Hypoglycemia
Conditions
Keywords
Glucagon, Dasiglucagon
Brief summary
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
Detailed description
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.
Interventions
DRUGdasiglucagon
glucagon analog
DRUGplacebo
placebo for dasiglucagon
DRUGGlucaGen HypoKit
native glucagon
Sponsors
Zealand Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Following receipt of verbal and written information about the trial, patient, parent(s) or guardian(s) of the patient must provide signed informed consent before any trial-related activity is carried out 2. Female or male patients with T1DM for at least 1 year, diagnostic criteria as defined by the American Diabetes Association; and receiving daily insulin 3. At least 6.0 years of age (inclusive) and less than 18.0 years 4. Body weight ≥20 kg 5. Female patients must meet one of the following criteria: a. Participant is of childbearing potential and agrees to use one of the accepted contraceptive regimens throughout the entire duration of the trial from screening until last follow-up visit. An acceptable method of contraception includes at least one of the following: i. Abstinence from heterosexual intercourse ii. Systemic contraceptives (birth control pills, injectable/implant/ insertable hormonal birth control products, transdermal patch); if the participant is using systemic contraceptives, she must use an additional form of acceptable contraception (iii or iv, below) iii. Intrauterine device (with and without hormones) iv. Condom with spermicide or b. Participant is of non-childbearing potential due to pre-puberty status or a medical condition confirmed by the investigator 6. Male patients must meet the following criteria: If sexually active, uses condom and partner practices contraception during the trial from screening and until last follow-up visit 7. Willingness to adhere to the protocol requirements \-
Exclusion criteria
1\. Females who are pregnant according to a positive urine pregnancy test, actively attempting to get pregnant, or are lactating 2. Known or suspected allergy to trial product(s) or related products 3. History of anaphylaxis or symptoms of severe systemic allergy (such as angioedema) 4. Previous randomization in this trial 5. History of an episode of severe hypoglycemia that required a third party assistance within a month prior to screening visit 6. History of hypoglycemic events associated with seizures or hypoglycemia unawareness in the last year prior to screening 7. History of epilepsy or seizure disorder 8. Receipt of any investigational drug within 3 months prior to screening 9. Active malignancy within the last 5 years 10. Congestive heart failure, New York Heart Association class II-IV 11. Current bleeding disorder, including anti-coagulant treatment 12. Known presence or history of pheochromocytoma (i.e. adrenal gland tumor) or insulinoma (i.e. insulin secreting pancreas tumor) 13. Use of a daily systemic beta-blocker drug, indomethacin, warfarin or anticholinergic drugs in the previous 28 days before Day 1 of this trial 14. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>2.5 × the upper limit of the normal range (ULN), bilirubin \>1.5 × ULN, estimated glomerular filtration rate \<30 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease study definition, or altered electrolyte values of clinical relevance for cardiac conduction, as judged by the investigator 15. Clinically significant abnormal electrocardiogram (ECG) at screening as judged by the investigator 16. Clinically significant illness within 4 weeks before screening, as judged by the investigator 17. Surgery or trauma with significant blood loss within the last 2 months prior to screening 18. Patients with mental incapacity or language barriers which preclude adequate understanding or cooperation, who are unwilling to participate in the trial, or who in the opinion of the investigator should not participate in the trial 19. Any condition interfering with trial participation or evaluation or that could be hazardous to the patient 20. The use of prescription or non-prescription medications known to cause QT prolongation \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Plasma Glucose Recovery | 0-45 minutes after dosing | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Glucose Changes From Baseline | 0-30 minutes after dosing: assessed at 10, 15, 20 and 30 minutes after study drug injection | 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 |
| Pharmacodynamics - Area Under the Effect Curve (0-30 Minutes) | 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. |
| Administration of Rescue IV Glucose Infusion After IMP Injection | 0-45 minutes | Number of patients receiving IV rescue glucose administration for hypoglycemia after administration of IMP. IV = intravenous. IMP = investigational medicinal product. |
| Time to First IV Glucose Infusion After IMP Administration | 0-45 minutes | Time to first IV rescue glucose administration for hypoglycemia after administration of IMP. IV = intravenous. IMP = investigational medicinal product. |
| Pharmacokinetics: AUC0-30 Min | 0-30 minutes | 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. |
