A Study of LY2605541 and Glargine and Exercise in Participants With Type 1 Diabetes

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01784211
• Collaborator: (none)
• Enrollment: 76
• Location: 1
• Arms: 6
• Duration (Months): 9
• Patients Per Site Per Month: 8.5

Study Details

Study Description

Brief Summary

The purpose of this study is to measure how much of the study drug or insulin glargine gets into the blood stream and how long it takes the body to get rid of it. The effect of exercise will also be evaluated.

This study has two parts. In Part A, each participant will receive a daily injection of LY2605541 or insulin glargine for about 15 days. Some participants may continue into Part B. In Part B, participants will receive a daily injection of LY2605541 or insulin glargine with or without exercise. Part B lasts about 6 days.

Participants will remain on their regular physician-prescribed mealtime insulin throughout the study.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 1	Drug: LY2605541; Drug: Insulin Glargine	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 76 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: The Pharmacokinetic and Pharmacodynamic Intra-subject Variability of LY2605541 and the Effect of Exercise on LY2605541 Pharmacokinetics in Patients With Type 1 Diabetes Mellitus
• Study Start Date: Feb 1, 2013
• Actual Primary Completion Date: Nov 1, 2013
• Actual Study Completion Date: Nov 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LY2605541 (Part A) 0.5 units per kilogram (U/kg) LY2605541 subcutaneously (SC) once daily for 15 days. Part A involved 3 clamp procedures on Days 8, 11, and 14. Participants remained on their regular physician-prescribed mealtime insulin.	Drug: LY2605541
Active Comparator: Glargine (Part A) 0.5 U/kg insulin glargine SC once daily for 15 days. Part A involved 3 clamp procedures on Days 8, 11, and 14. Participants remained on their regular physician-prescribed mealtime insulin.	Drug: Insulin Glargine
Experimental: First LY2605541 + Exercise,Then LY2605541 Alone (Part B) 0.5 U/kg LY2605541 SC once daily for an additional 6 days, beginning on Day 16. Exercise challenge on Day 17 (no exercise on Day 20).Participants remained on their regular physician-prescribed mealtime insulin.	Drug: LY2605541
Experimental: First LY2605541 Alone, Then LY2605541 + Exercise (Part B) 0.5 U/kg LY2605541 SC once daily for an additional 6 days, beginning on Day 16. Exercise challenge on Day 20 (no exercise on Day 17). Participants remained on their regular physician-prescribed mealtime insulin.	Drug: LY2605541
Active Comparator: First Glargine + Exercise, Then Glargine Alone (Part B) 0.5 U/kg insulin glargine SC once daily for an additional 6 days, beginning on Day 16. Exercise challenge on Day 17 (no exercise on Day 20). Participants remained on their regular physician-prescribed mealtime insulin.	Drug: Insulin Glargine
Active Comparator: First Glargine Alone, Then Glargine + Exercise (Part B) 0.5 U/kg insulin glargine SC once daily for an additional 6 days, beginning on Day 16. Exercise challenge on Day 20 (no exercise on Day 17).	Drug: Insulin Glargine

Outcome Measures

Primary Outcome Measures

1. Part A: Pharmacokinetics: Area Under the Concentration Versus Time Curve Over the Dosing Interval (AUCτ) of LY2605541 and Insulin Glargine: Intra-Participant Variability [Part A: Predose and 4, 8, 12, and 24 hours postdose on Days 8, 11, and 14]

   Venous blood samples for pharmacokinetic analysis were collected during the euglycemic glucose clamps during Part A. The intra-participant percentage of coefficient of variation (%CV) is presented. %CV was calculated by dividing the standard deviation by the mean, multiplied by 100.

2. Part A: Pharmacokinetics: Maximum Drug Concentration (Cmax) of LY2605541 and Insulin Glargine: Intra-Participant Variability [Part A: Predose and 4, 8, 12, and 24 hours postdose on Days 8, 11, and 14]

   Venous blood samples for pharmacokinetic analysis were collected during the euglycemic glucose clamps during Part A. The intra-participant percentage of coefficient of variation (%CV) is presented. %CV was calculated by dividing the standard deviation by the mean, multiplied by 100.

