Trial to Confirm the Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in T1DM Children

• Sponsor: Zealand Pharma (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03667053
• Collaborator: (none)
• Enrollment: 42
• Locations: 5
• Arms: 3
• Actual Duration (Months): 9
• Patients Per Site: 8.4
• Patients Per Site Per Month: 0.9

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Hypoglycemia	Drug: dasiglucagon; Drug: placebo; Drug: GlucaGen HypoKit	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase 3, Randomized, Double-blind, Placebo/Active-controlled, Parallel-arm Trial to Assess Efficacy, Safety, and Pharmacokinetics of Dasiglucagon Relative to Placebo/GlucaGen® as Rescue Therapy for Severe Hypoglycemia in Children With T1DM Treated With Insulin
• Actual Study Start Date: Sep 28, 2018
• Actual Primary Completion Date: Jun 28, 2019
• Actual Study Completion Date: Jun 28, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: dasiglucagon Single fixed dose (s.c.injection) of dasiglucagon	Drug: dasiglucagon; glucagon analog; Other Names: ZP4207
Placebo Comparator: placebo Single fixed dose (s.c.injection) of placebo	Drug: placebo; placebo for dasiglucagon; Other Names: placebo for dasiglucagon
Active Comparator: GlucaGen® Single fixed dose (s.c.injection) of GlucaGen®	Drug: GlucaGen HypoKit; native glucagon

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts 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:

1. 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

1. 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

2. 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
2. 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
3. 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
4. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	AMCR Institute, Inc	Escondido	California	United States	92025
2	Yale University School of Medicine	New Haven	Connecticut	United States	06520
3	Indiana University, Department of Pediatrics	Indianapolis	Indiana	United States	46202
4	Auf der Bult - Diabetes Center for Children	Hannover		Germany	30173
5	University Medical Center Ljubljana, Children's Hospital, Department for Endocrinology, Diabetes and Metabolism	Ljubljana		Slovenia	1000

Sponsors and Collaborators

• Zealand Pharma

Investigators

• Study Director: Christina M Sylvest, MSc Pharm, Zealand Pharma A/S

Study Documents (Full-Text)

• Study Protocol - Jan 8, 2019
• Statistical Analysis Plan - Aug 16, 2019

More Information

Publications

None provided.

• Responsible Party: Zealand Pharma
• ClinicalTrials.gov Identifier: NCT03667053
• Other Study ID Numbers: ZP4207-17086
• First Posted: Sep 12, 2018
• Last Update Posted: Jun 30, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• 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: Glucagon; Dasiglucagon
• Additional relevant MeSH terms: Hypoglycemia; Glucagon

Study Results

Participant Flow

Arm/Group Title	Dasiglucagon 0.6 mg	Placebo	GlucaGen® 1.0 mg
Arm/Group Description	Single fixed dose (subcutaneous injection) of dasiglucagon dasiglucagon: glucagon analog	Single fixed dose (subcutaneous injection) of placebo placebo: placebo for dasiglucagon	Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg) GlucaGen HypoKit: native glucagon
Period Title: Overall Study
STARTED	21	11	10
Randomized and Treated	20	11	10
COMPLETED	20	11	10
NOT COMPLETED	1	0	0

Baseline Characteristics

Arm/Group Title	Dasiglucagon 0.6 mg	Placebo	GlucaGen® 1.0 mg	Total
Arm/Group Description	Single fixed dose (subcutaneous injection) of dasiglucagon dasiglucagon: glucagon analog	Single fixed dose (subcutaneous injection) of placebo placebo: placebo for dasiglucagon	Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg) GlucaGen HypoKit: native glucagon	Total of all reporting groups
Overall Participants	20	11	10	41
Age (Count of Participants)
<=18 years	20 100%	11 100%	10 100%	41 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12.3 (3.42)	12.8 (3.25)	12.4 (3.50)	12.5 (3.32)
Age, Customized (Count of Participants)
Age 6-11 years	8 40%	4 36.4%	4 40%	16 39%
Age 12-17 years	12 60%	7 63.6%	6 60%	25 61%
Sex: Female, Male (Count of Participants)
Female	10 50%	6 54.5%	2 20%	18 43.9%
Male	10 50%	5 45.5%	8 80%	23 56.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 20%	2 18.2%	1 10%	7 17.1%
Not Hispanic or Latino	16 80%	8 72.7%	9 90%	33 80.5%
Unknown or Not Reported	0 0%	1 9.1%	0 0%	1 2.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	19 95%	10 90.9%	10 100%	39 95.1%
More than one race	1 5%	0 0%	0 0%	1 2.4%
Unknown or Not Reported	0 0%	1 9.1%	0 0%	1 2.4%
Region of Enrollment (participants) [Number]
United States	13 65%	9 81.8%	7 70%	29 70.7%
Slovenia	6 30%	2 18.2%	3 30%	11 26.8%
Germany	1 5%	0 0%	0 0%	1 2.4%
Body weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	51.54 (22.202)	54.95 (21.404)	48.81 (14.992)	51.79 (20.106)
Body mass index (kg per square meter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg per square meter]	20.74 (6.057)	20.39 (4.885)	18.92 (2.617)	20.20 (5.050)

Outcome Measures

1. Primary Outcome

Title	Time to Plasma Glucose Recovery
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Dasiglucagon 0.6 mg	Placebo	GlucaGen® 1.0 mg
Arm/Group Description	Single fixed dose (subcutaneous injection) of dasiglucagon dasiglucagon: glucagon analog	Single fixed dose (subcutaneous injection) of placebo placebo: placebo for dasiglucagon	Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg) GlucaGen HypoKit: native glucagon
Measure Participants	20	11	10
Median (95% Confidence Interval) [minutes]	10.00	30.00	10.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dasiglucagon 0.6 mg, Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Log Rank
	Comments

2. Secondary Outcome

Title	Plasma Glucose Recovery
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Dasiglucagon 0.6 mg	Placebo	GlucaGen® 1.0 mg
Arm/Group Description	Single fixed dose (subcutaneous injection) of dasiglucagon dasiglucagon: glucagon analog	Single fixed dose (subcutaneous injection) of placebo placebo: placebo for dasiglucagon	Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg) GlucaGen HypoKit: native glucagon
Measure Participants	20	11	10
Glucose recovery at 30 minutes	20 100%	6 54.5%	10 100%
Glucose recovery at 20 minutes	20 100%	2 18.2%	10 100%
Glucose recovery at 15 minutes	19 95%	0 0%	10 100%
Glucose recovery at 10 minutes	13 65%	0 0%	6 60%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dasiglucagon 0.6 mg, Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0073
	Comments	Assessed at 30 minutes. Note that p-value was 0.0005 at 10 minutes and <0.0001 at 15 and 20 minutes.
	Method	Cochran-Mantel-Haenszel
	Comments

3. Secondary Outcome

Title	Plasma Glucose Changes From Baseline
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Dasiglucagon 0.6 mg	Placebo	GlucaGen® 1.0 mg
Arm/Group Description	Single fixed dose (subcutaneous injection) of dasiglucagon dasiglucagon: glucagon analog	Single fixed dose (subcutaneous injection) of placebo placebo: placebo for dasiglucagon	Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg) GlucaGen HypoKit: native glucagon
Measure Participants	20	11	10
At 30 minutes	98.459 (19.6527)	17.510 (15.6313)	85.225 (12.5052)
At 20 minutes	65.369 (15.2461)	7.322 (13.3543)	58.000 (10.5297)
At 15 minutes	45.342 (15.0860)	0.835 (11.1276)	40.631 (9.7317)
At 10 minutes	27.225 (13.6768)	-3.405 (8.0276)	20.919 (6.7227)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dasiglucagon 0.6 mg, Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The p-value was <0.0001 at all time points (10, 15, 20 and 30 minutes)
	Method	ANOVA
	Comments

4. Secondary Outcome

Title	Pharmacodynamics - Area Under the Effect Curve (0-30 Minutes)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Dasiglucagon 0.6 mg	Placebo	GlucaGen® 1.0 mg
Arm/Group Description	Single fixed dose (subcutaneous injection) of dasiglucagon dasiglucagon: glucagon analog	Single fixed dose (subcutaneous injection) of placebo placebo: placebo for dasiglucagon	Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg) GlucaGen HypoKit: native glucagon
Measure Participants	20	11	10
Mean (Standard Deviation) [mmol*h/L]	22.83 (6.126)	1.81 (4.641)	19.66 (3.410)

5. Secondary Outcome

Title	Administration of Rescue IV Glucose Infusion After IMP Injection
Description	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

Outcome Measure Data

Analysis Population Description

Safety analysis set (same as the full analysis set) of all randomized and treated patients.

