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

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)

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

Study Overview

• Status: Completed
• Conditions: Hypoglycemia; Diabetes Mellitus, Type 1
• Intervention / Treatment: Drug: dasiglucagon; Drug: GlucaGen

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 112
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria
    • CRC - Clinical Research Center, Medizinische Universität Graz
• Canada
  • Barrie, Canada
    • LMC Manna Research
  • Calgary, Canada
    • LMC Calgary
  • Toronto, Canada
    • LMC Diabetes & Manna Research
• Germany
  • Hamburg, Germany
    • Diabeteszentrum Hamburg West, Gemeinschaftspraxis für Innere Medizin
• United States
  • Florida
    • Orlando, Florida, United States, 32806
      • Compass Research
  • Idaho
    • Meridian, Idaho, United States, 83642
      • Advanced Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: dasiglucagon (ZP4207); Repeated single fixed doses (s.c.injection) of dasiglucagon	Drug: dasiglucagon; Glucagon Analog; Other Names: ZP4207
Experimental: GlucaGen; Repeated single fixed doses (s.c.injection) of GlucaGen	Drug: GlucaGen; Native Glucagon; Other Names: GlucaGen HypoKit

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Zealand Pharma
• Collaborators: SynteractHCR
• Investigators: Study Director: Christina Sylvest, MSc Pharm, Zealand Pharma A/S

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2017
• Primary Completion (Actual): February 13, 2018
• Study Completion (Actual): February 13, 2018

Study Registration Dates

• First Submitted: July 7, 2017
• First Submitted That Met QC Criteria: July 10, 2017
• First Posted (Actual): July 13, 2017

Study Record Updates

• Last Update Posted (Actual): May 4, 2021
• Last Update Submitted That Met QC Criteria: April 8, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Glucagon; Dasiglucagon
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia; Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Glucagon
• Other Study ID Numbers: ZP4207-16136

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No