Secondary Outcome Measures

1. Part A: Pharmacodynamics: Total Amount of Glucose Infused Over the Duration of the Clamp (Gtot): Intra-Participant Variability [Part A: Predose up to 24 hours postdose on Days 8, 11, and 14]

   Glucodynamic measurements were collected during the euglycemic glucose clamps during Part A. The intra-participant percentage of coefficient of variation (%CV) is presented. %CV was calculated by dividing the standard deviation by the mean, multiplied by 100.

2. Part B: Pharmacokinetics: AUCτ of LY2605541 and Insulin Glargine: Exercise Versus Non-Exercise [Part B: Predose, 11 hours postdose, every 30 minutes from 16.5 to 20 hours postdose, and 24 hours postdose on Day 16 or 19]

   Venous blood samples for pharmacokinetic analysis were collected in Part B. Results were stratified by whether or not the participant was undergoing an exercise challenge (+ Exercise) at the time of sample collection.

3. Part B: Pharmacokinetics: Cmax of LY2605541 and Insulin Glargine: Exercise Versus Non-Exercise [Part B: Predose, 11 hours postdose, every 30 minutes from 16.5 to 20 hours postdose, and 24 hours postdose on Day 16 or 19]

   Venous blood samples for pharmacokinetic analysis were collected in Part B. Results were stratified by whether or not the participant was undergoing an exercise challenge (+ Exercise) at the time of sample collection.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Are males or females that have had a diagnosis of Type I Diabetes Mellitus (T1DM) for at least 12 months and are receiving multiple daily insulin injections. Total daily insulin dose <1.2 units per kilogram per day (U/kg/day); daily basal dose >0.2 U/kg/day

• Female participants: are women of child-bearing potential who test negative for pregnancy at the time of enrollment based on a urine pregnancy test and agree to use a reliable method of birth control during the study

• Have a body mass index (BMI) of 18 to 30 kilograms per meter squared (kg/m^2), inclusive

• Have a fasting c-peptide <0.3 nanomoles per liter (nmol/L)

• Have a hemoglobin A1c (HbA1c) <9% at screening

Participants with T1DM are eligible for enrollment in Part B of the study only if they meet all of the following criteria:

• Have a maximal oxygen uptake (VO2 max) of ≥25 milliliters (mL) of oxygen per kilogram per minute (O2/kg/min) (for women) or ≥30 mL O2/kg/min (for men)

• Perform regular physical cardiorespiratory activity to achieve an average total energy expenditure of ≥500 metabolic equivalent of task (MET)-minutes per week during the last 3 months prior to screening

Exclusion Criteria:

• Have known allergies to LY2605541, insulin glargine, related compounds or any components of the formulation

• Have a history of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine (apart from T1DM), hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; of constituting a risk when taking the study medication; or of interfering with the interpretation of data

• Have had episodes of severe hypoglycemia in the past 6 months (severe hypoglycemia is defined as having neurological symptoms consistent with neuroglycopenia and having required assistance in treatment by a second party)

• Have a history of hypoglycemia unawareness

• Regular use or intended use of any over-the-counter or prescription medications or nutritional supplements that may affect blood glucose, the body's sensitivity to insulin, or that promote weight loss within 14 days prior to dosing

• Have an average weekly alcohol intake that exceeds 21 units per week (males up to age

1. and 14 units per week (males over 65 and females), or are unwilling to comply with study requirements regarding alcohol consumption

• Currently smokes >5 cigarettes per day, or are unwilling to comply with study requirements regarding smoking or use of tobacco products

• Have a hemoglobin level <8.0 millimoles per liter (mmol/L) (male) or <6.4 mmol/L (female) at screening

• Are currently participating in a weight loss program or plan to do so during the course of the study

• Are receiving chronic (lasting longer than 14 consecutive days) systemic glucocorticoid therapy (excluding topical, intra-articular, and intra-ocular preparations) or have received such therapy within the 4 weeks before dosing

• Have fasting triglycerides >400 milligrams per deciliter (mg/dL) (4.52 mmol/L)

• Have previous history or family history of deep vein thrombosis

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.	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)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01784211
• Other Study ID Numbers: 14183; I2R-MC-BIAW
• First Posted: Feb 5, 2013
• Last Update Posted: Mar 15, 2019
• Last Verified: Mar 1, 2019

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin Glargine

Study Results

Participant Flow

Recruitment Details	Part A is 2- arm parallel open label. Part B is a crossover study with 2 treatment arms (LY2605541 & Glargine), each treatment arm consists of 2 sequences. Sequence 1: participants received treatment on days 16,17,18,19 & 20 with exercise on day 17. Sequence 2: participants received treatment on days 16,17,18,19, & 20 with exercise on day 20.

Arm/Group Title	LY2605541 (Part A)	Glargine (Part A)	First LY2605541 + Exercise, Then LY2605541 Alone (Part B)	First LY2605541 Alone, Then LY2605541 + Exercise (Part B)	First Glargine + Exercise, Then Glargine Alone (Part B)	First Glargine Alone, Then Glargine + Exercise (Part B)
Arm/Group Description	0.5 units per kilogram (U/kg) LY2605541 subcutaneously (SC) once daily for 15 days. Part A involved 3 clamp procedures on Days 8, 11, and 14.	0.5 U/kg insulin glargine SC once daily for 15 days. Part A involved 3 clamp procedures on Days 8, 11, and 14.	0.5 U/kg LY2605541 SC once daily for an additional 6 days, beginning on Day 16. Exercise challenge on Day 17 (no exercise on Day 20).	0.5 U/kg LY2605541 SC once daily for an additional 6 days, beginning on Day 16. Exercise challenge on Day 20 (no exercise on Day 17).	0.5 U/kg insulin glargine SC once daily for an additional 6 days, beginning on Day 16. Exercise challenge on Day 17 (no exercise on Day 20).	0.5 U/kg insulin glargine SC once daily for an additional 6 days, beginning on Day 16. Exercise challenge on Day 20 (no exercise on Day 17).
Period Title: Part A (Days 1-15)
STARTED	38	38	0	0	0	0
Received at Least 1 Dose of Study Drug	37	38	0	0	0	0
Entered Part B	19	21	0	0	0	0
COMPLETED	35	36	0	0	0	0
NOT COMPLETED	3	2	0	0	0	0
Period Title: Part A (Days 1-15)
STARTED	0	0	10	9	11	10
COMPLETED	0	0	10	9	11	10
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	LY2605541 (Part A)	Glargine (Part A)	Total
Arm/Group Description	0.5 units per kilogram (U/kg) LY2605541 subcutaneously (SC) once daily for 15 days. Part A involved 3 clamp procedures on Days 8, 11, and 14.	0.5 U/kg insulin Glargine SC once daily for 15 days. Part A involved 3 clamp procedures on Days 8, 11, and 14.	Total of all reporting groups
Overall Participants	37	38	75
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.2 (10.8)	42.0 (12.1)	42.6 (11.4)
Sex: Female, Male (Count of Participants)
Female	4 10.8%	11 28.9%	15 20%
Male	33 89.2%	27 71.1%	60 80%
Race/Ethnicity, Customized (Count of Participants)
White	36 97.3%	38 100%	74 98.7%
Multiple	1 2.7%	0 0%	1 1.3%
Region of Enrollment (Count of Participants)
Germany	37 100%	38 100%	75 100%

Outcome Measures

1. Primary Outcome

Title	Part A: Pharmacokinetics: Area Under the Concentration Versus Time Curve Over the Dosing Interval (AUCτ) of LY2605541 and Insulin Glargine: Intra-Participant Variability
Description	Venous blood samples for pharmacokinetic analysis were collected during the euglycemic glucose clamps during Part A. The intra-participant percentage of coefficient of variation (%CV) is presented. %CV was calculated by dividing the standard deviation by the mean, multiplied by 100.
Time Frame	Part A: Predose and 4, 8, 12, and 24 hours postdose on Days 8, 11, and 14

Outcome Measure Data

Analysis Population Description

Participants in Part A who received at least 1 dose of study drug and had evaluable AUCτ data.

Arm/Group Title	LY2605541 (Part A)	Glargine (Part A)
Arm/Group Description	0.5 U/kg LY2605541 SC once daily for 15 days. Part A involved 3 clamp procedures on Days 8, 11, and 14.	0.5 U/kg insulin glargine SC once daily for 15 days. Part A involved 3 clamp procedures on Days 8, 11, and 14.
Measure Participants	37	23
Number (90% Confidence Interval) [%CV]	11.3	19.2

2. Primary Outcome

Title	Part A: Pharmacokinetics: Maximum Drug Concentration (Cmax) of LY2605541 and Insulin Glargine: Intra-Participant Variability
Description	Venous blood samples for pharmacokinetic analysis were collected during the euglycemic glucose clamps during Part A. The intra-participant percentage of coefficient of variation (%CV) is presented. %CV was calculated by dividing the standard deviation by the mean, multiplied by 100.
Time Frame	Part A: Predose and 4, 8, 12, and 24 hours postdose on Days 8, 11, and 14

Outcome Measure Data

Analysis Population Description

Participants in Part A who received at least 1 dose of study drug and had evaluable Cmax data.

Arm/Group Title	LY2605541 (Part A)	Glargine (Part A)
Arm/Group Description	0.5 U/kg LY2605541 SC once daily for 15 days. Part A involved 3 clamp procedures on Days 8, 11, and 14.	0.5 U/kg insulin glargine SC once daily for 15 days. Part A involved 3 clamp procedures on Days 8, 11, and 14.
Measure Participants	37	35
Number (90% Confidence Interval) [%CV]	12.6	27.7

3. Secondary Outcome

Title	Part A: Pharmacodynamics: Total Amount of Glucose Infused Over the Duration of the Clamp (Gtot): Intra-Participant Variability
Description	Glucodynamic measurements were collected during the euglycemic glucose clamps during Part A. The intra-participant percentage of coefficient of variation (%CV) is presented. %CV was calculated by dividing the standard deviation by the mean, multiplied by 100.
Time Frame	Part A: Predose up to 24 hours postdose on Days 8, 11, and 14

Outcome Measure Data

Analysis Population Description

Participants in Part A who received at least 1 dose of study drug and had evaluable Gtot data.

Arm/Group Title	LY2605541 (Part A)	Glargine (Part A)
Arm/Group Description	0.5 U/kg LY2605541 SC once daily for 15 days. Part A involved 3 clamp procedures on Days 8, 11, and 14.	0.5 U/kg insulin glargine SC once daily for 15 days. Part A involved 3 clamp procedures on Days 8, 11, and 14.
Measure Participants	37	37
Number (90% Confidence Interval) [%CV]	41.4	63.9

4. Secondary Outcome

Title	Part B: Pharmacokinetics: AUCτ of LY2605541 and Insulin Glargine: Exercise Versus Non-Exercise
Description	Venous blood samples for pharmacokinetic analysis were collected in Part B. Results were stratified by whether or not the participant was undergoing an exercise challenge (+ Exercise) at the time of sample collection.
Time Frame	Part B: Predose, 11 hours postdose, every 30 minutes from 16.5 to 20 hours postdose, and 24 hours postdose on Day 16 or 19

Outcome Measure Data

Analysis Population Description

Participants in Part B who received at least 1 dose of study drug and had evaluable AUCτ data.