Arm/Group Title	Dasiglucagon 0.6 mg	Placebo	GlucaGen® 1.0 mg
Arm/Group Description	Single fixed dose (subcutaneous injection) of dasiglucagon dasiglucagon: glucagon analog	Single fixed dose (subcutaneous injection) of placebo placebo: placebo for dasiglucagon	Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg) GlucaGen HypoKit: native glucagon
Measure Participants	20	11	10
Count of Participants [Participants]	0 0%	1 9.1%	0 0%

6. Secondary Outcome

Title	Time to First IV Glucose Infusion After IMP Administration
Description	Time to first IV rescue glucose administration for hypoglycemia after administration of IMP. IV = intravenous. IMP = investigational medicinal product.
Time Frame	0-45 minutes

Outcome Measure Data

Analysis Population Description

Only the patient who received IV glucose administration is included.

Arm/Group Title	Dasiglucagon 0.6 mg	Placebo	GlucaGen® 1.0 mg
Arm/Group Description	Single fixed dose (subcutaneous injection) of dasiglucagon dasiglucagon: glucagon analog	Single fixed dose (subcutaneous injection) of placebo placebo: placebo for dasiglucagon	Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg) GlucaGen HypoKit: native glucagon
Measure Participants	0	1	0
Number [minutes]	12

7. Secondary Outcome

Title	Pharmacokinetics: AUC0-30 Min
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Dasiglucagon 0.6 mg	GlucaGen® 1.0 mg
Arm/Group Description	Single fixed dose (subcutaneous injection) of dasiglucagon dasiglucagon: glucagon analog	Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg) GlucaGen HypoKit: native glucagon
Measure Participants	20	10
Geometric Mean (Geometric Coefficient of Variation) [h*pmol/L]	376 (78.1)	376 (63.3)

8. Secondary Outcome

Title	Pharmacokinetics: AUC0-300min
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Dasiglucagon 0.6 mg	GlucaGen® 1.0 mg
Arm/Group Description	Single fixed dose (subcutaneous injection) of dasiglucagon dasiglucagon: glucagon analog	Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg) GlucaGen HypoKit: native glucagon
Measure Participants	20	10
Geometric Mean (Geometric Coefficient of Variation) [h*pmol/L]	1810 (44.8)	1370 (72.7)

9. Secondary Outcome

Title	Pharmacokinetics: AUC0-inf
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Dasiglucagon 0.6 mg	GlucaGen® 1.0 mg
Arm/Group Description	Single fixed dose (subcutaneous injection) of dasiglucagon dasiglucagon: glucagon analog	Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg) GlucaGen HypoKit: native glucagon
Measure Participants	20	10
Geometric Mean (Geometric Coefficient of Variation) [h*pmol/L]	1850 (45.1)	1530 (70.3)

10. Secondary Outcome

Title	Pharmacokinetics: Cmax
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Dasiglucagon 0.6 mg	GlucaGen® 1.0 mg
Arm/Group Description	Single fixed dose (subcutaneous injection) of dasiglucagon dasiglucagon: glucagon analog	Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg) GlucaGen HypoKit: native glucagon
Measure Participants	20	10
Geometric Mean (Geometric Coefficient of Variation) [pmol/L]	1160 (61.2)	1120 (80)

11. Secondary Outcome

Title	Pharmacokinetics: Tmax
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Dasiglucagon 0.6 mg	GlucaGen® 1.0 mg
Arm/Group Description	Single fixed dose (subcutaneous injection) of dasiglucagon dasiglucagon: glucagon analog	Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg) GlucaGen HypoKit: native glucagon
Measure Participants	20	10
Median (Full Range) [hours]	0.35	0.333

