Assessment of Intranasal Glucagon in Children and Adolescents With Type 1 Diabetes

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01997411
• Collaborator: Jaeb Center for Health Research (Other), Locemia Solutions ULC (Industry)
• Enrollment: 48
• Locations: 7
• Arms: 2
• Duration (Months): 14
• Patients Per Site: 6.9
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study was to assess how glucagon administered nasally, using a nasal dosing delivery device, works in children and adolescents compared with commercially-available glucagon given by injection. In addition, the safety and tolerability of glucagon given nasally was evaluated.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 1	Drug: Nasal Glucagon; Drug: Intramuscular Glucagon	Phase 2/Phase 3

Detailed Description

This study was conducted to permit determination of appropriate dose level(s) for pediatric use based on the safety observations and results of glucagon and glucose assays.

Each participant 12 to less than 17 years of age underwent two visits in random order and received glucagon nasal powder once and commercially available glucagon (GlucaGen, Novo Nordisk) by intramuscular (IM) injection once. Participants 4 to less than 12 years were randomly assigned to have either 1 visit with commercially available glucagon (GlucaGen, Novo Nordisk) by IM injection OR to have 2 visits with a 2.0 milligram (mg) dose of glucagon nasal powder administered during one visit and a 3.0 mg dose of glucagon nasal powder administered during the other visit. For those randomized to complete two research dosing visits, the dose of glucagon nasal powder given during each visit was masked to the participant and study personnel.

Glucagon was administered after glucose was lowered to <80 mg/dL using insulin if necessary on the dosing day. Participants were treated with either glucagon given nasally (either 2.0 mg or 3.0 mg for participants 4 to less than 12 years of age or 3.0 mg for those 12 to less than 17 years of age) or by intramuscular (IM) injection (1 mg for those 55 pounds [lbs] or more and 0.5 mg for those weighing less than 55 lbs) in the quadriceps muscle of the leg.

Blood glucose levels and adverse events were carefully monitored for 90 minutes post-dosing. After a wash-out period of 7 days or more, participants 12 to less than 17 years of age returned to the clinic and the procedure was repeated with each participant crossed over to the other treatment. Participants 4 to less than 12 years assigned to have 2 dosing visits returned to clinic for repeated procedures and received alternate dose of nasal glucagon (NG). Participants 4 to less than 12 years assigned to a single dosing visit did not return for a second dosing visit.

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: IM and NG arms are open labeled. NG cohorts, 2mg and 3mg, are quadruple blinded.
• Primary Purpose: Treatment
• Official Title: Assessment of Intranasal Glucagon in Children and Adolescents With Type 1 Diabetes
• Study Start Date: Nov 1, 2013
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Jan 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nasal Glucagon (NG) Nasal glucagon (NG) doses of 2.0 mg and 3.0 mg for participants 4 to less than 12 years of age and 3.0 mg for those 12 to less than 17 years of age were administered in a nostril with a prefilled delivery device that delivered a single dose upon activation.	Drug: Nasal Glucagon; Other Names: AMG504-1 LY900018
Active Comparator: Intramuscular (IM) Glucagon Participants who weighed at least 25 kilograms (kg)/55 pounds (lbs) were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 lbs, IM glucagon dosed with 0.5 mg	Drug: Intramuscular Glucagon; Other Names: GlucaGen HypoKit

Outcome Measures

Primary Outcome Measures

1. Maximum Change From Baseline Concentration (Cmax) of Glucagon [Pre-dose; 5, 10, 15, 20, 30, 40, 60 and 90 minutes following glucagon administration]

2. Time to Maximum Concentration (Tmax) of Baseline Adjusted Glucagon [Pre-dose; 5, 10, 15, 20, 30, 40, 60 and 90 minutes following glucagon administration]

3. Area Under the Curve (AUC0-1.5) of Baseline Adjusted Glucagon [Pre-dose; 5, 10, 15, 20, 30, 40, 60 and 90 minutes following glucagon administration]

4. Maximum Concentration (Cmax) of Baseline-Adjusted Glucose [Pre-dose; 5, 10, 15, 20, 30, 40, 60 and 90 minutes following glucagon administration]

5. Time to Maximum Concentration (Tmax) of Baseline-Adjusted Glucose [Pre-dose; 5, 10, 15, 20, 30, 40, 60 and 90 minutes following glucagon administration]

6. Area Under the Effect Concentration Time Curve (AUEC0-1.5) of Baseline-Adjusted Glucose From Time Zero up to 90 Minutes [Pre-dose; 5, 10, 15, 20, 30, 40, 60 and 90 minutes following glucagon administration]

Secondary Outcome Measures

1. Nasal and Non-nasal Effects/Symptoms [Pre-dose;15, 30, 60 and 90 minutes following glucagon administration]

   Symptoms of runny nose, nasal congestion and/or itching, sneezing, watery and/or itchy eyes, redness of eyes, and itching of ears and/or throat were assessed prior to administering glucagon and at 15, 30, 60 and 90 minutes following administration of glucagon. This was done via the "Nasal Non-nasal Score Questionnaire". Each of the 9 symptoms is assigned an integer value from 0 to 3; higher values indicate more severe symptoms (a score of 0 indicates no symptoms). The reported results indicate the cohort median out of a possible maximum value of 27 (summing all 9 questions for each participant and reporting the median/IQR across participants).

2. Number of Participants Achieving at Least a 25 mg/dL Rise in Blood Glucose Above Nadir Level Within 30 Minutes [Pre-dose; 5, 10, 15, 20, and 30 minutes following glucagon administration]

3. Time to Achieving ≥25 mg/dL Rise in Plasma Glucose Above Nadir Level Within 30 Minutes [Pre-dose; 5, 10, 15, 20, and 30 minutes following glucagon administration]

   Time (in minutes) when all participants experienced a rise in glucose >=25mg/dL. This is an absolute number and is not a calculated statistic. There is no distribution per cohort.

Other Outcome Measures

1. Percentage of Participants With >= 25 mg/dL Rise in Plasma Glucose Within 30 Minutes [Pre-dose; 5, 10,15, 20, and 30 minutes following glucagon administration]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years to 16 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

To be eligible, the following inclusion criteria were met:

• History of type 1 diabetes and receiving daily insulin therapy from the time of diagnosis for at least 12 months

• At least 4 years of age and less than 17 years

• Females must have met one of the following criteria:

• Of childbearing potential but agreed to use an accepted contraceptive regimen as described in the study procedure manual throughout the entire duration of the study (from screening until study completion)

• Of non-childbearing potential, defined as a female who had a hysterectomy or tubal ligation, was clinically considered infertile or had not yet reached menarche

• In good general health with no conditions that could have influenced the outcome of the trial, and in the judgment of the Investigator was a good candidate for the study based on review of available medical history, physical examination and clinical laboratory evaluations

• Willingness to adhere to the study requirements

Exclusion Criteria:

An individual was not eligible if any of the following exclusion criteria were present:

• Females who were pregnant according to a positive urine pregnancy test, actively attempting to get pregnant, or were lactating

• History of hypersensitivity to glucagon or any related products or severe hypersensitivity reactions (such as angioedema) to any drugs

• Presence of cardiovascular, gastrointestinal, liver or kidney disease, or any other conditions which in the judgment of the investigator could have interfered with the absorption, distribution, metabolism or excretion of drugs or could potentiate or predispose to undesired effects

• History of pheochromocytoma (i.e. adrenal gland tumor) or insulinoma

• History of an episode of severe hypoglycemia (as defined by an episode that required third party assistance for treatment) in the 1 month prior to enrolling in the study

• Use of daily systemic beta-blocker, indomethacin, warfarin or anticholinergic drugs

• History of epilepsy or seizure disorder

• Use of an Investigational Product in another clinical trial within the past 30 days

• Blood donation in 3 months prior to first glucagon dosing

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Barbara Davis Center for Diabetes	Aurora	Colorado	United States	80045
2	Yale University	New Haven	Connecticut	United States	06520
3	University of Florida	Gainesville	Florida	United States	32605
4	Nemours Children's Clinic	Jacksonville	Florida	United States	32207
5	Riley Hospital for Children Indiana University Health	Indianapolis	Indiana	United States	46202
6	University of Minnesota	Minneapolis	Minnesota	United States	55454
7	UPA Buffalo	Buffalo	New York	United States	14222

Sponsors and Collaborators

• Eli Lilly and Company
• Jaeb Center for Health Research
• Locemia Solutions ULC

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01997411
• Other Study ID Numbers: 16418; I8R-MC-IGBB; INGluc002; AMG103
• First Posted: Nov 28, 2013
• Last Update Posted: Aug 29, 2018
• Last Verified: Aug 1, 2018

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucagon; Glucagon-Like Peptide 1

Study Results

Participant Flow

Arm/Group Title	4 to<8 Years Old Intramuscular (IM) Glucagon Visit	4 to <8 Years Old NG 2.0 mg 1st Visit/3.0 mg 2nd Visit	4 to <8 Years Old NG 3.0 mg 1st Visit/2.0 mg 2nd Visit	8 to <12 Years Old Intramuscular Glucagon Visit	8 to <12 Years Old NG 2.0 mg 1st Visit/3.0 mg 2nd Visit	8 to <12 Years Old NG 3.0 mg 1st Visit/2.0 mg 2nd Visit	12 to <17 Years Old NG 1st Visit/IM Glucagon 2nd Visit	12 to <17 Years Old IM Glucagon 1st Visit/NG 2nd Visit
Arm/Group Description	Participants who weighed at least 25 kilograms (kg)/55 pounds (lbs) were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg. This was completed at one visit and was the only visit for this cohort.	At the first visit, a nasal glucagon (NG) dose of 2.0 milligrams (mg) for participants 4 to less than 8 years of age was administered nasally. At the second visit, NG dose of 3.0 mg was administered nasally.	At the first visit, a NG dose of 3.0 mg for participants 4 to less than 8 years of age was administered nasally. At the second visit, a NG dose of 2.0 mg was administered nasally.	Participants who weighed at least 25 kilograms kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg. This was completed at one visit and was the only visit for this cohort.	At the first visit, a NG dose of 2.0 mg for participants 8 to less than 12 years of age was administered nasally. At the second visit, a NG dose of 3.0 mg was administered nasally.	At the first visit, a NG dose of 3.0 mg for participants 8 to less than 12 years of age was administered nasally. At the second visit, a NG dose of 2.0 mg was administered nasally.	At the first visit, a NG dose of 3.0 mg was administered nasally. At the second visit, participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	At the first visit, participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg. At the second visit, a NG dose of 3.0 mg was administered nasally.
Period Title: Overall Study
STARTED	6	6	6	6	6	6	6	6
COMPLETED	6	6	6	6	6	5	6	6
NOT COMPLETED	0	0	0	0	0	1	0	0

Baseline Characteristics

Arm/Group Title	4 to <8 Years Old IM Glucagon Cohort	4 to <8 Years Old NG Cohort	8 to <12 Years Old IM Glucagon Cohort	8 to <12 Years Old NG Cohort	12 to <17 Years Old NG/IM Cohort	Total
Arm/Group Description	Participants who were 4 to < 8 years old at the time of enrollment into the study randomized to receive only the intramuscular glucagon at one visit.	Participants who were 4 to < 8 years old at the time of enrollment into the study randomized to receive 2.0 or 3.0 mg of nasal glucagon at two separate visits. Order of these visits was randomized.	Participants who were 8 to < 12 years old at the time of enrollment into the study randomized to receive only the intramuscular glucagon at one visit.	Participants who were 8 to < 12 years old at the time of enrollment into the study randomized to receive 2.0 or 3.0 mg of nasal glucagon at two separate visits. Order of these visits was randomized.	Participants who were 12 to < 17 years old at the time of enrollment into the study randomized to receive either intramuscular glucagon or nasal glucagon at two separate visits. Order of these visits was randomized.	Total of all reporting groups
Overall Participants	6	12	6	12	12	48
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	6.8	6.8	11.1	11.1	14.5	10.6
Sex: Female, Male (Count of Participants)
Female	0 0%	3 25%	3 50%	5 41.7%	5 41.7%	16 33.3%
Male	6 100%	9 75%	3 50%	7 58.3%	7 58.3%	32 66.7%
Region of Enrollment (Count of Participants)
United States	6 100%	12 100%	6 100%	12 100%	12 100%	48 100%
Local HbA1c (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	7.6 (0.5)	8.3 (0.8)	7.5 (1.1)	8.1 (0.7)	8.2 (1.5)	8.0 (1.0)
Duration of Diabetes (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	3.1	2.7	5.3	4.3	5.9	3.9

Outcome Measures

1. Primary Outcome

Title	Maximum Change From Baseline Concentration (Cmax) of Glucagon
Time Frame	Pre-dose; 5, 10, 15, 20, 30, 40, 60 and 90 minutes following glucagon administration

Outcome Measure Data

Analysis Population Description

All enrolled participants that completed the required dosing visit(s). One participant in the 4 to <8 year old 2.0 mg NG group was excluded due to blowing nose after NG administration. One participant in the 8 to <12 group withdrew after completion of the 3.0 mg NG visit and did not complete the 2.0 mg NG visit.

Arm/Group Title	4 to<8 Years Old IM Glucagon Visit	4 to<8 Years Old NG Visit 2.0 mg	4 to<8 Years Old NG Visit 3.0 mg	8 to <12 Years Old IM Glucagon Visit	8 to<12 Years Old NG Visit 2.0 mg	8 to<12 Years Old NG Visit 3.0 mg	12 to <17 Years Old IM Glucagon Visit	12 to<17 Years Old NG Visit 3.0 mg
Arm/Group Description	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 4 to less than 8 years of age.	NG dose of 3.0 mg for participants 4 to less than 8 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 8 to less than 12 years of age.	NG dose of 3.0 mg for participants 8 to less than 12 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 3.0 mg for participants 12 to less than 17 years of age.
Measure Participants	6	11	12	6	11	12	12	12
Mean (Standard Deviation) [picograms per millilitre (pg/mL)]	6290.33 (2045.96)	3463.55 (1760.28)	3958.58 (2438.60)	4743.00 (3094.61)	2776.27 (979.28)	5664.33 (2114.69)	4277.25 (3774.77)	3103.25 (2302.61)

2. Primary Outcome

Title	Time to Maximum Concentration (Tmax) of Baseline Adjusted Glucagon
Time Frame	Pre-dose; 5, 10, 15, 20, 30, 40, 60 and 90 minutes following glucagon administration

Outcome Measure Data

Analysis Population Description

All enrolled participants that completed the required dosing visit(s). One participant in the 4 to <8 year old 2.0 mg NG group was excluded due to blowing nose after NG administration. One participant in the 8 to <12 group withdrew after completion of the 3.0 mg NG visit and did not complete the 2.0 mg NG visit.

Arm/Group Title	4 to<8 Years Old IM Glucagon Visit	4 to<8 Years Old NG Visit 2.0 mg	4 to<8 Years Old NG Visit 3.0 mg	8 to <12 Years Old IM Glucagon Visit	8 to<12 Years Old NG Visit 2.0 mg	8 to<12 Years Old NG Visit 3.0 mg	12 to <17 Years Old IM Glucagon Visit	12 to<17 Years Old NG Visit 3.0 mg
Arm/Group Description	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 4 to less than 8 years of age.	NG dose of 3.0 mg for participants 4 to less than 8 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 8 to less than 12 years of age.	NG dose of 3.0 mg for participants 8 to less than 12 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 3.0 mg for participants 12 to less than 17 years of age.
Measure Participants	6	11	12	6	11	12	12	12
Median (Full Range) [hours (hr)]	0.29	0.25	0.29	0.29	0.25	0.25	0.29	0.33

3. Primary Outcome

Title	Area Under the Curve (AUC0-1.5) of Baseline Adjusted Glucagon
Time Frame	Pre-dose; 5, 10, 15, 20, 30, 40, 60 and 90 minutes following glucagon administration

Outcome Measure Data

Analysis Population Description

All enrolled participants that completed the required dosing visit(s). One participant in the 4 to <8 year old 2.0 mg NG group was excluded due to blowing nose after NG administration. One participant in the 8 to <12 group withdrew after completion of the 3.0 mg NG visit and did not complete the 2.0 mg NG visit.

Arm/Group Title	4 to<8 Years Old IM Glucagon Visit	4 to<8 Years Old NG Visit 2.0 mg	4 to<8 Years Old NG Visit 3.0 mg	8 to <12 Years Old IM Glucagon Visit	8 to<12 Years Old NG Visit 2.0 mg	8 to<12 Years Old NG Visit 3.0 mg	12 to <17 Years Old IM Glucagon Visit	12 to<17 Years Old NG Visit 3.0 mg
Arm/Group Description	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 4 to less than 8 years of age.	NG dose of 3.0 mg for participants 4 to less than 8 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 8 to less than 12 years of age.	NG dose of 3.0 mg for participants 8 to less than 12 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 3.0 mg for participants 12 to less than 17 years of age.
Measure Participants	6	11	12	6	11	12	12	12
Mean (Standard Deviation) [hour*picogram per millilitre (hr*pg/mL)]	4078.68 (2078.89)	1744.36 (978.81)	2472.40 (1435.45)	3635.77 (2069.11)	1506.23 (541.57)	2939.31 (1042.03)	3110.22 (2848.75)	1999.69 (1329.44)

