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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: Nasal Glucagon
* Drug: Intramuscular Glucagon


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nasal Glucagon (NG)<br>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<br> <br> * Other names: LY900018;|
| Active Comparator: Intramuscular (IM) Glucagon<br>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<br> <br> * Other names: GlucaGen HypoKit;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Change From Baseline Concentration (Cmax) of Glucagon |  | Pre-dose; 5, 10, 15, 20, 30, 40, 60 and 90 minutes following glucagon administration | 
| Time to Maximum Concentration (Tmax) of Baseline Adjusted Glucagon |  | Pre-dose; 5, 10, 15, 20, 30, 40, 60 and 90 minutes following glucagon administration | 
| 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 | 
| Maximum Concentration (Cmax) of Baseline-Adjusted Glucose |  | Pre-dose; 5, 10, 15, 20, 30, 40, 60 and 90 minutes following glucagon administration | 
| Time to Maximum Concentration (Tmax) of Baseline-Adjusted Glucose |  | Pre-dose; 5, 10, 15, 20, 30, 40, 60 and 90 minutes following glucagon administration | 
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nasal and Non-nasal Effects/Symptoms | 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). | Pre-dose;15, 30, 60 and 90 minutes following glucagon administration | 
| 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 | 
| Time to Achieving ≥25 mg/dL Rise in Plasma Glucose Above Nadir Level Within 30 Minutes | 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. | Pre-dose; 5, 10, 15, 20, and 30 minutes following glucagon administration |