A Study of Nasal Glucagon in Participants With Type 1 Diabetes Mellitus

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03339453
• Collaborator: (none)
• Enrollment: 70
• Locations: 2
• Arms: 2
• Actual Duration (Months): 2.1
• Patients Per Site: 35
• Patients Per Site Per Month: 16.6

Study Details

Study Description

Brief Summary

The purpose of this study is to compare a needle-free treatment of hypoglycemia with nasal glucagon (study drug) to a marketed glucagon administered by the intramuscular (IM) route, in participants with type 1 diabetes mellitus (T1DM).

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Comparison of Glucagon Administered by Either the Nasal (LY900018) or Intra-muscular (GlucaGen®) Routes in Adult Patients With Type 1 Diabetes Mellitus During Controlled Insulin-Induced Hypoglycemia
• Actual Study Start Date: Nov 10, 2017
• Actual Primary Completion Date: Dec 17, 2017
• Actual Study Completion Date: Jan 13, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nasal Glucagon Single dose of Nasal Glucagon.	Drug: Nasal Glucagon; Administered nasally; Other Names: LY900018
Active Comparator: Intramuscular Glucagon Single intramuscular (IM) dose of Glucagon.	Drug: Intramuscular Glucagon; Administered IM; Other Names: GlucaGen®

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Achieving Treatment Success During Controlled Insulin-Induced Hypoglycemia [Pre-dose up to 30 minutes post each glucagon administration]

   Treatment success is defined as an increase in plasma glucose to greater than or equal to (≥) 70 milligrams per deciliter (mg/dL) or an increase of ≥20 mg/dL from plasma glucose nadir, without receiving additional actions to increase the plasma glucose concentration. Nadir is defined as the minimum plasma glucose concentration at the time of or within 10 minutes following glucagon administration.

Secondary Outcome Measures

1. Pharmacodynamics (PD): Change From Baseline in Maximal Blood Glucose (BGmax) [Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60, and 90 minutes after glucagon administration]

2. PD: Time to Maximum Concentration (Tmax) of Baseline-Adjusted Glucose [Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60, and 90 minutes after glucagon administration]

3. Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to Tlast (AUC[0-tlast]) of Baseline Adjusted Glucagon [Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60, 90, 120, and 240 minutes after glucagon administration]

4. PK: Maximum Change From Baseline Concentration (Cmax) of Glucagon [Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60, 90, 120, and 240 minutes after glucagon administration]

5. PK: Time to Maximum Concentration (Tmax) of Baseline Adjusted Glucagon [Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60, 90, 120, and 240 minutes after glucagon administration]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Diagnosis of Type 1 Diabetes Mellitus (T1DM) for at least 2 years and receiving daily insulin since the time of diagnosis

Exclusion Criteria:

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

• Have a history of pheochromocytoma (that is, adrenal gland tumor) or insulinoma

• Occurrence of an episode of severe hypoglycemia (defined as requiring the assistance of another person in the 1 month prior to enrolling in the study)

• Have a history of epilepsy or seizure disorder

• Are women who are pregnant or lactating

• Have, except for the current regimen of insulin therapy and concomitant medication, regular use of or intended use of any over-the-counter or prescription medications or nutritional supplements that treat hyperglycemia or insulin resistance or that promote weight loss within 14 days before dosing

• Daily use of systemic beta-blocker, indomethacin, warfarin or anticholinergic drugs

• Require daily insulin treatment greater than (>)1.5 unit/kilograms (U/kg)/body weight

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri, 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician.	Mainz		Germany	55116
2	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri, 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician.	Neuss		Germany

Sponsors and Collaborators

• Eli Lilly and Company

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)

• Study Protocol - Oct 12, 2017
• Statistical Analysis Plan - Sep 22, 2017

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT03339453
• Other Study ID Numbers: 16547; I8R-MC-IGBI; 2017-000249-33
• First Posted: Nov 13, 2017
• Last Update Posted: Sep 23, 2019
• Last Verified: Jan 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia; Glucagon; Glucagon-Like Peptide 1

Study Results

Participant Flow

Pre-assignment Detail	In each period, either 3 milligram (mg) nasal glucagon (NG) or 1 mg intramuscular (IM) Glucagon was administered. After a wash-out period of at least 1 day (24 hours) from the first period (first visit), participants crossed over to the alternate glucagon treatment in period 2 (second visit).