4. Primary Outcome

Title	Maximum Concentration (Cmax) of Baseline-Adjusted Glucose
Time Frame	Pre-dose; 5, 10, 15, 20, 30, 40, 60 and 90 minutes following glucagon administration

Outcome Measure Data

Analysis Population Description

All enrolled participants that completed the required dosing visit(s). One participant in the 4 to <8 year old 2.0 mg NG group was excluded due to blowing nose after NG administration. One participant in the 8 to <12 group withdrew after completion of the 3.0 mg NG visit and did not complete the 2.0 mg NG visit.

Arm/Group Title	4 to<8 Years Old IM Glucagon Visit	4 to<8 Years Old NG Visit 2.0 mg	4 to<8 Years Old NG Visit 3.0 mg	8 to <12 Years Old IM Glucagon Visit	8 to<12 Years Old NG Visit 2.0 mg	8 to<12 Years Old NG Visit 3.0 mg	12 to <17 Years Old IM Glucagon Visit	12 to<17 Years Old NG Visit 3.0 mg
Arm/Group Description	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 4 to less than 8 years of age.	NG dose of 3.0 mg for participants 4 to less than 8 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 8 to less than 12 years of age.	NG dose of 3.0 mg for participants 8 to less than 12 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 3.0 mg for participants 12 to less than 17 years of age.
Measure Participants	6	11	12	6	11	12	12	12
Mean (Standard Deviation) [mg/dL]	138.17 (26.57)	118.18 (46.46)	137.50 (42.14)	130.50 (21.81)	125.09 (23.81)	132.82 (30.59)	123.17 (29.58)	102.33 (25.63)

5. Primary Outcome

Title	Time to Maximum Concentration (Tmax) of Baseline-Adjusted Glucose
Time Frame	Pre-dose; 5, 10, 15, 20, 30, 40, 60 and 90 minutes following glucagon administration

Outcome Measure Data

Analysis Population Description

All enrolled participants that completed the required dosing visit(s). One participant in the 4 to <8 year old 2.0 mg NG group was excluded due to blowing nose after NG administration. One participant in the 8 to <12 group withdrew after completion of the 3.0 mg NG visit and did not complete the 2.0 mg NG visit.

Arm/Group Title	4 to<8 Years Old IM Glucagon Visit	4 to<8 Years Old NG Visit 2.0 mg	4 to<8 Years Old NG Visit 3.0 mg	8 to <12 Years Old IM Glucagon Visit	8 to<12 Years Old NG Visit 2.0 mg	8 to<12 Years Old NG Visit 3.0 mg	12 to <17 Years Old IM Glucagon Visit	12 to<17 Years Old NG Visit 3.0 mg
Arm/Group Description	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 4 to less than 8 years of age.	NG dose of 3.0 mg for participants 4 to less than 8 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 8 to less than 12 years of age.	NG dose of 3.0 mg for participants 8 to less than 12 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 3.0 mg for participants 12 to less than 17 years of age.
Measure Participants	6	11	12	6	11	12	12	12
Median (Full Range) [hours (hr)]	1.00	0.67	1.00	1.50	1.00	1.00	1.00	1.00

6. Primary Outcome

Title	Area Under the Effect Concentration Time Curve (AUEC0-1.5) of Baseline-Adjusted Glucose From Time Zero up to 90 Minutes
Time Frame	Pre-dose; 5, 10, 15, 20, 30, 40, 60 and 90 minutes following glucagon administration

Outcome Measure Data

Analysis Population Description

All enrolled participants that completed the required dosing visit(s). One participant in the 4 to <8 year old 2.0 mg NG group was excluded due to blowing nose after NG administration. One participant in the 8 to <12 group withdrew after completion of the 3.0 mg NG visit and did not complete the 2.0 mg NG visit.

