A Trial to Confirm the Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in Type 1 Diabetes Subjects

A Phase 3, Randomized, Double-blind, Parallel Trial to Confirm the Clinical Efficacy and Safety of Dasiglucagon in Rescue Treatment of Hypoglycemia in Subjects With Type 1 Diabetes Mellitus Compared to Placebo and With Reference to GlucaGen

The objective of the trial is to demonstrate superiority of dasiglucagon compared to placebo following a single subcutaneous dose administered to subjects with type 1 diabetes mellitus (T1DM) with insulin-induced hypoglycemia. Additionally to compare the glycemic response observed after administration dasiglucagon with that of GlucaGen®.

Study Overview

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

Detailed Description

This was a global, multicenter, randomized, parallel, and double-blind clinical trial confirming the efficacy and safety of dasiglucagon for insulin-induced hypoglycemia in patients with T1DM. The patients were randomized 2:1:1 to receive a single subcutaneous 0.6 mg dose of dasiglucagon, placebo, or a 1 mg dose of GlucaGen and followed for at least 28 days after receiving treatment.

• Study Type: Interventional
• Enrollment (Actual): 170
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria
    • Clinical Research Center, Medizinische Universität Graz
• Canada
  • Toronto, Canada
    • LMC Diabetes & Manna Research
• Germany
  • Mainz, Germany
    • Profil
  • Neuss, Germany
    • Profil
• United States
  • California
    • Chula Vista, California, United States, 91911
      • ProSciento

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Female or male subjects with type 1 diabetes mellitus (T1DM) for at least 1 year, diagnostic criteria as defined by the American Diabetes Association
• Treated with insulin for T1DM for at least 1 year and with stable insulin treatment (defined as no more than a 10-unit daily variation in total daily insulin dose) 30 days prior to screening
• Hemoglobin A1c <10%

Exclusion Criteria:

• Previously treated with dasiglucagon (previously referred to as ZP4207)
• Known or suspected allergy to trial product(s) or related products
• Females who are pregnant according to a positive pregnancy test, are actively attempting to get pregnant, or are lactating.
• History of hypoglycemic events associated with seizures in the last year prior to screening
• History of severe hypoglycemia in the last month prior to screening
• Active malignancy within the last 5 years
• Current bleeding disorder, including anti-coagulant treatment
• Known presence or history of pheochromocytoma (i.e. adrenal gland tumor) or insulinoma (i.e. insulin secreting pancreas tumor)
• Use of a daily systemic beta-blocker drug, indomethacin, warfarin or anticholinergic drugs in the previous 28 days before Day 1 of this trial
• Clinically significant abnormal ECG at screening as judged by the investigator
• Donation of blood or plasma in the past month, or in excess of 500 mL within 12 weeks prior to screening
• Surgery or trauma with significant blood loss within the last 2 months 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: GlucaGen®; Single fixed dose (s.c.injection) of GlucaGen®	Drug: GlucaGen; Native glucagon; Other Names: GlucaGen HypoKit
EXPERIMENTAL: Dasiglucagon; Single fixed dose (s.c.injection) of dasiglucagon	Drug: Dasiglucagon; Glucagon analog; Other Names: ZP4207
PLACEBO_COMPARATOR: Placebo; Single fixed dose (s.c.injection) of placebo	Drug: Placebo; Placebo for dasiglucagon; Other Names: Placebo for dasiglucagon