| Pharmacokinetics: AUC0-300min | 0-300 minutes | 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. |
| Pharmacokinetics: AUC0-inf | 0-300 minutes | 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. |
| Plasma Glucose Recovery | 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 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. |
| Pharmacokinetics: Tmax | 0-300 minutes | 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. |
| Pharmacokinetics: λz | 0-300 minutes | 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. |
| Pharmacokinetics: t½ | 0-300 minutes | 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. |
| Pharmacokinetics: CL/f | 0-300 minutes | 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. |
| Pharmacokinetics: Vz/f | 0-300 minutes | 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. |
| Pharmacokinetics: MRT | 0-300 minutes | 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. |
| Pharmacokinetics: Cmax | 0-300 minutes | 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. |
Countries
Germany, Slovenia, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dasiglucagon 0.6 mg Single fixed dose (subcutaneous injection) of dasiglucagon
dasiglucagon: glucagon analog | 20 |
| Placebo Single fixed dose (subcutaneous injection) of placebo
placebo: placebo for dasiglucagon | 11 |
| GlucaGen® 1.0 mg Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight \<25 kg)
GlucaGen HypoKit: native glucagon | 10 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | GlucaGen® 1.0 mg | Total | Dasiglucagon 0.6 mg | Placebo |
|---|---|---|---|---|
| Age, Categorical <=18 years | 10 Participants | 41 Participants | 20 Participants | 11 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 12.4 years STANDARD_DEVIATION 3.5 | 12.5 years STANDARD_DEVIATION 3.32 | 12.3 years STANDARD_DEVIATION 3.42 | 12.8 years STANDARD_DEVIATION 3.25 |
| Age, Customized Age 12-17 years | 6 Participants | 25 Participants | 12 Participants | 7 Participants |
| Age, Customized Age 6-11 years | 4 Participants | 16 Participants | 8 Participants | 4 Participants |
| Body mass index | 18.92 kg per square meter STANDARD_DEVIATION 2.617 | 20.20 kg per square meter STANDARD_DEVIATION 5.05 | 20.74 kg per square meter STANDARD_DEVIATION 6.057 | 20.39 kg per square meter STANDARD_DEVIATION 4.885 |
| Body weight | 48.81 kg STANDARD_DEVIATION 14.992 | 51.79 kg STANDARD_DEVIATION 20.106 | 51.54 kg STANDARD_DEVIATION 22.202 | 54.95 kg STANDARD_DEVIATION 21.404 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 7 Participants | 4 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 33 Participants | 16 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 10 Participants | 39 Participants | 19 Participants | 10 Participants |
| Region of Enrollment Germany | 0 participants | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Slovenia | 3 participants | 11 participants | 6 participants | 2 participants |
| Region of Enrollment United States | 7 participants | 29 participants | 13 participants | 9 participants |
| Sex: Female, Male Female | 2 Participants | 18 Participants | 10 Participants | 6 Participants |
| Sex: Female, Male Male | 8 Participants | 23 Participants | 10 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 4 | 0 / 4 | 0 / 12 | 0 / 7 | 0 / 6 | 0 / 20 | 0 / 11 | 0 / 10 |
| other Total, other adverse events | 3 / 8 | 1 / 4 | 4 / 4 | 12 / 12 | 6 / 7 | 5 / 6 | 15 / 20 | 7 / 11 | 9 / 10 |
| serious Total, serious adverse events | 0 / 8 | 0 / 4 | 0 / 4 | 0 / 12 | 0 / 7 | 0 / 6 | 0 / 20 | 0 / 11 | 0 / 10 |
Outcome results
Primary
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
Population: Full analysis set (same as the safety analysis set) of all randomized and treated patients. Treatment assignment was based on the randomized treatment. Assignment to the stratification factor injection site was based on the planned and not the actual used injection site.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasiglucagon 0.6 mg | Time to Plasma Glucose Recovery | 10.00 minutes |
| Placebo | Time to Plasma Glucose Recovery | 30.00 minutes |
| GlucaGen® 1.0 mg | Time to Plasma Glucose Recovery | 10.00 minutes |
Comparison: The treatment group difference between dasiglucagon and placebo was evaluated inferentially using a pairwise two-sided log rank test stratified by injection site and age group.p-value: <0.001Log Rank
Secondary
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
Population: Safety analysis set (same as the full analysis set) of all randomized and treated patients.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dasiglucagon 0.6 mg | Administration of Rescue IV Glucose Infusion After IMP Injection | 0 Participants |
| Placebo | Administration of Rescue IV Glucose Infusion After IMP Injection | 1 Participants |
| GlucaGen® 1.0 mg | Administration of Rescue IV Glucose Infusion After IMP Injection | 0 Participants |
Secondary
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
Population: Full analysis set (same as the safety analysis set) of all randomized and treated patients. Treatment assignment was based on the randomized treatment. Assignment to the stratification factor injection site was based on the planned and not the actual used injection site.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacodynamics - Area Under the Effect Curve (0-30 Minutes) | 22.83 mmol*h/L | Standard Deviation 6.126 |