12. Secondary Outcome

Title	Pharmacokinetics: λz
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Dasiglucagon 0.6 mg	GlucaGen® 1.0 mg
Arm/Group Description	Single fixed dose (subcutaneous injection) of dasiglucagon dasiglucagon: glucagon analog	Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg) GlucaGen HypoKit: native glucagon
Measure Participants	20	10
Geometric Least Squares Mean (Geometric Coefficient of Variation) [1/hour]	1.11 (37.4)	0.504 (27.2)

13. Secondary Outcome

Title	Pharmacokinetics: t½
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Dasiglucagon 0.6 mg	GlucaGen® 1.0 mg
Arm/Group Description	Single fixed dose (subcutaneous injection) of dasiglucagon dasiglucagon: glucagon analog	Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg) GlucaGen HypoKit: native glucagon
Measure Participants	20	10
Geometric Mean (Geometric Coefficient of Variation) [hours]	0.623 (37.4)	1.38 (27.2)

14. Secondary Outcome

Title	Pharmacokinetics: CL/f
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Dasiglucagon 0.6 mg	GlucaGen® 1.0 mg
Arm/Group Description	Single fixed dose (subcutaneous injection) of dasiglucagon dasiglucagon: glucagon analog	Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg) GlucaGen HypoKit: native glucagon
Measure Participants	20	10
Geometric Mean (Geometric Coefficient of Variation) [L/h]	96.1 (45.1)	188 (70.3)

15. Secondary Outcome

Title	Pharmacokinetics: Vz/f
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Dasiglucagon 0.6 mg	GlucaGen® 1.0 mg
Arm/Group Description	Single fixed dose (subcutaneous injection) of dasiglucagon dasiglucagon: glucagon analog	Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg) GlucaGen HypoKit: native glucagon
Measure Participants	20	10
Geometric Least Squares Mean (Geometric Coefficient of Variation) [litres]	86.4 (62.2)	373 (81.1)

16. Secondary Outcome

Title	Pharmacokinetics: MRT
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Dasiglucagon 0.6 mg	GlucaGen® 1.0 mg
Arm/Group Description	Single fixed dose (subcutaneous injection) of dasiglucagon dasiglucagon: glucagon analog	Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg) GlucaGen HypoKit: native glucagon
Measure Participants	20	10
Geometric Mean (Geometric Coefficient of Variation) [hours]	1.27 (29.5)	1.86 (21.1)