Arm/Group Title	4 to<8 Years Old IM Glucagon Visit	4 to<8 Years Old NG Visit 2.0 mg	4 to<8 Years Old NG Visit 3.0 mg	8 to <12 Years Old IM Glucagon Visit	8 to<12 Years Old NG Visit 2.0 mg	8 to<12 Years Old NG Visit 3.0 mg	12 to <17 Years Old IM Glucagon Visit	12 to<17 Years Old NG Visit 3.0 mg
Arm/Group Description	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 4 to less than 8 years of age.	NG dose of 3.0 mg for participants 4 to less than 8 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 8 to less than 12 years of age.	NG dose of 3.0 mg for participants 8 to less than 12 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 3.0 mg for participants 12 to less than 17 years of age.
Measure Participants	6	11	12	6	11	12	12	12
Mean (Standard Deviation) [hr*mg/dL]	145.86 (26.94)	118.82 (60.73)	142.38 (51.98)	132.42 (22.14)	128.82 (28.45)	138.12 (35.24)	126.94 (30.40)	101.46 (27.38)

7. Secondary Outcome

Title	Nasal and Non-nasal Effects/Symptoms
Description	Symptoms of runny nose, nasal congestion and/or itching, sneezing, watery and/or itchy eyes, redness of eyes, and itching of ears and/or throat were assessed prior to administering glucagon and at 15, 30, 60 and 90 minutes following administration of glucagon. This was done via the "Nasal Non-nasal Score Questionnaire". Each of the 9 symptoms is assigned an integer value from 0 to 3; higher values indicate more severe symptoms (a score of 0 indicates no symptoms). The reported results indicate the cohort median out of a possible maximum value of 27 (summing all 9 questions for each participant and reporting the median/IQR across participants).
Time Frame	Pre-dose;15, 30, 60 and 90 minutes following glucagon administration

Outcome Measure Data

Analysis Population Description

All enrolled participants. One participant in the 8 to <12 group withdrew from the study after completion of the 3.0 mg NG visit and did not complete the 2.0 mg NG visit.

Arm/Group Title	4 to<8 Years Old IM Glucagon Visit	4 to<8 Years Old NG Visit 2.0 mg	4 to<8 Years Old NG Visit 3.0 mg	8 to <12 Years Old IM Glucagon Visit	8 to<12 Years Old NG Visit 2.0 mg	8 to<12 Years Old NG Visit 3.0 mg	12 to <17 Years Old IM Glucagon Visit	12 to<17 Years Old NG Visit 3.0 mg
Arm/Group Description	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 4 to less than 8 years of age.	NG dose of 3.0 mg for participants 4 to less than 8 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 8 to less than 12 years of age.	NG dose of 3.0 mg for participants 8 to less than 12 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 3.0 mg for participants 12 to less than 17 years of age.
Measure Participants	6	12	12	6	11	12	12	12
Pre-dose	0.50	0.00	0.00	0.00	0.00	0.00	0.00	0.50
15 minutes post glucagon administration	0.00	1.00	0.50	0.00	3.00	3.00	0.00	2.00
30 minutes post glucagon administration	0.00	1.00	0.50	0.00	2.00	2.50	0.00	1.00
60 minutes post glucagon administration	0.00	0.50	0.00	0.00	0.00	0.50	0.00	1.00
90 minutes post glucagon administration	0.00	0.00	0.00	0.00	0.00	0.00	0.00	1.00

8. Secondary Outcome

Title	Number of Participants Achieving at Least a 25 mg/dL Rise in Blood Glucose Above Nadir Level Within 30 Minutes
Time Frame	Pre-dose; 5, 10, 15, 20, and 30 minutes following glucagon administration

Outcome Measure Data

Analysis Population Description

All enrolled participants that completed the required dosing visit(s). One participant in the 4 to <8 year old 2.0 mg NG group was excluded due to blowing nose after NG administration. One participant in the 8 to <12 group withdrew after completion of the 3.0 mg NG visit and did not complete the 2.0 mg NG visit.

Arm/Group Title	4 to<8 Years Old IM Glucagon Visit	4 to<8 Years Old NG Visit 2.0 mg	4 to<8 Years Old NG Visit 3.0 mg	8 to <12 Years Old IM Glucagon Visit	8 to<12 Years Old NG Visit 2.0 mg	8 to<12 Years Old NG Visit 3.0 mg	12 to <17 Years Old IM Glucagon Visit	12 to<17 Years Old NG Visit 3.0 mg
Arm/Group Description	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 4 to less than 8 years of age.	NG dose of 3.0 mg for participants 4 to less than 8 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 8 to less than 12 years of age.	NG dose of 3.0 mg for participants 8 to less than 12 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 3.0 mg for participants 12 to less than 17 years of age.
Measure Participants	6	11	12	6	11	12	12	12
Count of Participants [Participants]	6 100%	11 91.7%	12 200%	6 50%	11 91.7%	12 25%	12 NaN	12 NaN

