A Study of LY2605541 in Participants With Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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The primary purpose of participation in this study is to compare the safety and efficacy of different dosing schedules of LY2605541 and how different dosing schedules of LY2605541 affect Hemoglobin A1c (HbA1c). Participants will be treated for up to 36 weeks with LY2605541 (one 12-week Lead-in period and two 12-week Randomization periods) and will participate in a total of 42 weeks of total study enrollment, including a 2-week Screening period and a 4-week Follow-up period.

Detailed Description
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This study involved a comparison of LY2605541 regimens, each administered with bolus insulin lispro. Eligible participants were switched to a fixed evening LY2605541dosing regimen at the beginning of the 12-week lead-in period. LY2605541 was administered SQ once-daily using a prefilled insulin device. The LY2605541dose was adjusted using a dosing algorithm adapted from Bartley and Bolli (Bartley et al. 2008, Bolli et al. 2009) based on the participant's blood glucose (BG) values and documented hypoglycemia during the previous week. Participants not already receiving insulin lispro for prandial dosing were switched to insulin lispro at the beginning of the 12-week lead-in period. Adjustments to insulin lispro doses were based on the insulin dosing algorithms adapted from Riddle and Bergenstal (Riddle et al. 2003, Bergenstal et al. 2008). At the time of randomization, participants were randomized to begin either the fixed evening dosing regimen or the variable time dosing regimen. Each participant was crossed over to the alternate regimen after 12 weeks. The insulin device (prefilled pen) remained the same throughout the study.

Official Title
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A Comparison of LY2605541 Once Daily at a Fixed Time With LY2605541 Variable Time of Dosing in Participants With Type 1 Diabetes Mellitus: An Open Label, Randomized, Crossover Study

Conditions
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Type 1 Diabetes Mellitus

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 diabetes mellitus for at least 1 year Have an HbA1c value <9.0% Have a body mass index (BMI) ≤35.0 kilogram per square meter (kg/m^2) Currently using basal/ bolus insulin Women of childbearing potential are not breastfeeding and must use methods to prevent pregnancy Exclusion Criteria: Have excessive insulin resistance Are taking medications other than insulin for diabetes High triglycerides Have had more than 1 episode of severe hypoglycemia (defined as requiring assistance due to neurologically disabling hypoglycemia as determined by the investigator) within 6 months prior to entry into the study Have had 2 or more emergency room visits or hospitalizations due to poor glucose control (hyperglycemia or diabetic ketoacidosis) in the past 6 months Have cardiac disease with functional status that is New York Heart Association (NYHA) Class III or IV (per NYHA Cardiac Disease Classification) Have impaired renal function Have impaired liver function Have had a blood transfusion or severe blood loss within 3 months prior to screening or have known hemoglobinopathy, hemolytic anemia, sickle cell anemia, or any other traits of hemoglobin abnormalities known to interfere with HbA1c measurement Have cancer, recent cancer, or risk of cancer Have a known hypersensitivity or allergy to any of the study insulins or their excipients Have chronic systemic glucocorticoid users Have clinically significant diabetic autonomic neuropathy Have irregular sleep/wake cycle Have been treated with a drug within the last 30 days that has not received regulatory approval at the time of study entry Prior study participation Are using or have used niacin preparations as a lipid-lowering medication and/or bile acid sequestrants within 90 days prior to screening

