A Stable Glucagon Analog Administered by a Bihormonal Closed Loop System (STABLE-1)

A Stable Glucagon Analog Administered by a Bihormonal Closed Loop System; a Feasibility Study

The main objective is to determine the feasibility of dasiglucagon in a bi-hormonal reactive closed loop system for automated glucose regulation (artificial pancreas; AP®) in patients with diabetes mellitus type 1. Safety parameters and pharmacodynamics are compared between Dasiglucagon and GlucaGen®.

This study is a single-center, double-blinded, randomized, cross over trial in 12 subjects. The subjects will be randomized to receive either dasiglucagon or GlucaGen® for the first three day study period and switch to the alternate treatment after a wash-out treatment.

Study Overview

• Status: Withdrawn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

Detailed Description

Background of the study:

Inreda Diabetic B.V. (Goor, The Netherlands) developed a bi-hormonal reactive closed loop system to automate glucose regulation (artificial pancreas; AP) in patients with diabetes mellitus type 1. In the current CE-marked AP, GlucaGen® (Novo Nordisk, Denmark) is used as glucagon. This glucagon formulation is not stable and therefore fibrillation and infusion set occlusion could occur, resulting in reduced glucagon action with risk for hypoglycemia. Dasiglucagon (Zealand Pharma, Denmark) is a glucagon analog stable in aqueous solution and does therefore not suffer from fibrillation.

Objective of the study:

The main objective is to determine the feasibility of dasiglucagon in the Inreda AP-system. Secondary objectives are to assess safety parameters, differences in pharmacodynamics between dasiglucagon and GlucaGen® and differences in AP related outcomes.

Study design:

This study is a single-center, double-blinded, randomized, cross over trial which will be performed out-patient.

Study population:

The study population will comprise 12 subjects with diabetes type 1 using the AP system. Inclusion criteria are subjects from 18 years and older and treated with the Inreda AP system for a minimum of 1 month.

Intervention:

The intervention contains use of dasiglucagon administered by the Inreda AP-system. The subject will be randomized to receive either dasiglucagon or GlucaGen® during the first three days. After a wash-out period of four days, the subject will be switched to the alternate treatment. During both study periods subjects have to keep a diary, perform exercise, keep a WiFi access point with them, and have some eating restrictions.

Primary study parameters/outcome of the study:

Main parameter to express feasibility is the time in range (3.9 - 10.0 mmol/l), which will be compared between the dasiglucagon and reference glucagon.

Secondary study parameters/outcome of the study:

• Safety will be expressed as side effects of dasiglucagon compared to side effects of GlucaGen.
• The amount of extra food intakes to prevent/ combat hypoglycemia.
• Pharmacodynamics will be expressed in proportion of time spent in hypo-/hyperglycemia, median/mean glucose value, glycemic variability and PD curves, which will all be compared between the dasiglucagon and reference glucagon.
• AP related outcomes will be expressed in daily administered (maintenance) dosage of insulin/glucagon and the percentage of time that the closed loop algorithm is active.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Overijssel
    • Almelo, Overijssel, Netherlands, 7609 PP
      • ZGT hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Diagnosed with diabetes mellitus type 1;

  • Treated with the Inreda AP system for a minimum of 1 month;
  • Age between 18 and 75 years;
  • Adequate contraception is required (only applicable for female participants);
  • Willing and able to sign informed consent.

Since subjects are treated with the Inreda AP, the following inclusion criteria will be met:

• Treated with SAP or CSII for a minimum of 6 months;
• HbA1c < 97 mmol/mol;
• BMI < 35 kg/m2;
• No use of acetaminophen, as this may influence the sensor glucose measurements.

Exclusion Criteria:

• Impaired awareness of hypoglycemia (score ≥ 4) according to Gold and/or Clarke questionnaire [3], [4];

  • Pregnancy and/or breastfeeding;
  • Use of oral antidiabetic agents;
  • Pheochromocytoma;
  • Insulinoma;
  • Severe liver/heart/renal failure;
  • Alcohol abuse;
  • Hypersensitivity reactions to dasiglucagon, glucagon or any of the excipients;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dasiglucagon; Dasiglucagon 1mg/ml solution for subcutaneous injection. Size and frequency of dosing will be determined by the AP algorithm. Duration: 3 days.	Drug: Dasiglucagon; Use of dasiglucagon in the AP system.
Active Comparator: GlucaGen; Glucagon 1mg/ml solution for subcutaneous injection. Size and frequency of dosing will be determined by the AP algorithm. Duration: 3 days.	Drug: GlucaGen; Use of GlucaGen in the AP system.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time in range	Time of glucose concentration in the range 3.9-10.0 mmol/L in %	3 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Side effects	Side effects of dasiglucagon and GlucaGen	3 days
Extra food intakes (food intake diary)	The participant is instructed to eat the same meals in the intervention and control period. Except extra food intakes when needed to prevent/combat hypoglycemia. Food intakes not present in the other period are extra food intakes.	3 days
Pharmacodynamics - hypo/hyper	Time spent in hypo-/hyperglycemia in percent	3 days
Pharmacodynamics - glucose value	Median glucose value in mmol/L	3 days
Pharmacodynamics - glycemic variability	Coefficient of variation (Standard deviation divided by the mean) in percent	3 days
Pharmacodynamics - glycemic variability	Inter quartile range in mmol/L	3 days
Pharmacodynamics - PD curves	Pharmacodynamics curves	3 days
AP related parameters - doses	Daily administered dose of insulin and glucagon in units	3 days
AP related parameters - algorithm	Time that algorithm is active in percent	3 days

Collaborators and Investigators

• Sponsor: Inreda Diabetic B.V.
• Investigators: Principal Investigator: G Laverman, MD, ZGT hospital

Study record dates

Study Major Dates

• Study Start (Estimated): December 29, 2023
• Primary Completion (Estimated): December 29, 2023
• Study Completion (Estimated): December 29, 2023

Study Registration Dates

• First Submitted: May 6, 2022
• First Submitted That Met QC Criteria: July 7, 2022
• First Posted (Actual): July 12, 2022

Study Record Updates

• Last Update Posted (Estimated): January 3, 2024
• Last Update Submitted That Met QC Criteria: December 29, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Glucagon
• Other Study ID Numbers: NL76691.100.22

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