9. Secondary Outcome

Title	Time to Achieving ≥25 mg/dL Rise in Plasma Glucose Above Nadir Level Within 30 Minutes
Description	Time (in minutes) when all participants experienced a rise in glucose >=25mg/dL. This is an absolute number and is not a calculated statistic. There is no distribution per cohort.
Time Frame	Pre-dose; 5, 10, 15, 20, and 30 minutes following glucagon administration

Outcome Measure Data

Analysis Population Description

All enrolled participants that completed the required dosing visit(s). One participant in the 4 to <8 year old 2.0 mg NG group was excluded due to blowing nose after NG administration. One participant in the 8 to <12 group withdrew after completion of the 3.0 mg NG visit and did not complete the 2.0 mg NG visit.

Arm/Group Title	4 to<8 Years Old IM Glucagon Visit	4 to<8 Years Old NG Visit 2.0 mg	4 to<8 Years Old NG Visit 3.0 mg	8 to <12 Years Old IM Glucagon Visit	8 to<12 Years Old NG Visit 2.0 mg	8 to<12 Years Old NG Visit 3.0 mg	12 to <17 Years Old IM Glucagon Visit	12 to<17 Years Old NG Visit 3.0 mg
Arm/Group Description	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 4 to less than 8 years of age.	NG dose of 3.0 mg for participants 4 to less than 8 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 8 to less than 12 years of age.	NG dose of 3.0 mg for participants 8 to less than 12 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 3.0 mg for participants 12 to less than 17 years of age.
Measure Participants	6	11	12	6	11	12	12	12
Number [minutes]	10	20	15	20	20	15	20	20

10. Other Pre-specified Outcome

Title	Percentage of Participants With >= 25 mg/dL Rise in Plasma Glucose Within 30 Minutes
Time Frame	Pre-dose; 5, 10,15, 20, and 30 minutes following glucagon administration

Outcome Measure Data

Analysis Population Description

All enrolled participants that completed the required dosing visit(s). One participant in the 4 to <8 year old 2.0 mg NG group was excluded due to blowing nose after NG administration. One participant in the 8 to <12 group withdrew after completion of the 3.0 mg NG visit and did not complete the 2.0 mg NG visit.

Arm/Group Title	4 to<8 Years Old IM Glucagon Visit	4 to<8 Years Old NG Visit 2.0 mg	4 to<8 Years Old NG Visit 3.0 mg	8 to <12 Years Old IM Glucagon Visit	8 to<12 Years Old NG Visit 2.0 mg	8 to<12 Years Old NG Visit 3.0 mg	12 to <17 Years Old IM Glucagon Visit	12 to<17 Years Old NG Visit 3.0 mg
Arm/Group Description	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 4 to less than 8 years of age.	NG dose of 3.0 mg for participants 4 to less than 8 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 2.0 mg for participants 8 to less than 12 years of age.	NG dose of 3.0 mg for participants 8 to less than 12 years of age.	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.	NG dose of 3.0 mg for participants 12 to less than 17 years of age.
Measure Participants	6	11	12	6	11	12	12	12
Number [percentage of participants]	100 1666.7%	100 833.3%	100 1666.7%	100 833.3%	100 833.3%	100 208.3%	100 NaN	100 NaN

