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

• ClinicalTrials.gov Identifier: NCT01994746
• Recruitment Status: Completed
• First Posted: November 26, 2013
• Results First Posted: October 10, 2016
• Last Update Posted: September 23, 2019
• Sponsor: Eli Lilly and Company
• Collaborators: T1D Exchange Clinic Network Coordinating Center; Locemia Solutions ULC
• Information provided by (Responsible Party): Eli Lilly and Company

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 1	Drug: Nasal Glucagon; Drug: Intramuscular Glucagon	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 77 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Nasal Glucagon for Treatment of Insulin Induced Hypoglycemia in Adults With Diabetes
• Study Start Date: November 2013
• Actual Primary Completion Date: January 2015
• Actual Study Completion Date: January 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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.	Drug: Nasal Glucagon; Other Names: AMG504-1; LY900018
Active Comparator: Intramuscular Glucagon; At a separate visit, 1 mg of glucagon was administered into the deltoid muscle of the non-dominant arm (intramuscular [IM]).	Drug: Intramuscular Glucagon; Other Name: GlucaGen HypoKit

Outcome Measures

Primary Outcome Measures :

1. Increase in Plasma Glucose Level to >=70mg/dL or an Increase of >=20mg/dL From Glucose Nadir [ Time Frame: 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 :

1. Nasal and Non-nasal Effects/Symptoms [ Time Frame: 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).
2. Recovery From Symptoms of Hypoglycemia [ Time Frame: 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.
3. Time From Glucagon Administration to Blood Glucose >/=70 mg/dL or an Increase ≥20 mg/dL in Blood Glucose From Nadir [ Time Frame: 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.
4. Area Under the Curve From Time Zero to the Last Quantifiable Concentration (AUC0-t) of Baseline-Adjusted Glucagon [ Time Frame: Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration ]
5. Maximum Change From Baseline Concentration (Cmax) of Glucagon [ Time Frame: Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration ]
6. Time to Maximum Change From Baseline Concentration (Tmax) of Glucagon [ Time Frame: Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration ]
7. 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, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration ]
8. Maximum Change From Baseline Concentration (Cmax) of Glucose [ Time Frame: Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration ]
9. Time to Maximum Change From Baseline Concentration (Tmax) of Glucose [ Time Frame: Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 64 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

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

Contacts and Locations

Locations

United States, Colorado

Barbara Davis Center for Diabetes

Aurora, Colorado, United States, 80045

United States, Connecticut

Yale University

New Haven, Connecticut, United States, 06520

United States, Florida

University of Florida

Gainesville, Florida, United States, 32605

United States, Indiana

Riley Hospital for Children Indiana University Health

Indianapolis, Indiana, United States, 46202

United States, Minnesota

University of Minnesota

Minneapolis, Minnesota, United States, 55454

United States, New York

UPA Buffalo

Buffalo, New York, United States, 14222

United States, Oregon

Oregon Health and Science University

Portland, Oregon, United States, 97239

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

Sponsors and Collaborators

Eli Lilly and Company

T1D Exchange Clinic Network Coordinating Center

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

More Information

Publications:

Rickels MR, Ruedy KJ, Foster NC, Piché CA, Dulude H, Sherr JL, Tamborlane WV, Bethin KE, DiMeglio LA, Wadwa RP, Ahmann AJ, Haller MJ, Nathan BM, Marcovina SM, Rampakakis E, Meng L, Beck RW; T1D Exchange Intranasal Glucagon Investigators. Intranasal Glucagon for Treatment of Insulin-Induced Hypoglycemia in Adults With Type 1 Diabetes: A Randomized Crossover Noninferiority Study. Diabetes Care. 2016 Feb;39(2):264-70. doi: 10.2337/dc15-1498. Epub 2015 Dec 17.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01994746
• Other Study ID Numbers: 16422; INGluc001 ( Other Identifier: Jaeb Center for Health Research ); I8R-MC-IGBC ( Other Identifier: Eli Lilly and Company ); AMG106 ( Other Identifier: Locemia )
• First Posted: November 26, 2013
• Results First Posted: October 10, 2016
• Last Update Posted: September 23, 2019
• Last Verified: September 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)
• Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
• Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• URL: https://vivli.org/

Additional relevant MeSH terms:

Hypoglycemia; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Diabetes Mellitus; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Glucagon; Glucagon-Like Peptide 1; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Incretins