Adverse Events

Time Frame	Adverse events were collected from the first trial-related activity after the patient had signed the informed consent to the end of the follow-up period (28 days).
Arm/Group Title	Age Group 6-11 Years - Dasiglucagon		Age Group 6-11 Years - Placebo		Age Group 6-11 Years - GlucaGen		Age Group 12-17 Years - Dasiglucagon		Age Group 12-17 Years - Placebo		Age Group 12-17 Years - Glucagen		Dasiglucagon 0.6 mg		Placebo		GlucaGen® 1.0 mg
Arm/Group Description	Patients in the dasiglucagon group in the age group 6-11 years		Patients in the placebo group in the age group 6-11 years		Patients in the GlucaGen group in the age group 6-11 years		Patients in the dasiglucagon group in the age group 12-17 years		Patients in the placebo group in the age group 12-17 years		Patients in the GlucaGen group in the age group 12-17 years		Full population. Single fixed dose (subcutaneous injection) of dasiglucagon		Full population. Single fixed dose (subcutaneous injection) of placebo		Full population. Single fixed dose (subcutaneous injection) of GlucaGen® (0.5 mg if body weight <25 kg)
All Cause Mortality
	Age Group 6-11 Years - Dasiglucagon		Age Group 6-11 Years - Placebo		Age Group 6-11 Years - GlucaGen		Age Group 12-17 Years - Dasiglucagon		Age Group 12-17 Years - Placebo		Age Group 12-17 Years - Glucagen		Dasiglucagon 0.6 mg		Placebo		GlucaGen® 1.0 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/4 (0%)		0/4 (0%)		0/12 (0%)		0/7 (0%)		0/6 (0%)		0/20 (0%)		0/11 (0%)		0/10 (0%)
Serious Adverse Events
	Age Group 6-11 Years - Dasiglucagon		Age Group 6-11 Years - Placebo		Age Group 6-11 Years - GlucaGen		Age Group 12-17 Years - Dasiglucagon		Age Group 12-17 Years - Placebo		Age Group 12-17 Years - Glucagen		Dasiglucagon 0.6 mg		Placebo		GlucaGen® 1.0 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/4 (0%)		0/4 (0%)		0/12 (0%)		0/7 (0%)		0/6 (0%)		0/20 (0%)		0/11 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Age Group 6-11 Years - Dasiglucagon		Age Group 6-11 Years - Placebo		Age Group 6-11 Years - GlucaGen		Age Group 12-17 Years - Dasiglucagon		Age Group 12-17 Years - Placebo		Age Group 12-17 Years - Glucagen		Dasiglucagon 0.6 mg		Placebo		GlucaGen® 1.0 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/8 (37.5%)		1/4 (25%)		4/4 (100%)		12/12 (100%)		6/7 (85.7%)		5/6 (83.3%)		15/20 (75%)		7/11 (63.6%)		9/10 (90%)
Blood and lymphatic system disorders
Leukopenia	0/8 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0	0/6 (0%)	0	1/20 (5%)	1	0/11 (0%)	0	0/10 (0%)	0
Thrombocytopenia	0/8 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/12 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/20 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Gastrointestinal disorders
Nausea	2/8 (25%)	2	0/4 (0%)	0	2/4 (50%)	2	11/12 (91.7%)	12	0/7 (0%)	0	1/6 (16.7%)	1	13/20 (65%)	14	0/11 (0%)	0	3/10 (30%)	3
Vomiting	2/8 (25%)	2	0/4 (0%)	0	1/4 (25%)	1	8/12 (66.7%)	11	0/7 (0%)	0	0/6 (0%)	0	10/20 (50%)	13	0/11 (0%)	0	1/10 (10%)	1
General disorders
Injection site erythema	0/8 (0%)	0	0/4 (0%)	0	2/4 (50%)	2	0/12 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/20 (0%)	0	0/11 (0%)	0	3/10 (30%)	3
Injection site pain	0/8 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0	1/6 (16.7%)	1	1/20 (5%)	1	0/11 (0%)	0	1/10 (10%)	1
Injection site edema	0/8 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/12 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/20 (0%)	0	0/11 (0%)	0	1/10 (10%)	1
Injection site induration	0/8 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/12 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/20 (0%)	0	0/11 (0%)	0	1/10 (10%)	1
Infusion site bruising	0/8 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/12 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/20 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Infusion site pain	0/8 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/12 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/20 (0%)	0	0/11 (0%)	0	1/10 (10%)	1
Infections and infestations
Upper respiratory tract infection	0/8 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	2/12 (16.7%)	3	0/7 (0%)	0	0/6 (0%)	0	2/20 (10%)	3	0/11 (0%)	0	0/10 (0%)	0
Gastroenteritis	0/8 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/12 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/20 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Sinusitis	0/8 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/12 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/20 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Metabolism and nutrition disorders
Hypoglycemia	1/8 (12.5%)	1	0/4 (0%)	0	0/4 (0%)	0	1/12 (8.3%)	1	4/7 (57.1%)	16	2/6 (33.3%)	2	2/20 (10%)	2	4/11 (36.4%)	16	2/10 (20%)	2
Nervous system disorders
Headache	0/8 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	2/12 (16.7%)	2	1/7 (14.3%)	1	0/6 (0%)	0	2/20 (10%)	2	1/11 (9.1%)	1	1/10 (10%)	1
Renal and urinary disorders
Urinary incontinence	0/8 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/12 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/20 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Skin and subcutaneous tissue disorders
Rash	0/8 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/12 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/20 (0%)	0	0/11 (0%)	0	1/10 (10%)	1
Vascular disorders
Hypertension	0/8 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/12 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/20 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.