Arm/Group Title	NG 1st/IM Glucagon 2nd	IM Glucagon 1st/NG 2nd
Arm/Group Description	Participants received 3 mg of NG at the first treatment visit followed by 1 mg of IM glucagon at the second treatment visit.	Participants received 1 mg of IM glucagon at the first treatment visit followed by 3 mg of NG at the second treatment visit.
Period Title: First Visit of Glucagon Treatment
STARTED	35	35
Received at Least 1 Dose of Study Drug	35	35
COMPLETED	35	34
NOT COMPLETED	0	1
Period Title: First Visit of Glucagon Treatment
STARTED	35	34
COMPLETED	35	34
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Glucagon
Arm/Group Description	All enrolled participants who received either 3 mg NG or 1 mg IM Glucagon.
Overall Participants	70
Age (years) [Median (Standard Deviation) ]
Median (Standard Deviation) [years]	41.7 (12.7)
Sex: Female, Male (Count of Participants)
Female	27 38.6%
Male	43 61.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	70 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	70 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
Germany	70 100%
Weight (Kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kilogram (kg)]	78.79 (13.28)
Height (Centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Centimeter (cm)]	175.21 (8.43)
Body Mass Index (BMI) (kilogram per square meter (kg/m2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m2)]	25.53 (2.97)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Achieving Treatment Success During Controlled Insulin-Induced Hypoglycemia
Description	Treatment success is defined as an increase in plasma glucose to greater than or equal to (≥) 70 milligrams per deciliter (mg/dL) or an increase of ≥20 mg/dL from plasma glucose nadir, without receiving additional actions to increase the plasma glucose concentration. Nadir is defined as the minimum plasma glucose concentration at the time of or within 10 minutes following glucagon administration.
Time Frame	Pre-dose up to 30 minutes post each glucagon administration

Outcome Measure Data

Analysis Population Description

All participants who completed both treatment visits with evaluable data.

Arm/Group Title	Nasal Glucagon (NG)	IM Glucagon
Arm/Group Description	Dose of 3 mg nasal glucagon.	Dose of 1 mg IM glucagon.
Measure Participants	66	66
Count of Participants [Participants]	66 94.3%	66 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nasal Glucagon (NG), IM Glucagon
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	95% Confidence Interval of the treatment differences in treatment success rate.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -1.52 to 1.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Pharmacodynamics (PD): Change From Baseline in Maximal Blood Glucose (BGmax)
Time Frame	Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60, and 90 minutes after glucagon administration

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of the study drug with evaluable PD data.

Arm/Group Title	Nasal Glucagon (NG)	IM Glucagon
Arm/Group Description	Dose of 3 mg nasal glucagon.	Dose of 1 mg IM glucagon.
Measure Participants	68	69
Geometric Mean (Geometric Coefficient of Variation) [Milligrams per deciliter (mg/dL)]	132 (36)	161 (29)

3. Secondary Outcome

Title	PD: Time to Maximum Concentration (Tmax) of Baseline-Adjusted Glucose
Time Frame	Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60, and 90 minutes after glucagon administration

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of the study drug with evaluable PD data.

Arm/Group Title	Nasal Glucagon (NG)	IM Glucagon
Arm/Group Description	Dose of 3 mg nasal glucagon.	Dose of 1 mg IM glucagon.
Measure Participants	68	69
Median (Full Range) [Hour (hr)]	1.00	1.50

4. Secondary Outcome

Title	Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to Tlast (AUC[0-tlast]) of Baseline Adjusted Glucagon
Time Frame	Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60, 90, 120, and 240 minutes after glucagon administration

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of the study drug with evaluable PK data.

Arm/Group Title	Nasal Glucagon (NG)	IM Glucagon
Arm/Group Description	Dose of 3 mg nasal glucagon.	Dose of 1 mg IM glucagon.
Measure Participants	63	66
Geometric Mean (Geometric Coefficient of Variation) [picogram*hour per millilitre (pg*hr/mL)]	2740 (68)	3320 (40)

5. Secondary Outcome

Title	PK: Maximum Change From Baseline Concentration (Cmax) of Glucagon
Time Frame	Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60, 90, 120, and 240 minutes after glucagon administration

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of the study drug with evaluable PK data.

Arm/Group Title	Nasal Glucagon (NG)	IM Glucagon
Arm/Group Description	Dose of 3 mg nasal glucagon.	Dose of 1 mg IM glucagon.
Measure Participants	63	66
Geometric Mean (Geometric Coefficient of Variation) [picograms per millilitre (pg/mL)]	6130 (74)	3750 (44)

6. Secondary Outcome

Title	PK: Time to Maximum Concentration (Tmax) of Baseline Adjusted Glucagon
Time Frame	Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60, 90, 120, and 240 minutes after glucagon administration

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of the study drug with evaluable PK data.

Arm/Group Title	Nasal Glucagon (NG)	IM Glucagon
Arm/Group Description	Dose of 3 mg nasal glucagon.	Dose of 1 mg IM glucagon.
Measure Participants	63	66
Median (Full Range) [Hour (hr)]	0.25	0.25

Adverse Events

Time Frame	First dose of study drug (Day 1) until post-study completion (Day 30).
Arm/Group Title	Nasal Glucagon (NG)		Intramuscular (IM) Glucagon
Arm/Group Description	Dose of 3 mg nasal glucagon.		Dose of 1 mg intramuscular glucagon.
All Cause Mortality
	Nasal Glucagon (NG)		Intramuscular (IM) Glucagon
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/70 (0%)		0/69 (0%)
Serious Adverse Events
	Nasal Glucagon (NG)		Intramuscular (IM) Glucagon
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/70 (0%)		0/69 (0%)
Other (Not Including Serious) Adverse Events
	Nasal Glucagon (NG)		Intramuscular (IM) Glucagon
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/70 (48.6%)		35/69 (50.7%)
Eye disorders
Eye pain	1/70 (1.4%)	1	0/69 (0%)	0
Ocular discomfort	1/70 (1.4%)	1	0/69 (0%)	0
Gastrointestinal disorders
Abdominal discomfort	1/70 (1.4%)	1	0/69 (0%)	0
Abdominal pain upper	0/70 (0%)	0	1/69 (1.4%)	1
Diarrhoea	0/70 (0%)	0	1/69 (1.4%)	1
Nausea	22/70 (31.4%)	22	29/69 (42%)	29
Vomiting	10/70 (14.3%)	10	12/69 (17.4%)	12
Infections and infestations
Nasopharyngitis	4/70 (5.7%)	4	2/69 (2.9%)	2
Otitis media	0/70 (0%)	0	1/69 (1.4%)	1
Investigations
Body temperature increased	0/70 (0%)	0	1/69 (1.4%)	1
Nervous system disorders
Headache	11/70 (15.7%)	13	7/69 (10.1%)	7
Respiratory, thoracic and mediastinal disorders
Cough	1/70 (1.4%)	1	0/69 (0%)	0
Epistaxis	1/70 (1.4%)	1	0/69 (0%)	0
Nasal discomfort	0/70 (0%)	0	1/69 (1.4%)	1
Oropharyngeal pain	2/70 (2.9%)	2	0/69 (0%)	0
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/70 (1.4%)	1	0/69 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.