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Plasma Glucose Recovery	Plasma glucose recovery is defined as first increase in plasma glucose of ≥20 mg/dL (1.1 mmol/L) from baseline without administration of rescue intravenous glucose. The outcome measure used a Kaplan-Meier estimate with 95% confidence interval. Treatment groups without censoring utilized a distribution free method to compute the confidence interval for median time.	0-45 minutes after dosing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Glucose Recovery	Plasma glucose recovery within 30 minutes, within 20 minutes, within 15 minutes, and within 10 minutes after study drug injection without administration of rescue IV glucose. Plasma glucose recovery was defined as the first increase in plasma glucose of ≥20 mg/dL (1.1 mmol/L) from baseline without administration of rescue intravenous glucose.	0-30 minutes after dosing: assessed at 10, 15, 20 and 30 minutes after study drug injection
Plasma Glucose Changes From Baseline	Plasma glucose changes from baseline at 30 minutes, 20 minutes, 15 minutes and 10 minutes after study drug injection without administration of rescue intravenous glucose	0-30 minutes after dosing: assessed at 10, 15, 20 and 30 minutes after study drug injection
Time to Target	Time to first plasma glucose concentration ≥70 mg/dL (3.9 mmol/L) without administration of rescue intravenous glucose. The outcome measure used a Kaplan-Meier estimate with 95% confidence interval. Treatment groups without censoring utilized a distribution free method to compute the confidence interval for median time.	0-45 minutes after dosing
Pharmacodynamics - Area Under the Effect Curve	Plasma glucose response as area under the effect curve (AUE) above baseline from time zero to 30 minutes. Samples were collected pre-dose, and at 4, 6, 8, 10, 12, 15, 17, 20, 25 and 30 minutes after dosing.	0-30 minutes after dosing
Pharmacokinetics - Area Under the Plasma Concentration Curve	Area under the drug concentration curve from time zero to 90 minutes, AUC0-90min. To calculate the AUC the standard trapezoidal method was used, based on actual rather than nominal time points. Samples were collected pre-dose, and at 15, 30, 35, 40, 50, 60, 90 and 120 minutes after dosing.	0-90 minutes after dosing
Pharmacokinetics - Area Under the Plasma Concentration Curve	Area under the drug concentration curve from time zero to 120 minutes, AUC0-120min. To calculate the AUC the standard trapezoidal method was used, based on actual rather than nominal time points. Samples were collected pre-dose, and at 15, 30, 35, 40, 50, 60, 90 and 120 minutes after dosing.	0-120 minutes after dosing
Pharmacokinetics - Maximum Plasma Concentration	Maximum plasma drug concentration (Cmax). Maximum plasma drug concentration was determined as the maximum of all valid plasma dasiglucagon/glucagon concentrations. Samples were collected pre-dose, and at 15, 30, 35, 40, 50, 60, 90 and 120 minutes after dosing.	0-120 minutes after dosing
Pharmacokinetics - Time to Maximum Plasma Concentration	Time to maximum plasma drug concentration (tmax). Median Tmax was determined as the time point where the maximum of all valid plasma dasiglucagon/glucagon concentration measurements for each measurement series was observed. Samples were collected pre-dose, and at 15, 30, 35, 40, 50, 60, 90 and 120 minutes after dosing.	0-120 minutes after dosing
Immunogenicity - Occurence of Anti-drug Antibodies	Occurence of antibodies against dasiglucagon/GlucaGen	28 days
Rescue Infusion of IV Glucose During the Hypoglycemic Clamp Procedure	Number of patients receiving administration of rescue infusion of IV glucose during the hypoglycemic clamp procedure. IV = intravenous	0-45 minutes after dosing
Time to First Rescue Infusion of IV Glucose	Time to first rescue administration of rescue infusion of IV glucose. IV = intravenous	0-45 minutes after dosing

Collaborators and Investigators

• Sponsor: Zealand Pharma
• Investigators: Study Director: Christina Sylvest, MSc Pharm, Zealand Pharma

Publications and helpful links

General Publications

• Pieber TR, Aronson R, Hovelmann U, Willard J, Plum-Morschel L, Knudsen KM, Bandak B, Tehranchi R. Dasiglucagon-A Next-Generation Glucagon Analog for Rapid and Effective Treatment of Severe Hypoglycemia: Results of Phase 3 Randomized Double-Blind Clinical Trial. Diabetes Care. 2021 Jun 1;44(6):1361-1367. doi: 10.2337/dc20-2995.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 7, 2017
• Primary Completion (ACTUAL): April 27, 2018
• Study Completion (ACTUAL): May 25, 2018

Study Registration Dates

• First Submitted: December 8, 2017
• First Submitted That Met QC Criteria: December 13, 2017
• First Posted (ACTUAL): December 20, 2017

Study Record Updates

• Last Update Posted (ACTUAL): June 10, 2021
• Last Update Submitted That Met QC Criteria: May 27, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Dasiglucagon; Glucagon analog
• 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: ZP4207-16137

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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