A phase 3, randomized, double-blind, placebo- and active-controlled, parallel-arm trial to assess the efficacy, safety, and pharmacokinetics of dasiglucagon relative to placebo and GlucaGen® when administered as a rescue therapy for severe hypoglycemia in children with type 1 diabetes mellitus (T1DM) treated with insulin
At least 40 children ≥6 years and \<18 years of age with T1DM were planned to be randomized into the trial (2:1:1 for dasiglucagon:placebo:GlucaGen) and stratified by age intervals: 6 years to \<12 years, and 12 years to \<18 years; and by injection site (abdomen or thigh). A minimum of 16 patients were enrolled into each age group, including a minimum of 8 patients in each age group in the dasiglucagon treatment arm. In Germany only, a staggered approach was applied, whereby a positive safety assessment needed to be available for at least 10 patients in the age group of 12 years to \<18 years who had completed the dosing visit in the overall trial before younger patients (6 to 11 years of age) were allowed to be enrolled.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
42
glucagon analog
placebo for dasiglucagon
native glucagon
AMCR Institute, Inc
Escondido, California, United States
Yale University School of Medicine
New Haven, Connecticut, United States
Indiana University, Department of Pediatrics
Indianapolis, Indiana, United States
Auf der Bult - Diabetes Center for Children
Hanover, Germany
Time to Plasma Glucose Recovery
Plasma glucose recovery was defined as first increase in plasma glucose of ≥20 mg/dL (1.1 mmol/L) from baseline during the hypoglycemic clamp procedure without administration of rescue intravenous (IV) glucose. Patients who received rescue IV glucose before 45 minutes and patients not recovering within 45 minutes after dosing were censored at 45 minutes. Time to plasma glucose recovery was summarized for each treatment group using Kaplan Meier (KM) estimates together with the 95% confidence interval. Note that the upper confidence limit for the placebo median was not estimable, but is set to 45 minutes (censored value) here.
Time frame: 0-45 minutes after dosing
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 intravenous (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.
Time frame: 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 within 30 minutes, within 20 minutes, within 15 minutes, and within 10 minutes after trial product injection or at the time of rescue intravenous (IV) glucose
Time frame: 0-30 minutes after dosing: assessed at 10, 15, 20 and 30 minutes after study drug injection
Pharmacodynamics - Area Under the Effect Curve (0-30 Minutes)
Plasma glucose response as area under the effect curve above baseline from time 0 to 30 minutes (AUE0-30min). Plasma glucose was determined at pre-dose and at 4, 6, 8, 10, 12, 15, 17, 20, 30, and 45 minutes (and at 60 minutes if the patient weighed ≥21 kg) after dosing.
Time frame: 0-30 minutes
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University Medical Center Ljubljana, Children's Hospital, Department for Endocrinology, Diabetes and Metabolism
Ljubljana, Slovenia
Administration of Rescue IV Glucose Infusion After IMP Injection
Number of patients receiving IV rescue glucose administration for hypoglycemia after administration of IMP. IV = intravenous. IMP = investigational medicinal product.
Time frame: 0-45 minutes
Time to First IV Glucose Infusion After IMP Administration
Time to first IV rescue glucose administration for hypoglycemia after administration of IMP. IV = intravenous. IMP = investigational medicinal product.
Time frame: 0-45 minutes
Pharmacokinetics: AUC0-30 Min
Area under the plasma dasiglucagon or GlucaGen concentration versus time curve from 0 to 30 minutes post-dose. Samples were collected before dosing and at 10, 20, 30, 40, 60, 90, 140, 220, and 300 minutes after dosing.
Time frame: 0-30 minutes
Pharmacokinetics: AUC0-300min
Area under the plasma dasiglucagon or GlucaGen concentration versus time curve from 0 to 300 minutes post-dose. Samples were collected before dosing and at 10, 20, 30, 40, 60, 90, 140, 220, and 300 minutes after dosing.
Time frame: 0-300 minutes
Pharmacokinetics: AUC0-inf
Area under the plasma dasiglucagon or GlucaGen concentration versus time curve from 0 to infinitely post-dose. Samples were collected before dosing and at 10, 20, 30, 40, 60, 90, 140, 220, and 300 minutes after dosing.
Time frame: 0-300 minutes
Pharmacokinetics: Cmax
Maximum of all valid plasma dasiglucagon or GlucaGen concentration measurements from 0 to 300 minutes post-dose. Samples were collected before dosing and at 10, 20, 30, 40, 60, 90, 140, 220, and 300 minutes after dosing.
Time frame: 0-300 minutes
Pharmacokinetics: Tmax
Time to maximum of plasma dasiglucagon or GlucaGen concentration measurements. Samples were collected before dosing and at 10, 20, 30, 40, 60, 90, 140, 220, and 300 minutes after dosing.
Time frame: 0-300 minutes
Pharmacokinetics: λz
Terminal elimination rate constant of plasma dasiglucagon or GlucaGen. Samples were collected before dosing and at 10, 20, 30, 40, 60, 90, 140, 220, and 300 minutes after dosing.
Time frame: 0-300 minutes
Pharmacokinetics: t½
Terminal plasma elimination half-life of dasiglucagon or GlucaGen. Samples were collected before dosing and at 10, 20, 30, 40, 60, 90, 140, 220, and 300 minutes after dosing.
Time frame: 0-300 minutes
Pharmacokinetics: CL/f
Total body clearance of plasma dasiglucagon or GlucaGen. Samples were collected before dosing and at 10, 20, 30, 40, 60, 90, 140, 220, and 300 minutes after dosing.
Time frame: 0-300 minutes
Pharmacokinetics: Vz/f
Volume of distribution of plasma dasiglucagon or GlucaGen. Samples were collected before dosing and at 10, 20, 30, 40, 60, 90, 140, 220, and 300 minutes after dosing.
Time frame: 0-300 minutes
Pharmacokinetics: MRT
Mean residence time of plasma dasiglucagon or GlucaGen. Samples were collected before dosing and at 10, 20, 30, 40, 60, 90, 140, 220, and 300 minutes after dosing.
Time frame: 0-300 minutes