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

Study Overview
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Brief Summary
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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.

Official Title
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The Pharmacokinetic and Pharmacodynamic Intra-subject Variability of LY2605541 and the Effect of Exercise on LY2605541 Pharmacokinetics in Patients With Type 1 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: LY2605541
* Drug: Insulin Glargine


Participation Criteria
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Eligibility Criteria
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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 65) 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2605541 (Part A)<br>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<br> <br> |
| Active Comparator: Glargine (Part A)<br>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<br> <br> |
| Experimental: First LY2605541 + Exercise,Then LY2605541 Alone (Part B)<br>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<br> <br> |
| Experimental: First LY2605541 Alone, Then LY2605541 + Exercise (Part B)<br>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<br> <br> |
| Active Comparator: First Glargine + Exercise, Then Glargine Alone (Part B)<br>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<br> <br> |
| Active Comparator: First Glargine Alone, Then Glargine + Exercise (Part B)<br>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<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Pharmacokinetics: Area Under the Concentration Versus Time Curve Over the Dosing Interval (AUCτ) of LY2605541 and Insulin Glargine: Intra-Participant Variability | 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. | Part A: Predose and 4, 8, 12, and 24 hours postdose on Days 8, 11, and 14 | 
| Part A: Pharmacokinetics: Maximum Drug Concentration (Cmax) of LY2605541 and Insulin Glargine: Intra-Participant Variability | 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. | Part A: Predose and 4, 8, 12, and 24 hours postdose on Days 8, 11, and 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Pharmacodynamics: Total Amount of Glucose Infused Over the Duration of the Clamp (Gtot): Intra-Participant Variability | 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. | Part A: Predose up to 24 hours postdose on Days 8, 11, and 14 | 
| Part B: Pharmacokinetics: AUCτ of LY2605541 and Insulin Glargine: Exercise Versus Non-Exercise | 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. | 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 | 
| Part B: Pharmacokinetics: Cmax of LY2605541 and Insulin Glargine: Exercise Versus Non-Exercise | 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. | 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 |