Diabetes Mellitus, Type 1
Conditions
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.
Interventions
DRUGLY2605541
DRUGInsulin Glargine
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
Germany
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 37 |
| 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. | 38 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Part A (Days 1-15) | Adverse Event | 1 | 1 | 0 | 0 | 0 | 0 |
| Part A (Days 1-15) | Withdrawal by Subject | 2 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | LY2605541 (Part A) | Glargine (Part A) | Total |
|---|---|---|---|
| Age, Continuous | 43.2 years STANDARD_DEVIATION 10.8 | 42.0 years STANDARD_DEVIATION 12.1 | 42.6 years STANDARD_DEVIATION 11.4 |
| Race/Ethnicity, Customized Multiple | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 36 Participants | 38 Participants | 74 Participants |
| Region of Enrollment Germany | 37 Participants | 38 Participants | 75 Participants |
| Sex: Female, Male Female | 4 Participants | 11 Participants | 15 Participants |
| Sex: Female, Male Male | 33 Participants | 27 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 37 | 12 / 38 |
| serious Total, serious adverse events | 1 / 37 | 0 / 38 |
Outcome results
Primary
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.
Time frame: Part A: Predose and 4, 8, 12, and 24 hours postdose on Days 8, 11, and 14
Population: Participants in Part A who received at least 1 dose of study drug and had evaluable AUCτ data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2605541 (Part A) | Part A: Pharmacokinetics: Area Under the Concentration Versus Time Curve Over the Dosing Interval (AUCτ) of LY2605541 and Insulin Glargine: Intra-Participant Variability | 11.3 %CV |
| Glargine (Part A) | Part A: Pharmacokinetics: Area Under the Concentration Versus Time Curve Over the Dosing Interval (AUCτ) of LY2605541 and Insulin Glargine: Intra-Participant Variability | 19.2 %CV |
Primary
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.
Time frame: Part A: Predose and 4, 8, 12, and 24 hours postdose on Days 8, 11, and 14
Population: Participants in Part A who received at least 1 dose of study drug and had evaluable Cmax data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2605541 (Part A) | Part A: Pharmacokinetics: Maximum Drug Concentration (Cmax) of LY2605541 and Insulin Glargine: Intra-Participant Variability | 12.6 %CV |
| Glargine (Part A) | Part A: Pharmacokinetics: Maximum Drug Concentration (Cmax) of LY2605541 and Insulin Glargine: Intra-Participant Variability | 27.7 %CV |
Secondary
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.
Time frame: Part A: Predose up to 24 hours postdose on Days 8, 11, and 14
Population: Participants in Part A who received at least 1 dose of study drug and had evaluable Gtot data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2605541 (Part A) | Part A: Pharmacodynamics: Total Amount of Glucose Infused Over the Duration of the Clamp (Gtot): Intra-Participant Variability | 41.4 %CV |
| Glargine (Part A) | Part A: Pharmacodynamics: Total Amount of Glucose Infused Over the Duration of the Clamp (Gtot): Intra-Participant Variability | 63.9 %CV |
Secondary
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.
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
Population: Participants in Part B who received at least 1 dose of study drug and had evaluable AUCτ data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2605541 (Part A) | Part B: Pharmacokinetics: AUCτ of LY2605541 and Insulin Glargine: Exercise Versus Non-Exercise | 147000 picomoles*hour per liter (pmol*h/L) | Geometric Coefficient of Variation 25 |
| Glargine (Part A) | Part B: Pharmacokinetics: AUCτ of LY2605541 and Insulin Glargine: Exercise Versus Non-Exercise | 130000 picomoles*hour per liter (pmol*h/L) | Geometric Coefficient of Variation 23 |
| Glargine + Exercise (Part B) | Part B: Pharmacokinetics: AUCτ of LY2605541 and Insulin Glargine: Exercise Versus Non-Exercise | 2950 picomoles*hour per liter (pmol*h/L) | Geometric Coefficient of Variation 24 |
| Glargine (Part B) | Part B: Pharmacokinetics: AUCτ of LY2605541 and Insulin Glargine: Exercise Versus Non-Exercise | 2650 picomoles*hour per liter (pmol*h/L) | Geometric Coefficient of Variation 23 |
Secondary
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.
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
Population: Participants in Part B who received at least 1 dose of study drug and had evaluable Cmax data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2605541 (Part A) | Part B: Pharmacokinetics: Cmax of LY2605541 and Insulin Glargine: Exercise Versus Non-Exercise | 11100 picomoles per liter (pmol/L) | Geometric Coefficient of Variation 27 |
| Glargine (Part A) | Part B: Pharmacokinetics: Cmax of LY2605541 and Insulin Glargine: Exercise Versus Non-Exercise | 6760 picomoles per liter (pmol/L) | Geometric Coefficient of Variation 28 |
| Glargine + Exercise (Part B) | Part B: Pharmacokinetics: Cmax of LY2605541 and Insulin Glargine: Exercise Versus Non-Exercise | 166 picomoles per liter (pmol/L) | Geometric Coefficient of Variation 51 |
| Glargine (Part B) | Part B: Pharmacokinetics: Cmax of LY2605541 and Insulin Glargine: Exercise Versus Non-Exercise | 153 picomoles per liter (pmol/L) | Geometric Coefficient of Variation 35 |