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

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.

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