes | 
| Pharmacodynamics - Time to Maximum Plasma Glucose Concentration | Time to maximum plasma glucose concentration (Tmax) at visit 2 and 4 (days 0 and 14). Plasma glucose concentrations were measured before dosing and at 5, 10, 30, 60 and 90 minutes after dosing. | 90 minutes | 
| Pharmacodynamics - An Increase in the Plasma Glucose Concentration of ≥20 mg/dL Within 30 Minutes After Treatment | An increase in the plasma glucose concentration of ≥20 mg/dL within 30 minutes after treatment at visit 2 and visit 4. Plasma glucose concentrations were measured before dosing and at 5, 10, 30, 60 and 90 minutes after dosing. | 30 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glucagon, Dasiglucagon