Low-dose Dasiglucagon for Prevention of Insulin-Induced Hypoglycemia in People With Type 1 Diabetes

The aim of the study is to compare the efficacy of low-dose dasiglucagon (Zealand Pharma, Denmark) to oral carbohydrate consumption for prevention of s.c. insulin-induced hypoglycemia in CSII- and MDI-treated people with type 1 diabetes.

Study Overview

• Status: Completed
• Conditions: Hypoglycemia; Type 1 Diabetes
• Intervention / Treatment: Drug: Dasiglucagon; Other: Carbohydrate (dextrose tablets)

Detailed Description

Near-normalization of blood glucose levels through intensive insulin therapy has shown to reduce the risk of diabetes late complications, but the approach is associated with two major side effects: hypoglycemia and weight gain. Although management of hypoglycemia through oral carbohydrate consumption is generally effective, the approach can lead to excessive carbohydrate intake and cause rebound hyperglycemia. It has previously been demonstrated that subcutaneous (s.c.) low-dose glucagon can be utilized to effectively treat mild hypoglycemia in people with type 1 diabetes. However, the instability in aqueous solution of currently available glucagon and the need for reconstitution with sterile water immediately prior to administration has limited its clinical role outside emergency settings. Due to the stability and ready-to-use formulation, dasiglucagon does not hold the limitations known for the currently available glucagon preparations.

The aim of this randomized, partially single-blinded, three-arm cross-over study is to compare the efficacy of low-dose dasiglucagon (80 and 120 μg) to oral carbohydrate (15 g) consumption for prevention of s.c. insulin-induced hypoglycemia in CSII- and MDI-treated people with type 1 diabetes. On each study visit (separated by ≥ 3 days), an initial insulin bolus will be administered (at t = 0) aiming for a plasma glucose (PG) level of 3.0 mmol/l. When reaching 4.5 mmol/l, the intervention (s.c. dasiglucagon or oral carbohydrates) will be administered (t-intervention = 0), whereafter PG will me monitored for an additional 180 min.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Gentofte, Denmark, 2820
    • Steno Diabetes Center Copenhagen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18-64 years
• Duration of T1D ≥ 3 years
• Use of CSII or MDI therapy for ≥ 6 months
• Current use of Novorapid (change from another fast-acting insulin to Novorapid prior to study initiation is allowed)
• HbA1c ≤ 8.0%
• Regular use of carbohydrate counting in the judgement of the investigator

Exclusion Criteria:

• Use of anti-diabetic medicine (other than insulin), corticosteroids or other drugs affecting glucose metabolism during the study period or within 30 days prior to study start
• History of allergy or intolerance to glucagon or glucagon-like products
• Patients with pheochromocytoma
• Clinically significant ECG abnormalities
• Females who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods (sterilization, intrauterine device, contraceptive pill, patch or injection)
• Inability to understand the individual information and to give informed consent
• Current participation in another clinical trial that, in the judgment of the principle investigator, will compromise the results of the study or the safety of the subject
• Other concomitant medical or psychological condition that, according to the investigator's assessment, makes the individual unsuitable for study participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 80 µg s.c. dasiglucagon; 80 µg of dasiglucagon will be administered subcutaneously when plasma glucose levels reach 4.5 mmol/l	Drug: Dasiglucagon; Abdominal s.c. administration
Experimental: 120 µg s.c. dasiglucagon; 120 µg of dasiglucagon will be administered subcutaneously when plasma glucose levels reach 4.5 mmol/l	Drug: Dasiglucagon; Abdominal s.c. administration
Active Comparator: 15 g oral carbohydrate (dextrose tablets); 15 g of oral carbohydrate (dextrose tablets) will be administered when plasma glucose levels reach 4.5 mmol/l	Other: Carbohydrate (dextrose tablets); Oral administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Difference between study visits in time (min) in hypoglycemia (plasma glucose < 3.9 mmol/l) from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)

Secondary Outcome Measures

Outcome Measure	Time Frame
Difference between study visits in incidence rate of hypoglycemia (plasma glucose < 3.9 mmol/l) from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in incidence rate of level 2 hypoglycemia (plasma glucose < 3.0 mmol/l) from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in incidence rate of rebound hyperglycemia (plasma glucose > 10 mmol/l) from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in nadir plasma glucose concentration from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in peak plasma glucose concentration from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in incremental peak in plasma glucose concentration from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in mean plasma glucose concentration from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in time (min) from intervention to first increase in plasma glucose concentration of 1.1 mmol/l	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in plasma glucose Area Under the Curve (AUC) from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in time (min) to peak plasma glucose concentration from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in time (min) in range (plasma glucose ≥ 3.9 mmol/l and 10.0 mmol/l) from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in time (min) in hyperglycemia (plasma glucose > 10 mmol/l) from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in time (%) in hypoglycemia (plasma glucose < 3.9 mmol/l) (per protocol) from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in incidence rate of rescue carbohydrate administration from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in time (min) to rescue carbohydrate administration from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in plasma dasiglucagon Area Under the Curve (AUC) from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in peak plasma dasiglucagon concentration from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in time to peak plasma dasiglucagon concentration from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in serum insulin concentration at visit start (t = 0) and immediately before administration of the intervention (t-intervention = 0)	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in serum insulin AUC from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in dose (units) of insulin bolus at study start (t = 0)	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in change in Edinburgh Hypoglycemia Symptoms Scale (EHSS) from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in change in visual analogue scale (VAS) for nausea, headache, stomach ache, injection site pain, palpitations and hunger from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)
Difference between study visits in incidence rate of vomiting from 0-180 minutes post-intervention	Study visit 1 (day 1), study visit 2 (estimated day 4) and study visit 3 (estimated day 7)

Collaborators and Investigators

• Sponsor: Steno Diabetes Center Copenhagen
• Investigators: Principal Investigator: Christian Laugesen, MD, MD, PhD Candidate

Publications and helpful links

General Publications

• Laugesen C, Ranjan AG, Schmidt S, Norgaard K. Low-Dose Dasiglucagon Versus Oral Glucose for Prevention of Insulin-Induced Hypoglycemia in People With Type 1 Diabetes: A Phase 2, Randomized, Three-Arm Crossover Study. Diabetes Care. 2022 Jun 2;45(6):1391-1399. doi: 10.2337/dc21-2304.

Study record dates

Study Major Dates

• Study Start (Actual): July 2, 2020
• Primary Completion (Actual): January 4, 2021
• Study Completion (Actual): January 4, 2021

Study Registration Dates

• First Submitted: June 24, 2020
• First Submitted That Met QC Criteria: June 26, 2020
• First Posted (Actual): June 29, 2020

Study Record Updates

• Last Update Posted (Actual): February 9, 2021
• Last Update Submitted That Met QC Criteria: February 8, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Hypoglycemia; Type 1 Diabetes; 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
• Other Study ID Numbers: H-20013256 (Registry Identifier: Regional Scientific Ethics Committee); 2020-000551-12 (EudraCT Number)

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