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

• ClinicalTrials.gov Identifier: NCT03378635
• Recruitment Status: Completed
• First Posted: December 20, 2017
• Results First Posted: May 10, 2021
• Last Update Posted: June 10, 2021
• Sponsor: Zealand Pharma
• Information provided by (Responsible Party): Zealand Pharma

Study Description

Brief Summary:

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®.

Condition or disease	Intervention/treatment	Phase
Hypoglycemia; Diabetes Mellitus, Type 1	Drug: Dasiglucagon; Drug: GlucaGen; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 170 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: December 7, 2017
• Actual Primary Completion Date: April 27, 2018
• Actual Study Completion Date: May 25, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dasiglucagon; Single fixed dose (s.c.injection) of dasiglucagon	Drug: Dasiglucagon; Glucagon analog; Other Name: ZP4207
Placebo Comparator: Placebo; Single fixed dose (s.c.injection) of placebo	Drug: Placebo; Placebo for dasiglucagon; Other Name: Placebo for dasiglucagon
Active Comparator: GlucaGen®; Single fixed dose (s.c.injection) of GlucaGen®	Drug: GlucaGen; Native glucagon; Other Name: GlucaGen HypoKit

Outcome Measures

Primary Outcome Measures :

1. Time to Plasma Glucose Recovery [ Time Frame: 0-45 minutes after dosing ]
   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.

Secondary Outcome Measures :

1. Plasma Glucose Recovery [ Time Frame: 0-30 minutes after dosing: assessed at 10, 15, 20 and 30 minutes after study drug injection ]
   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.
2. Plasma Glucose Changes From Baseline [ Time Frame: 0-30 minutes after dosing: assessed at 10, 15, 20 and 30 minutes after study drug injection ]
   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
3. Time to Target [ Time Frame: 0-45 minutes after dosing ]
   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.
4. Pharmacodynamics - Area Under the Effect Curve [ Time Frame: 0-30 minutes after dosing ]
   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.
5. Pharmacokinetics - Area Under the Plasma Concentration Curve [ Time Frame: 0-90 minutes after dosing ]
   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.
6. Pharmacokinetics - Area Under the Plasma Concentration Curve [ Time Frame: 0-120 minutes after dosing ]
   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.
7. Pharmacokinetics - Maximum Plasma Concentration [ Time Frame: 0-120 minutes after dosing ]
   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.
8. Pharmacokinetics - Time to Maximum Plasma Concentration [ Time Frame: 0-120 minutes after dosing ]
   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.
9. Immunogenicity - Occurence of Anti-drug Antibodies [ Time Frame: 28 days ]
   Occurence of antibodies against dasiglucagon/GlucaGen
10. Rescue Infusion of IV Glucose During the Hypoglycemic Clamp Procedure [ Time Frame: 0-45 minutes after dosing ]
    Number of patients receiving administration of rescue infusion of IV glucose during the hypoglycemic clamp procedure. IV = intravenous
11. Time to First Rescue Infusion of IV Glucose [ Time Frame: 0-45 minutes after dosing ]
    Time to first rescue administration of rescue infusion of IV glucose. IV = intravenous

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

ProSciento

Chula Vista, California, United States, 91911

Austria

Clinical Research Center, Medizinische Universität Graz

Graz, Austria

Canada

LMC Diabetes & Manna Research

Toronto, Canada

Germany

Profil

Mainz, Germany

Profil

Neuss, Germany

Sponsors and Collaborators

Zealand Pharma

Investigators

• Study Director: Christina Sylvest, MSc Pharm; Zealand Pharma

  Study Documents (Full-Text)

Documents provided by Zealand Pharma:

Study Protocol  [PDF] October 8, 2019

Statistical Analysis Plan  [PDF] October 8, 2019

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Pieber TR, Aronson R, Hövelmann U, Willard J, Plum-Mörschel 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.

• Responsible Party: Zealand Pharma
• ClinicalTrials.gov Identifier: NCT03378635
• Other Study ID Numbers: ZP4207-16137
• First Posted: December 20, 2017
• Results First Posted: May 10, 2021
• Last Update Posted: June 10, 2021
• Last Verified: May 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Zealand Pharma:

Dasiglucagon; Glucagon analog

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Glucagon; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs