A Study of Glucagon Administered in Different Forms and Routes to Healthy Adults

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02778113
• Collaborator: Locemia Solutions ULC (Industry)
• Enrollment: 16
• Location: 1
• Arms: 4
• Duration (Months): 1
• Patients Per Site Per Month: 15.7

Study Details

Study Description

Brief Summary

The main purpose of this study was to evaluate the safety and tolerability of nasal glucagon (NG). The study drug was delivered into the participant's nostril (intranasally) or was given as an injection just under the skin (subcutaneously) once in each of four study periods. The study lasted about 23 days for each participant.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Nasal Glucagon; Drug: Glucagon	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: A Single Site, Randomized, Four-Way, Four-Period PK/PD Crossover Phase 1 Clinical Study in 16 Fasted Healthy Adult Volunteers Receiving 3 Dose Levels of Intranasally Administered Glucagon and One Dose Level of Glucagon Administered by Subcutaneous Injection
• Study Start Date: Oct 1, 2011
• Actual Primary Completion Date: Oct 1, 2011
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nasal Glucagon (NG) - 0.5 mg Ng dose at 0.5 milligram (mg) administered once in one of four study periods.	Drug: Nasal Glucagon; Administered intranasally.; Other Names: AMG 504-1 LY900018
Experimental: NG - 1.0 mg Ng dose at 1.0 milligram (mg) administered once in one of four study periods.	Drug: Nasal Glucagon; Administered intranasally.; Other Names: AMG 504-1 LY900018
Experimental: NG - 2.0 mg Ng dose at 2.0 milligram (mg) administered once in one of four study periods.	Drug: Nasal Glucagon; Administered intranasally.; Other Names: AMG 504-1 LY900018
Active Comparator: SC Glucagon 1 mg Subcutaneous (SC) glucagon dose of 1 mg, in one of four study periods.	Drug: Glucagon; Administered SC.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With One or More Serious Adverse Event(s) (SAEs) [Baseline through Study Completion (Day 23)]

   Safety and tolerability evaluated through the assessment of adverse events. A SAE (serious adverse event) was defined as any untoward medical occurrence in a clinical investigation, which did not necessarily have a causal relationship with this treatment. A summary of other non-serious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section.

Secondary Outcome Measures

1. Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to T (AUC[0-tlast]) of Baseline Adjusted Glucagon [Day 1: -0.5, -0.25, 0, 0.08, 0.17, 0.25, 0.33, 0.5, 0.67, 1.0, 1.5, 2, 2.5, 3 and 4 hours post dose for each treatment]

2. PK: Area Under the Curve Extrapolated to Infinity (AUC[0-inf]) of Baseline Adjusted Glucagon [Day 1: -0.5, -0.25, 0, 0.08, 0.17, 0.25, 0.33, 0.5, 0.67, 1.0, 1.5, 2, 2.5, 3 and 4 hours post dose for each treatment]

3. PK: Time to Maximum Concentration (Tmax) of Baseline Adjusted Glucagon [Day 1: -0.5, -0.25, 0, 0.08, 0.17, 0.25, 0.33, 0.5, 0.67, 1.0, 1.5, 2, 2.5, 3 and 4 hours post dose for each treatment]

4. PK: Maximum Change From Baseline Concentration (Cmax) of Glucagon [Day 1: -0.5, -0.25, 0, 0.08, 0.17, 0.25, 0.33, 0.5, 0.67, 1.0, 1.5, 2, 2.5, 3 and 4 hours post dose for each treatment]

5. Pharmacodynamics (PD): Area Under the Effect Concentration Time Curve (AUEC₀-₄) of Glucose [Day 1: -0.5, -0.25, 0, 0.08, 0.17, 0.25, 0.33, 0.5, 0.67, 1.0, 1.5, 2, 2.5, 3 and 4 hours post dose for each treatment]

6. PD: Time to Maximum Concentration (Tmax) of Baseline-Adjusted Glucose [Day 1: -0.5, -0.25, 0, 0.08, 0.17, 0.25, 0.33, 0.5, 0.67, 1.0, 1.5, 2, 2.5, 3 and 4 hours post dose for each treatment]

7. PD: Baseline-Adjusted Glucose Maximum Concentration (BGmax) [Day 1: -0.5, -0.25, 0, 0.08, 0.17, 0.25, 0.33, 0.5, 0.67, 1.0, 1.5, 2, 2.5, 3 and 4 hours post dose for each treatment]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Body mass index (BMI) greater than or equal to 20.00 and below or equal to 28.00 kg/m².

• Light-, non- or ex-smokers.

• Have no clinically significant diseases captured in the medical history or evidence of clinically significant findings on physical examination and/or clinical laboratory evaluations (hematology, biochemistry, ECG and urinalysis).

Exclusion Criteria:

• Presence of any nose piercings.

• History of significant hypersensitivity to glucagon or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs.

• Presence of significant gastrointestinal, liver or kidney disease, or any other conditions known to interfere with the absorption, distribution, metabolism or excretion of drugs or known to potentiate or predispose to undesired effects.

• Presence of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic or dermatologic disease.

• Presence of clinically significant findings on nasal examination and bilateral anterior rhinoscopy.

• Fasting blood glucose above 5.0 millimoles per liter (mmol/L) at screening, following a 12-hour fasting period.

• Fasting blood glucose assessed with a glucose meter above 5.5 mmol/L 0.5 hour before each dosing.

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 from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Mount-Royal	Quebec	Canada	H3P 3P1

Sponsors and Collaborators

• Eli Lilly and Company
• 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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT02778113
• Other Study ID Numbers: 16424; I8R-MC-IGBD; AMG 101; GUO-P1-557
• First Posted: May 19, 2016
• Last Update Posted: Sep 19, 2019
• Last Verified: May 1, 2016

• Additional relevant MeSH terms: Glucagon; Glucagon-Like Peptide 1

Study Results

Participant Flow

Recruitment Details	This was a four-period crossover study in which participants received a single dose of study drug in each period, with seven days between each dose.

Arm/Group Title	Sequence 1 (T1/T2/T3/T4)	Sequence 2 (T2/T3/T4/T1)	Sequence 3 (T3/T4/T1/T2)	Sequence 4 (T4/T1/T2/T3)
Arm/Group Description	Treatment (T1) = nasal glucagon (NG) dose of 0.5 milligram (mg), T2 = NG dose of 1 mg, T3 = NG dose of 2 mg, T4 = subcutaneous (SC) glucagon dose of 1 mg. In each of four study periods, a single dose of NG was administered or SC glucagon was administered.	T2 = NG dose of 1 mg, T3 = NG dose of 2 mg, T4 = SC glucagon dose of 1 mg, T1 = NG dose of 0.5 mg. In each of four study periods, a single dose of NG was administered or SC glucagon was administered.	T3 = NG dose of 2 mg, T4 = SC glucagon dose of 1 mg, T1 = NG dose of 0.5 mg, T2 = NG dose of 1 mg. In each of four study periods, a single dose of NG was administered or SC glucagon was administered.	T4 = SC glucagon dose of 1 mg, T1 = NG dose of 0.5 mg, T2 = NG dose of 1 mg, T3 = NG dose of 2 mg. In each of four study periods, a single dose of NG was administered or SC glucagon was administered.
Period Title: Study Period One
STARTED	4	4	4	4
Received Study Drug	4	4	4	4
COMPLETED	4	4	4	4
NOT COMPLETED	0	0	0	0
Period Title: Study Period One
STARTED	4	4	4	4
Received Study Drug	4	4	4	4
COMPLETED	4	4	4	4
NOT COMPLETED	0	0	0	0
Period Title: Study Period One
STARTED	4	4	3	4
Received Study Drug	4	4	3	4
COMPLETED	4	4	3	4
NOT COMPLETED	0	0	0	0
Period Title: Study Period One
STARTED	3	4	2	4
Received Study Drug	3	4	2	4
COMPLETED	3	4	2	4
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	In each of four study periods, a single dose of either NG or SC glucagon was administered.
Overall Participants	16
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33 (9)
Sex: Female, Male (Count of Participants)
Female	6 37.5%
Male	10 62.5%
Race/Ethnicity, Customized (Count of Participants)
White	14 87.5%
Black	1 6.3%
Other	1 6.3%
Region of Enrollment (Count of Participants)
Canada	16 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With One or More Serious Adverse Event(s) (SAEs)
Description	Safety and tolerability evaluated through the assessment of adverse events. A SAE (serious adverse event) was defined as any untoward medical occurrence in a clinical investigation, which did not necessarily have a causal relationship with this treatment. A summary of other non-serious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section.
Time Frame	Baseline through Study Completion (Day 23)

Outcome Measure Data

Analysis Population Description

All randomized participants who entered study period four.

Arm/Group Title	NG 0.5 mg	NG 1 mg	NG 2 mg	SC Glucagon 1 mg
Arm/Group Description	Nasal glucagon (NG) dose of 0.5 milligram (mg).	NG dose of 1 mg.	NG dose of 2 mg.	Subcutaneous (SC) glucagon dose of 1 mg.
Measure Participants	15	14	16	15
Count of Participants [Participants]	0 0%	0 NaN	0 NaN	0 NaN

2. Secondary Outcome

Title	Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to T (AUC[0-tlast]) of Baseline Adjusted Glucagon
Time Frame	Day 1: -0.5, -0.25, 0, 0.08, 0.17, 0.25, 0.33, 0.5, 0.67, 1.0, 1.5, 2, 2.5, 3 and 4 hours post dose for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants with evaluable PK data. In the NG 0.5 mg arm, all participants had serum glucagon levels that were below the lower limit of quantification (100 picogram per milliliter [pg/mL]) except for one participant at one time point.

Arm/Group Title	NG 0.5 mg	NG 1 mg	NG 2 mg	SC Glucagon 1 mg
Arm/Group Description	NG dose of 0.5 mg.	NG dose of 1 mg.	NG dose of 2 mg.	SC glucagon dose of 1 mg.
Measure Participants	1	7	15	15
Geometric Mean (Geometric Coefficient of Variation) [picogram*hour per milliliter (pg*h/mL)]	NA (NA)	38.9 (483)	293 (172)	2060 (68)

3. Secondary Outcome

Title	PK: Area Under the Curve Extrapolated to Infinity (AUC[0-inf]) of Baseline Adjusted Glucagon
Time Frame	Day 1: -0.5, -0.25, 0, 0.08, 0.17, 0.25, 0.33, 0.5, 0.67, 1.0, 1.5, 2, 2.5, 3 and 4 hours post dose for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants with evaluable PK data. AUC(0-inf) could not be calculated for the NG 0.5 mg arm, because all participants had serum glucagon levels below the lower limit of quantification (100 pg/mL) except for one participant at one time point.

Arm/Group Title	NG 0.5 mg	NG 1 mg	NG 2 mg	SC Glucagon 1 mg
Arm/Group Description	NG dose of 0.5 mg.	NG dose of 1 mg.	NG dose of 2 mg.	SC glucagon dose of 1 mg.
Measure Participants	0	1	5	14
Geometric Mean (Geometric Coefficient of Variation) [pg*h/mL]	NA (NA)	589 (50)	2250 (66)

4. Secondary Outcome

Title	PK: Time to Maximum Concentration (Tmax) of Baseline Adjusted Glucagon
Time Frame	Day 1: -0.5, -0.25, 0, 0.08, 0.17, 0.25, 0.33, 0.5, 0.67, 1.0, 1.5, 2, 2.5, 3 and 4 hours post dose for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants with evaluable PK data. In the NG 0.5 mg arm, all participants had serum glucagon levels that were below the lower limit of quantification (100 pg/mL) except for one participant at one time point.

Arm/Group Title	NG 0.5 mg	NG 1 mg	NG 2 mg	SC Glucagon 1 mg
Arm/Group Description	NG dose of 0.5 mg.	NG dose of 1 mg.	NG dose of 2 mg.	SC glucagon dose of 1 mg.
Measure Participants	1	7	15	15
Median (Full Range) [hour (h)]	0.17	0.25	0.25	0.33

5. Secondary Outcome

Title	PK: Maximum Change From Baseline Concentration (Cmax) of Glucagon
Time Frame	Day 1: -0.5, -0.25, 0, 0.08, 0.17, 0.25, 0.33, 0.5, 0.67, 1.0, 1.5, 2, 2.5, 3 and 4 hours post dose for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants with evaluable PK data. In the NG 0.5 mg arm, all participants had serum glucagon levels that were below the lower limit of quantification (100 pg/mL) except for one participant at one time point.

Arm/Group Title	NG 0.5 mg	NG 1 mg	NG 2 mg	SC Glucagon 1 mg
Arm/Group Description	NG dose of 0.5 mg.	NG dose of 1 mg.	NG dose of 2 mg.	SC glucagon dose of 1 mg.
Measure Participants	1	7	15	15
Geometric Mean (Geometric Coefficient of Variation) [picogram per milliliter (pg/mL)]	NA (NA)	217 (231)	1000 (104)	3260 (59)

6. Secondary Outcome

Title	Pharmacodynamics (PD): Area Under the Effect Concentration Time Curve (AUEC₀-₄) of Glucose
Time Frame	Day 1: -0.5, -0.25, 0, 0.08, 0.17, 0.25, 0.33, 0.5, 0.67, 1.0, 1.5, 2, 2.5, 3 and 4 hours post dose for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants with evaluable PD data.

Arm/Group Title	NG 0.5 mg	NG 1 mg	NG 2 mg	SC Glucagon 1 mg
Arm/Group Description	NG dose of 0.5 mg.	NG dose of 1 mg.	NG dose of 2 mg.	SC glucagon dose of 1 mg.
Measure Participants	15	14	16	15
Mean (Standard Error) [millimole*hour per liter (mmol*h/L)]	-0.168 (0.202)	0.0617 (0.177)	0.566 (0.324)	0.448 (0.490)

7. Secondary Outcome

Title	PD: Time to Maximum Concentration (Tmax) of Baseline-Adjusted Glucose
Time Frame	Day 1: -0.5, -0.25, 0, 0.08, 0.17, 0.25, 0.33, 0.5, 0.67, 1.0, 1.5, 2, 2.5, 3 and 4 hours post dose for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants with evaluable PD data.

Arm/Group Title	NG 0.5 mg	NG 1 mg	NG 2 mg	SC Glucagon 1 mg
Arm/Group Description	NG dose of 0.5 mg.	NG dose of 1 mg.	NG dose of 2 mg.	SC glucagon dose of 1 mg.
Measure Participants	15	14	16	15
Median (Full Range) [hour (h)]	0.33	0.36	0.50	0.37

8. Secondary Outcome

Title	PD: Baseline-Adjusted Glucose Maximum Concentration (BGmax)
Time Frame	Day 1: -0.5, -0.25, 0, 0.08, 0.17, 0.25, 0.33, 0.5, 0.67, 1.0, 1.5, 2, 2.5, 3 and 4 hours post dose for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants with evaluable PD data.

Arm/Group Title	NG 0.5 mg	NG 1 mg	NG 2 mg	SC Glucagon 1 mg
Arm/Group Description	NG dose of 0.5 mg.	NG dose of 1 mg.	NG dose of 2 mg.	SC glucagon dose of 1 mg.
Measure Participants	15	14	16	15
Mean (Standard Error) [millimole per liter (mmol/L)]	0.811 (0.119)	1.92 (0.173)	3.20 (0.252)	3.28 (0.326)

Adverse Events

Time Frame	First dose of study drug (Day 1) until post-study completion (Day 23)
Adverse Event Reporting Description	All randomized participants who entered study period four.
Arm/Group Title	NG 0.5 mg		NG 1 mg		NG 2 mg		SC Glucagon 1 mg
Arm/Group Description	NG dose of 0.5 mg.		NG dose of 1 mg.		NG dose of 2 mg.		SC glucagon dose of 1 mg.
All Cause Mortality
	NG 0.5 mg		NG 1 mg		NG 2 mg		SC Glucagon 1 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	NG 0.5 mg		NG 1 mg		NG 2 mg		SC Glucagon 1 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/14 (0%)		0/16 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	NG 0.5 mg		NG 1 mg		NG 2 mg		SC Glucagon 1 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/15 (13.3%)		6/14 (42.9%)		8/16 (50%)		6/15 (40%)
Eye disorders
Eye irritation	0/15 (0%)	0	0/14 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Eye pruritus	0/15 (0%)	0	2/14 (14.3%)	2	2/16 (12.5%)	3	1/15 (6.7%)	1
Eyelid oedema	0/15 (0%)	0	0/14 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Lacrimation increased	0/15 (0%)	0	1/14 (7.1%)	2	1/16 (6.3%)	1	0/15 (0%)	0
Ocular hyperaemia	0/15 (0%)	0	0/14 (0%)	0	3/16 (18.8%)	3	0/15 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/15 (0%)	0	0/14 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Nausea	0/15 (0%)	0	0/14 (0%)	0	0/16 (0%)	0	6/15 (40%)	6
Vomiting	0/15 (0%)	0	0/14 (0%)	0	0/16 (0%)	0	3/15 (20%)	3
General disorders
Asthenia	0/15 (0%)	0	0/14 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Fatigue	1/15 (6.7%)	1	1/14 (7.1%)	1	0/16 (0%)	0	1/15 (6.7%)	1
Feeling cold	0/15 (0%)	0	0/14 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Injection site pain	0/15 (0%)	0	0/14 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Injection site pruritus	0/15 (0%)	0	0/14 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Injection site reaction	0/15 (0%)	0	0/14 (0%)	0	0/16 (0%)	0	3/15 (20%)	3
Injection site swelling	0/15 (0%)	0	0/14 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Injury, poisoning and procedural complications
Injury	0/15 (0%)	0	0/14 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Vessel puncture site haematoma	1/15 (6.7%)	1	0/14 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Vessel puncture site reaction	0/15 (0%)	0	0/14 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Nervous system disorders
Dizziness	0/15 (0%)	0	0/14 (0%)	0	0/16 (0%)	0	2/15 (13.3%)	2
Headache	0/15 (0%)	0	2/14 (14.3%)	2	1/16 (6.3%)	1	1/15 (6.7%)	1
Somnolence	2/15 (13.3%)	2	2/14 (14.3%)	2	2/16 (12.5%)	2	2/15 (13.3%)	2
Psychiatric disorders
Restlessness	0/15 (0%)	0	0/14 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/15 (0%)	0	1/14 (7.1%)	1	0/16 (0%)	0	0/15 (0%)	0
Epistaxis	0/15 (0%)	0	0/14 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Nasal congestion	1/15 (6.7%)	1	3/14 (21.4%)	3	4/16 (25%)	4	0/15 (0%)	0
Nasal discomfort	1/15 (6.7%)	1	3/14 (21.4%)	4	3/16 (18.8%)	3	0/15 (0%)	0
Oropharyngeal pain	0/15 (0%)	0	1/14 (7.1%)	1	0/16 (0%)	0	0/15 (0%)	0
Rhinorrhoea	0/15 (0%)	0	4/14 (28.6%)	4	4/16 (25%)	4	0/15 (0%)	0
Sneezing	0/15 (0%)	0	1/14 (7.1%)	1	0/16 (0%)	0	1/15 (6.7%)	1
Throat irritation	0/15 (0%)	0	1/14 (7.1%)	1	0/16 (0%)	0	0/15 (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.