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2605541 Fixed Time Dosing<br>Participant-specific dose of LY2605541 administered subcutaneously (SQ) at approximately the same time every evening for 12 weeks in the Lead-in Period and in Randomization Period 1 or Randomization Period 2. Participant-specific dose of insulin lispro SQ when >20% of calories were consumed (pre-meal). Insulin dose and adjustments to insulin dose were determined by insulin algorithms based on self-monitored blood glucose (SMBG). Target glucose values were as follows: Preprandial and bedtime BG between 71 and 130 milligrams/deciliter (mg/dL) Insulin adjustment and glucose correction between 71 and 100 mg/dL. | Drug: LY2605541<br> <br> * Other names: Insulin Peglispro;Drug: Insulin Lispro<br>* All participants will be administering insulin lispro SQ as their pre-meal insulin during the course of the trial.<br>|
| Experimental: LY2605541 Variable Time Dosing<br>Participant-specific dose of LY2605541 administered SQ on a variable time schedule (8- and 40-hour dosing intervals) for 12 weeks in Randomization Period 1 or Randomization Period 2. Dosing schedules were to remain approximately the same throughout the 12 weeks. Participant-specific dose of insulin lispro SQ when >20% of calories were consumed (pre-meal). Insulin dose and adjustments to insulin dose were determined by insulin algorithms based on SMBG. Target glucose values were as follows: Preprandial and bedtime BG between 71 and 130 mg/dL Insulin adjustment and glucose correction between 71 and 100 mg/dL. | Drug: LY2605541<br> <br> * Other names: Insulin Peglispro;Drug: Insulin Lispro<br>* All participants will be administering insulin lispro SQ as their pre-meal insulin during the course of the trial.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemoglobin A1c (HbA1c) at 12 Weeks | HbA1c is a test that measures a person's average blood glucose level over the past 2 to 3 months. Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis including the following fixed effects: treatment, period, sequence, baseline HbA1c (last nonmissing value at or before randomization), week (defined from the start of each Randomization Period), and treatment-by-week interaction. | At 12 Week in Each Randomization Period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Randomization to 12 Weeks in 9-Point SMBG | SMBG measurements were taken at 9 time points: pre-morning meal, 2 hours post-morning meal, pre-midday meal, 2 hours post-midday meal, pre-evening meal, 2 hours post-evening meal, bedtime, at approximately 0300 hours, and the subsequent morning prior to the morning meal. SMBG measures were assessed at Weeks 0, 4, 8, and 12 within each Randomization Period. LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline SMBG (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction. | Randomization, 12 Weeks in Each Randomization Period | 
| 30-Day Adjusted Rate of Total and Nocturnal Hypoglycemic Events | Total hypoglycemic events (HE) include any event based on a blood glucose <=70 milligrams per deciliter (mg/dL) (3.9 millimoles per liter [mmol/L]), with or without signs/symptoms of hypoglycemia or an event associated with signs/symptoms of hypoglycemia but without a glucose measurement. Nocturnal HE include any total HE that occurred between bedtime and waking. Group Means are presented and were calculated from negative binomial regression models (number of episodes = treatment + period + treatment sequence + baseline HbA1c [<=8.0% or >8.0%], with log [exposure in days/30] as an offset variable). Group Mean (LS mean) is estimated by taking the inverse link function on individual participant covariates first and then averages over all participants. | Baseline (Day 1) of Randomization Period through 24 Weeks (12 weeks in each Randomization Period) | 
| Percentage of Participants With Total and Nocturnal Hypoglycemic Events | Total HE include any event based on a blood glucose <=70 mg/dL (3.9 mmol/L), with or without signs/symptoms of hypoglycemia or an event associated with signs/symptoms of hypoglycemia but without a glucose measurement. Nocturnal HE include any total HE that occurred between bedtime and waking. The percentage of participants was calculated by dividing the number of participants with hypoglycemic episodes by the total number of participants analyzed, multiplied by 100. | Baseline (Day 1) of Randomization Period through 24 weeks (12 weeks in each Randomization Period) | 
| Fasting Blood Glucose (FBG) Measured by Self-Monitored Blood Glucose | FBG was measured by self-monitored blood glucose (SMBG). LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline FBG (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction. | At 12 Weeks in Each Randomization Period | 
| Intra-Participant Variability of FBG at 12 Weeks | FBG was measured by SMBG. Between-day glucose variability is measured by the standard deviation of FBG. LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline intra-participant variability in FBG (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction. | At 12 Weeks in Each Randomization Period | 
| Fasting Serum Glucose (FSG) at 12 Weeks | LS means for FSG (obtained from clinical laboratory tests) were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline FSG (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction. | At 12 Weeks in Each Randomization Period | 
| Self-Monitored Blood Glucose (SMBG) at 12 Weeks | SMBG measurements were taken at 9 time points: pre-morning meal, 2 hours post-morning meal, pre-midday meal, 2 hours post-midday meal, pre-evening meal, 2 hours post-evening meal, bedtime, at approximately 0300 hours, and the subsequent morning prior to the morning meal. SMBG measures were assessed at Weeks 0, 4, 8, and 12 within each Randomization Period. LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline SMBG (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction. | At 12 Week in Each Randomization Period | 
| Intra-participant Variability in SMBG at 12 Weeks | A summary of glucose variability (intra-participant variability) as measured by the average of between-day standard deviations of individual SMBG time points. LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline intra-participant variability in SMBG (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction. | At 12 Week in Each Randomization Period | 
| Change From Randomization to 12 Weeks in Body Weight | LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline body weight (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction. | Randomization, 12 Weeks in Each Randomization Period | 
| Change From Day 1 of Lead-In Period to 36 Weeks in Body Weight | LS means were calculated using MMRM analysis, including visit and baseline weight (last non-missing value at or before the beginning of Lead-in Period) as covariates. | Day 1 of Lead-In Period, 36 Weeks | 
| Change From Randomization to 12 Weeks in HbA1c | LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline HbA1c (last nonmissing value at or before randomization), week (defined from the start of each Randomization Period), and treatment-by-week interaction. | Randomization, 12 Weeks in Each Randomization Period | 
| Participants With Treatment-Emergent Anti-LY2605541 Antibody Response | The number of participants with a treatment emergent anti-LY2605541 antibody response (TEAR) is presented. Positive TEAR was defined as change from baseline to post-baseline in the anti-LY2605541 antibody level either from 1) undetectable to detectable or from 2) detectable to the value with at least 130% relative increase from baseline. | Day 1 of Lead-in Period through 36 Weeks | 
| Basal, Bolus, and Total Insulin Doses at 12 Weeks | LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline insulin dose (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction. | At 12 Weeks in Each Randomization Period | 
| Proportion of Bolus to Total Insulin Doses at 12 Weeks | Proportion of bolus to total insulin dose is presented, where LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline proportion of bolus to total insulin dose (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction. | At 12 Weeks in Each Randomization Period | 
| 0300-Hour Blood Glucose to Fasting Blood Glucose Excursion | Excursion results were calculated by subtracting the 0300 hours glucose value from the next day pre-morning glucose value within a single SMBG profile. LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline 0300-hour to next day pre-breakfast excursion (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction. | At 12 Week in Each Randomization Period | 
| Change From Day 1 of Lead-in to 36 Weeks in Triglycerides, Total Cholesterol, Low-Density Lipoprotein Cholesterol (LDL-C), and High-Density Lipoprotein Cholesterol (HDL-C) | LS means were calculated using MMRM analysis including visit and baseline lipid level (last nonmissing value at or before the beginning of Lead-in) as covariates. | Day 1 of Lead-In Period, 36 Weeks | 
| Percentage of Participants With HbA1c <7.0% and ≤6.5% at 12 Weeks | The percentage of participants was calculated by dividing the number of participants reaching target HbA1c by the total number of participants analyzed, multiplied by 100. | At 12 Weeks in Each Randomization Period |