| Placebo | Pharmacodynamics - Area Under the Effect Curve (0-30 Minutes) | 1.81 mmol*h/L | Standard Deviation 4.641 |
| GlucaGen® 1.0 mg | Pharmacodynamics - Area Under the Effect Curve (0-30 Minutes) | 19.66 mmol*h/L | Standard Deviation 3.41 |
Secondary
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
Population: Full analysis set (same as the safety analysis set) of all randomized and treated patients. Treatment assignment was based on the randomized treatment. Assignment to the stratification factor injection site was based on the planned and not the actual used injection site.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacokinetics: AUC0-300min | 1810 h*pmol/L | Geometric Coefficient of Variation 44.8 |
| Placebo | Pharmacokinetics: AUC0-300min | 1370 h*pmol/L | Geometric Coefficient of Variation 72.7 |
Secondary
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
Population: Full analysis set (same as the safety analysis set) of all randomized and treated patients. Treatment assignment was based on the randomized treatment. Assignment to the stratification factor injection site was based on the planned and not the actual used injection site.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacokinetics: AUC0-30 Min | 376 h*pmol/L | Geometric Coefficient of Variation 78.1 |
| Placebo | Pharmacokinetics: AUC0-30 Min | 376 h*pmol/L | Geometric Coefficient of Variation 63.3 |
Secondary
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
Population: Full analysis set (same as the safety analysis set) of all randomized and treated patients. Treatment assignment was based on the randomized treatment. Assignment to the stratification factor injection site was based on the planned and not the actual used injection site.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacokinetics: AUC0-inf | 1850 h*pmol/L | Geometric Coefficient of Variation 45.1 |
| Placebo | Pharmacokinetics: AUC0-inf | 1530 h*pmol/L | Geometric Coefficient of Variation 70.3 |
Secondary
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
Population: Full analysis set (same as the safety analysis set) of all randomized and treated patients. Treatment assignment was based on the randomized treatment. Assignment to the stratification factor injection site was based on the planned and not the actual used injection site.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacokinetics: CL/f | 96.1 L/h | Geometric Coefficient of Variation 45.1 |
| Placebo | Pharmacokinetics: CL/f | 188 L/h | Geometric Coefficient of Variation 70.3 |
Secondary
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
Population: Full analysis set (same as the safety analysis set) of all randomized and treated patients. Treatment assignment was based on the randomized treatment. Assignment to the stratification factor injection site was based on the planned and not the actual used injection site.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacokinetics: Cmax | 1160 pmol/L | Geometric Coefficient of Variation 61.2 |
| Placebo | Pharmacokinetics: Cmax | 1120 pmol/L | Geometric Coefficient of Variation 80 |
Secondary
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
Population: Full analysis set (same as the safety analysis set) of all randomized and treated patients. Treatment assignment was based on the randomized treatment. Assignment to the stratification factor injection site was based on the planned and not the actual used injection site.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacokinetics: MRT | 1.27 hours | Geometric Coefficient of Variation 29.5 |
| Placebo | Pharmacokinetics: MRT | 1.86 hours | Geometric Coefficient of Variation 21.1 |
Secondary
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
Population: Full analysis set (same as the safety analysis set) of all randomized and treated patients. Treatment assignment was based on the randomized treatment. Assignment to the stratification factor injection site was based on the planned and not the actual used injection site.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacokinetics: t½ | 0.623 hours | Geometric Coefficient of Variation 37.4 |
| Placebo | Pharmacokinetics: t½ | 1.38 hours | Geometric Coefficient of Variation 27.2 |
Secondary
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
Population: Full analysis set (same as the safety analysis set) of all randomized and treated patients. Treatment assignment was based on the randomized treatment. Assignment to the stratification factor injection site was based on the planned and not the actual used injection site.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacokinetics: Tmax | 0.35 hours |
| Placebo | Pharmacokinetics: Tmax | 0.333 hours |
Secondary
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
Population: Full analysis set (same as the safety analysis set) of all randomized and treated patients. Treatment assignment was based on the randomized treatment. Assignment to the stratification factor injection site was based on the planned and not the actual used injection site.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacokinetics: Vz/f | 86.4 litres | Geometric Coefficient of Variation 62.2 |
