Efficacy and Safety of Nasal Glucagon for Treatment of Hypoglycemia in Adults

Phase 3

Completed

• Conditions: Diabetes Mellitus, Type 1
• Interventions: Drug: Intramuscular Glucagon; Drug: Nasal Glucagon

• Registration Number: NCT01994746
• Lead Sponsor: Eli Lilly and Company

Brief Summary

The purpose of this study is to assess the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), and safety of 3 milligrams (mg) glucagon (glucagon nasal powder) administered nasally compared with commercially available glucagon given by intramuscular injection.

Detailed Description

Each glucagon dosing visit was conducted after an overnight fast of at least 8 h with a starting plasma glucose \>= 90 mg/dL. Hypoglycemia was induced by an intravenous (IV) infusion of regular insulin diluted in normal saline during the clinic visit. Five minutes after stopping the insulin infusion (once the plasma glucose was \<60 mg/dL), participants were treated with either a 3 mg glucagon dose nasally or 1 mg of glucagon administered by intramuscular (IM) injection.

After a wash-out period of 7 days or more, participants returned to the clinic and the procedure repeated with each participant crossed over to the other treatment. As such, each participant underwent two episodes of insulin-induced hypoglycemia in random order and received glucagon nasal powder during one episode and commercially available glucagon (GlucaGen, Novo Nordisk) by IM injection during the other episode.

Study Timeline

• Study Start: 2013-11
• Study First Submitted: 2013-11-20
• Study First Submitted QC: 2013-11-20
• Study First Posted: 2013-11-26
• Primary Completion: 2015-01
• Study Completion: 2015-01
• Results First Submitted: 2016-05-26
• Results First Submitted QC: 2016-10-07
• Results First Posted: 2016-10-10
• Status Verified: 2019-09
• Last Update Submitted: 2019-09-05
• Last Update Posted: 2019-09-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 77

Inclusion Criteria

To be eligible, the following inclusion criteria must be met:

• Clinical diagnosis of either type 1 diabetes receiving daily insulin since the time of diagnosis for at least 2 years or type 2 diabetes receiving multiple daily insulin doses for at least 2 years

• At least 18.0 years of age and less than 65.0 years

• Body mass index (BMI) greater than or equal to 20.0 and below or equal to 35.0 kilograms per meter squared (kg/m²)

• Weighs at least 50 kg (110 pounds)

• Females must meet one of the following criteria:

  • Of childbearing potential but agree to use an accepted contraceptive regimen as described in the study procedure manual throughout the entire duration of the study (from the screening until study completion)
  • Of non-childbearing potential, defined as a female who has had a hysterectomy or tubal ligation, is clinically considered infertile or is in a menopausal state (at least 1 year without menses)

• In good general health with no conditions that could influence the outcome of the trial, and in the judgment of the Investigator is 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

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Exclusion Criteria

An individual is not eligible if any of the following exclusion criteria are present:

• Females who are pregnant according to a positive urine pregnancy test, actively attempting to get pregnant, or are 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 interfere 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
• Regularly consumes 3 or more alcoholic beverages per day
• Use of an Investigational Product in another clinical trial within the past 30 days
• Donated 225 milliliters (mL) or more of blood in the previous 8 weeks before the first glucagon dosing

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Intramuscular Glucagon	Intramuscular Glucagon	At a separate visit, 1 mg of glucagon was administered into the deltoid muscle of the non-dominant arm (intramuscular \[IM\]).
Nasal Glucagon	Nasal Glucagon	At one visit, a glucagon dose of 3 mg was administered in a nostril with a prefilled delivery device that delivers a single dose upon activation.

Primary Outcome Measures

Name	Time	Method
Increase in Plasma Glucose Level to >=70mg/dL or an Increase of >=20mg/dL From Glucose Nadir	Within 30 minutes after receiving glucagon at both dosing visits (glucose was measured at pre-dose; 5, 10, 15, 20, 25, and 30 minutes following glucagon administration)	Increase in blood glucose to ≥70 mg/dL or an increase of ≥20 mg/dL from glucose nadir within 30 minutes after receiving study glucagon, without receiving additional actions to increase the blood glucose level defines treatment success. Due to the residual activity of circulating insulin, glucose nadir was defined as the minimum glucose measurement at the time of, or within 10 minutes following glucagon administration.

Secondary Outcome Measures

Name	Time	Method
Nasal and Non-nasal Effects/Symptoms	Pre-dose; 15, 30, 60, and 90 post 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. 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 subject and reporting the median/IQR across participants).
Time to Maximum Change From Baseline Concentration (Tmax) of Glucagon	Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration
Maximum Change From Baseline Concentration (Cmax) of Glucagon	Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration
Recovery From Symptoms of Hypoglycemia	Pre-dose;15, 30, 45 and 60 minutes following administration of glucagon	Recovery from hypoglycemia symptoms were assessed using the Edinburgh Hypoglycemia Scale. The Edinburgh Hypoglycemia Symptom Scale measures the intensity of 15 commonly experienced hypoglycemic symptoms on a 7-point Likert scale (1 = not present, 7 = very intense). The higher the score, the more intense the hypoglycemia symptoms. The sum of each symptom score would yield a range of 15 to 105 (i.e., 15 x 7 =105). The total score was calculated as the sum of each symptom score minus 15, and summarized at each time point by treatment group.
Time From Glucagon Administration to Blood Glucose >/=70 mg/dL or an Increase ≥20 mg/dL in Blood Glucose From Nadir	Pre-dose; 5, 10, 15, 20, 25, and 30 minutes following glucagon administration	The mean time from glucagon administration to blood glucose \>/=70 mg/dL or an increase ≥20 mg/dL in blood glucose from nadir.
Area Under the Curve From Time Zero to the Last Quantifiable Concentration (AUC0-t) of Baseline-Adjusted Glucagon	Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 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, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration
Maximum Change From Baseline Concentration (Cmax) of Glucose	Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration
Time to Maximum Change From Baseline Concentration (Tmax) of Glucose	Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration

Trial Locations

Locations (8)

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

Barbara Davis Center for Diabetes; 🇺🇸 Aurora, Colorado, United States

University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

UPA Buffalo; 🇺🇸 Buffalo, New York, United States

University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States

University of Florida; 🇺🇸 Gainesville, Florida, United States

Yale University; 🇺🇸 New Haven, Connecticut, United States

Riley Hospital for Children Indiana University Health; 🇺🇸 Indianapolis, Indiana, United States