Adverse Events

Time Frame	Through study completion, up to 69 days
Adverse Event Reporting Description	Included all participants received at least one dose of glucagon.
Arm/Group Title	4 to<8 Years Old IM Glucagon Visit		4 to<8 Years Old NG Visit 2.0 mg		4 to<8 Years Old NG Visit 3.0 mg		8 to <12 Years Old IM Glucagon Visit		8 to<12 Years Old NG Visit 2.0 mg		8 to<12 Years Old NG Visit 3.0 mg		12 to <17 Years Old IM Glucagon Visit		12 to<17 Years Old NG Visit 3.0 mg
Arm/Group Description	Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.		NG dose of 2.0 mg for participants 4 to less than 8 years of age.		NG dose of 3.0 mg for participants 4 to less than 8 years of age.		Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.		NG of 2.0 mg for participants 8 to less than 12 years of age.		NG dose of 3.0 mg for participants 8 to less than 12 years of age.		Participants who weighed at least 25 kg/55 lbs were dosed 1 mg of IM glucagon; participants who weighed less than 25 kg/55 Ibs, IM glucagon dose was 0.5 mg.		NG dose of 3.0 mg for participants 12 to less than 17 years of age.
All Cause Mortality
	4 to<8 Years Old IM Glucagon Visit		4 to<8 Years Old NG Visit 2.0 mg		4 to<8 Years Old NG Visit 3.0 mg		8 to <12 Years Old IM Glucagon Visit		8 to<12 Years Old NG Visit 2.0 mg		8 to<12 Years Old NG Visit 3.0 mg		12 to <17 Years Old IM Glucagon Visit		12 to<17 Years Old NG Visit 3.0 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
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	4 to<8 Years Old IM Glucagon Visit		4 to<8 Years Old NG Visit 2.0 mg		4 to<8 Years Old NG Visit 3.0 mg		8 to <12 Years Old IM Glucagon Visit		8 to<12 Years Old NG Visit 2.0 mg		8 to<12 Years Old NG Visit 3.0 mg		12 to <17 Years Old IM Glucagon Visit		12 to<17 Years Old NG Visit 3.0 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
Total	1/6 (16.7%)		0/12 (0%)		0/12 (0%)		0/6 (0%)		0/11 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)
Endocrine disorders
Hypoglycemia	1/6 (16.7%)		0/12 (0%)		0/12 (0%)		0/6 (0%)		0/11 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	4 to<8 Years Old IM Glucagon Visit		4 to<8 Years Old NG Visit 2.0 mg		4 to<8 Years Old NG Visit 3.0 mg		8 to <12 Years Old IM Glucagon Visit		8 to<12 Years Old NG Visit 2.0 mg		8 to<12 Years Old NG Visit 3.0 mg		12 to <17 Years Old IM Glucagon Visit		12 to<17 Years Old NG Visit 3.0 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
Total	5/6 (83.3%)		6/12 (50%)		5/12 (41.7%)		6/6 (100%)		5/11 (45.5%)		6/12 (50%)		7/12 (58.3%)		9/12 (75%)
Cardiac disorders
Tachycardia	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/6 (0%)		0/11 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)
Eye disorders
Eye irritation	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/6 (0%)		0/11 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)
Lacrimation increase	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/6 (0%)		1/11 (9.1%)		0/12 (0%)		0/12 (0%)		0/12 (0%)
Ocular discomfort	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/6 (0%)		0/11 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)
Gastrointestinal disorders
Abdominal pain	1/6 (16.7%)		1/12 (8.3%)		0/12 (0%)		0/6 (0%)		0/11 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)
Diarrhea	0/6 (0%)		0/12 (0%)		0/12 (0%)		1/6 (16.7%)		0/11 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)
Nausea	4/6 (66.7%)		4/12 (33.3%)		2/12 (16.7%)		3/6 (50%)		1/11 (9.1%)		1/12 (8.3%)		1/12 (8.3%)		3/12 (25%)
Vomiting	1/6 (16.7%)		1/12 (8.3%)		3/12 (25%)		3/6 (50%)		3/11 (27.3%)		4/12 (33.3%)		5/12 (41.7%)		4/12 (33.3%)
General disorders
Catheter site pain	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		1/6 (16.7%)		0/11 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)
Injection site discomfort	2/6 (33.3%)		0/12 (0%)		0/12 (0%)		3/6 (50%)		0/11 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)
Nervous system disorders
Headache	0/6 (0%)		2/12 (16.7%)		1/12 (8.3%)		2/6 (33.3%)		2/11 (18.2%)		4/12 (33.3%)		1/12 (8.3%)		4/12 (33.3%)
Dizziness	0/6 (0%)		0/12 (0%)		0/12 (0%)		1/6 (16.7%)		0/11 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/6 (0%)		0/11 (0%)		0/12 (0%)		0/12 (0%)		2/12 (16.7%)
Nasal discomfort	0/6 (0%)		0/12 (0%)		2/12 (16.7%)		0/6 (0%)		0/11 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)
Sneezing	0/6 (0%)		0/12 (0%)		0/12 (0%)		0/6 (0%)		0/11 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)
Rhinalgia	0/6 (0%)		1/12 (8.3%)		0/12 (0%)		0/6 (0%)		0/11 (0%)		0/12 (0%)		0/12 (0%)		0/12 (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.