| Placebo | Pharmacokinetics: Vz/f | 373 litres | Geometric Coefficient of Variation 81.1 |
Secondary
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
Population: Full analysis set (same as the safety analysis set) of all randomized and treated patients. Treatment assignment was based on the randomized treatment. Assignment to the stratification factor injection site was based on the planned and not the actual used injection site.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacokinetics: λz | 1.11 1/hour | Geometric Coefficient of Variation 37.4 |
| Placebo | Pharmacokinetics: λz | 0.504 1/hour | Geometric Coefficient of Variation 27.2 |
Secondary
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
Population: Full analysis set (same as the safety analysis set) of all randomized and treated patients. Treatment assignment was based on the randomized treatment. Assignment to the stratification factor injection site was based on the planned and not the actual used injection site.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasiglucagon 0.6 mg | Plasma Glucose Changes From Baseline | At 30 minutes | 98.459 mg/dL | Standard Deviation 19.6527 |
| Dasiglucagon 0.6 mg | Plasma Glucose Changes From Baseline | At 20 minutes | 65.369 mg/dL | Standard Deviation 15.2461 |
| Dasiglucagon 0.6 mg | Plasma Glucose Changes From Baseline | At 15 minutes | 45.342 mg/dL | Standard Deviation 15.086 |
| Dasiglucagon 0.6 mg | Plasma Glucose Changes From Baseline | At 10 minutes | 27.225 mg/dL | Standard Deviation 13.6768 |
| Placebo | Plasma Glucose Changes From Baseline | At 10 minutes | -3.405 mg/dL | Standard Deviation 8.0276 |
| Placebo | Plasma Glucose Changes From Baseline | At 30 minutes | 17.510 mg/dL | Standard Deviation 15.6313 |
| Placebo | Plasma Glucose Changes From Baseline | At 15 minutes | 0.835 mg/dL | Standard Deviation 11.1276 |
| Placebo | Plasma Glucose Changes From Baseline | At 20 minutes | 7.322 mg/dL | Standard Deviation 13.3543 |
| GlucaGen® 1.0 mg | Plasma Glucose Changes From Baseline | At 10 minutes | 20.919 mg/dL | Standard Deviation 6.7227 |
| GlucaGen® 1.0 mg | Plasma Glucose Changes From Baseline | At 20 minutes | 58.000 mg/dL | Standard Deviation 10.5297 |
| GlucaGen® 1.0 mg | Plasma Glucose Changes From Baseline | At 15 minutes | 40.631 mg/dL | Standard Deviation 9.7317 |
| GlucaGen® 1.0 mg | Plasma Glucose Changes From Baseline | At 30 minutes | 85.225 mg/dL | Standard Deviation 12.5052 |
Comparison: Change from baseline in plasma glucose at 30, 20, 15, and 10 minutes after investigational product injection was calculated using nominal sampling times and analyzed using an analysis of variance model with treatment, age group and injection site for each endpoint. Testing followed an a priori defined hierarchical inferential test order, proceeding until the first failure to reject the null hypothesis comparing dasiglucagon versus placebo.p-value: <0.0001ANOVA
Secondary
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
Population: Full analysis set (same as the safety analysis set) of all randomized and treated patients. Treatment assignment was based on the randomized treatment. Assignment to the stratification factor injection site was based on the planned and not the actual used injection site.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Plasma Glucose Recovery | Glucose recovery at 15 minutes | 19 Participants |
| Dasiglucagon 0.6 mg | Plasma Glucose Recovery | Glucose recovery at 20 minutes | 20 Participants |
| Dasiglucagon 0.6 mg | Plasma Glucose Recovery | Glucose recovery at 30 minutes | 20 Participants |
| Dasiglucagon 0.6 mg | Plasma Glucose Recovery | Glucose recovery at 10 minutes | 13 Participants |
| Placebo | Plasma Glucose Recovery | Glucose recovery at 15 minutes | 0 Participants |
| Placebo | Plasma Glucose Recovery | Glucose recovery at 30 minutes | 6 Participants |
| Placebo | Plasma Glucose Recovery | Glucose recovery at 20 minutes | 2 Participants |
| Placebo | Plasma Glucose Recovery | Glucose recovery at 10 minutes | 0 Participants |
| GlucaGen® 1.0 mg | Plasma Glucose Recovery | Glucose recovery at 30 minutes | 10 Participants |
| GlucaGen® 1.0 mg | Plasma Glucose Recovery | Glucose recovery at 15 minutes | 10 Participants |
| GlucaGen® 1.0 mg | Plasma Glucose Recovery | Glucose recovery at 10 minutes | 6 Participants |
| GlucaGen® 1.0 mg | Plasma Glucose Recovery | Glucose recovery at 20 minutes | 10 Participants |
Comparison: The recovery rates of dasiglucagon and placebo were compared at each time point using a Cochran-Mantel-Haenszel test stratified by age group and injection site. Testing followed an a priori defined hierarchical inferential test order, proceeding until the first failure to reject the null hypothesis comparing dasiglucagon versus placebo.p-value: 0.0073Cochran-Mantel-Haenszel
Secondary
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
Population: Only the patient who received IV glucose administration is included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to First IV Glucose Infusion After IMP Administration | 12 minutes |