Arm/Group Title	LY2605541 + Exercise (Part B)	LY2605541 (Part B)	Glargine + Exercise (Part B)	Glargine (Part B)
Arm/Group Description	0.5 U/kg LY2605541 SC once daily for an additional 6 days. Exercise challenge on Day 17 or 20.	0.5 U/kg LY2605541 SC once daily for an additional 6 days.	0.5 U/kg insulin glargine SC once daily for an additional 6 days. Exercise challenge on Day 17 or 20.	0.5 U/kg insulin glargine SC once daily for an additional 6 days.
Measure Participants	18	18	10	9
Geometric Mean (Geometric Coefficient of Variation) [picomoles*hour per liter (pmol*h/L)]	147000 (25)	130000 (23)	2950 (24)	2650 (23)

5. Secondary Outcome

Title	Part B: Pharmacokinetics: Cmax of LY2605541 and Insulin Glargine: Exercise Versus Non-Exercise
Description	Venous blood samples for pharmacokinetic analysis were collected in Part B. Results were stratified by whether or not the participant was undergoing an exercise challenge (+ Exercise) at the time of sample collection.
Time Frame	Part B: Predose, 11 hours postdose, every 30 minutes from 16.5 to 20 hours postdose, and 24 hours postdose on Day 16 or 19

Outcome Measure Data

Analysis Population Description

Participants in Part B who received at least 1 dose of study drug and had evaluable Cmax data.

Arm/Group Title	LY2605541 + Exercise (Part B)	LY2605541 - No Exercise (Part B)	Glargine + Exercise (Part B)	Glargine - No Exercise (Part B)
Arm/Group Description	0.5 U/kg LY2605541 SC once daily for an additional 6 days. Exercise challenge on Day 17 or 20.	0.5 U/kg LY2605541 SC once daily for an additional 6 days.	0.5 U/kg insulin glargine SC once daily for an additional 6 days. Exercise challenge on Day 17 or 20.	0.5 U/kg insulin glargine SC once daily for an additional 6 days.
Measure Participants	19	19	14	14
Geometric Mean (Geometric Coefficient of Variation) [picomoles per liter (pmol/L)]	11100 (27)	6760 (28)	166 (51)	153 (35)

Adverse Events

Adverse Event Reporting Description	As per planned analysis adverse events were reported per intervention irrespective of exercise/ no exercise..
Arm/Group Title	LY2605541 (Part A and Part B)		Glargine (Part A and Part B)
Arm/Group Description	Part A: 0.5 U/kg LY2605541 SC once daily for 15 days. Part A involved 3 clamp procedures on Days 8, 11, and 14. Participants who completed Part A and met certain criteria had the option of continuing to Part B. Part B: 0.5 U/kg LY2605541 SC once daily for an additional 6 days. Exercise challenge on Day 17 or 20.		Part A: 0.5 U/kg insulin glargine SC once daily for 15 days. Part A involved 3 clamp procedures on Days 8, 11, and 14. Participants who completed Part A and met certain criteria had the option of continuing to Part B. Part B: 0.5 U/kg insulin glargine SC once daily for an additional 6 days. Exercise challenge on Day 17 or 20.
All Cause Mortality
	LY2605541 (Part A and Part B)		Glargine (Part A and Part B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	LY2605541 (Part A and Part B)		Glargine (Part A and Part B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/37 (2.7%)		0/38 (0%)
Metabolism and nutrition disorders
Hypoglycaemia	1/37 (2.7%)	1	0/38 (0%)	0
Other (Not Including Serious) Adverse Events
	LY2605541 (Part A and Part B)		Glargine (Part A and Part B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/37 (27%)		12/38 (31.6%)
Gastrointestinal disorders
Diarrhoea	0/37 (0%)	0	2/38 (5.3%)	2
Musculoskeletal and connective tissue disorders
Back pain	1/37 (2.7%)	1	2/38 (5.3%)	2
Nervous system disorders
Headache	8/37 (21.6%)	14	7/38 (18.4%)	19
Presyncope	1/37 (2.7%)	1	2/38 (5.3%)	2

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.