A Study in Participants With Type I Diabetes Mellitus

Study Overview
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Brief Summary
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The purpose of this study is: To compare blood sugar control on LY2605541 with insulin glargine after 52 weeks of treatment. To compare the rate of nocturnal low blood sugar episodes on LY2605541 with insulin glargine during 52 weeks of treatment. To compare the number of participants on LY2605541 reaching blood sugar targets without low blood sugar episodes at night to those taking insulin glargine after 52 weeks of treatment. To compare the rate of low blood sugar episodes on LY2605541 with insulin glargine during 52 weeks of treatment

Official Title
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The Impact of LY2605541 Versus Insulin Glargine for Patients With Type 1 Diabetes Mellitus Treated With Preprandial Insulin Lispro: a Double-Blind, Randomized, 52-week Study

Conditions
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Diabetes Mellitus, Type 1

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 diabetes for at least 1 year HbA1c value less than 12 percent according to the central laboratory at screening Body mass index of less than or equal to 35.0 kilograms per square meter (kg/m^2) Have been treated for at least 90 days prior to screening with insulin detemir, insulin glargine, or Neutral Protamine Hagedorn (NPH) in combination with pre-meal insulin, or self-mixed or pre-mixed insulin regimens with any basal and bolus insulin combination administered at least twice daily, or continuous SC insulin infusion therapy Women who are not breast feeding and test negative for pregnancy before receiving treatment and agree to use reliable birth control until 2 weeks after last treatment with study drug Are capable and willing to adhere to multiple daily injections, inject with a vial and syringe and prefilled pen and perform self-monitored blood glucose (SMBG) readings and record keeping Exclusion Criteria: Are using twice daily insulin glargine having been inadequately controlled on single daily dose of glargine prior to screening Excessive insulin resistance defined as having received a total daily dose of insulin greater than 1.5 units per kilogram (U/kg) at the time of randomization Receiving any oral or injectable medication (other than insulins or metformin for treatment of polycystic ovarian disease) intended for the treatment of diabetes mellitus in the 90 days prior to screening Lipid lowering medications: are using niacin preparations as lipid lowering medication and/or bile acid sequestrants within 90 days prior to screening; or, are using lipid lowering medication at a dose that has not been stable for 90 days or more prior to screening Have fasting hypertriglyceridemia (defined as greater than 4.5 millimoles per liter [mmol/L], greater than 400 milligrams per deciliter [mg/dL]) at screening, as determined by the central laboratory. Have had more than 1 episode of severe hypoglycemia (defined as requiring assistance due to neurologically disabling hypoglycemia) within 6 months prior to screening Have had 2 or more emergency room visits or hospitalizations due to poor glucose control within 6 months prior to screening Have cardiac disease with functional status that is New York Heart Association Class III or IV Have a history of renal transplantation or are currently receiving renal dialysis or have serum creatinine greater than 2.5 mg/dL Have obvious clinical signs or symptoms of liver disease (excluding non-alcoholic fatty liver disease [NAFLD]), acute or chronic hepatitis, non-alcoholic steatohepatitis (NASH), or elevated liver enzyme measurements as indicated below: total bilirubin 2 times or more than the upper limit of normal (ULN) as defined by the central laboratory, or alanine aminotransferase (ALT)/(serum glutamic pyruvic transaminase (SGPT) more than 2.5 times ULN as defined by the central laboratory, or aspartate aminotransferase (AST)/(serum glutamic oxaloacetic transaminase (SGOT) more than 2.5 times ULN as defined by the central laboratory Have active or untreated malignancy, have been in remission from clinically significant malignancy (other than basal cell or squamous cell skin cancer) for less than 5 years, or are at increased risk for developing cancer or a recurrence of cancer Diagnosed clinically significant diabetic autonomic neuropathy

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2605541 + Insulin Lispro<br>LY2605541 titrated based on blood glucose readings, administered subcutaneously (SC) once daily at bedtime for 52 weeks in combination with Insulin Lispro. Insulin Lispro titrated based on blood glucose readings, administered SC at meal times for 52 weeks. | Drug: LY2605541<br> <br> Drug: Insulin Lispro<br> <br> * Other names: Humalog;|
| Active Comparator: Glargine + Insulin Lispro<br>Glargine dose titrated based on blood glucose readings, administered SC once daily at bedtime for 52 weeks in combination with Insulin Lispro. Insulin Lispro dose titrated based on blood glucose readings, administered SC at meal times for 52 weeks. | Drug: Glargine<br> <br> Drug: Insulin Lispro<br> <br> * Other names: Humalog;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemoglobin A1c (HbA1c) | HbA1c is a test that measures a participant's average blood glucose level over a 2 to 3 month timeframe. Least squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, stratification factors (country, baseline low density lipoprotein cholesterol [LDL-C] [<100 milligrams/deciliter (mg/dL) (2.6 millimoles/liter [mmol/L]) and ≥100 mg/dL (2.6 mmol/L)], baseline prior basal insulin therapy [insulin glargine/detemir/other]), visit, treatment-by-visit interaction, and baseline HbA1c as the fixed effects and participant as the random effect. | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemoglobin A1c (HbA1c) | HbA1c is a test that measures a participant's average blood glucose level over the past 2 to 3 months. LS means were calculated using MMRM adjusting for treatment, stratification factors (country, baseline LDL-C [<100 mg/dL (2.6 mmol/L) and ≥100 mg/dL (2.6 mmol/L)], baseline prior basal insulin therapy [insulin glargine/detemir/other]), visit, treatment-by-visit interaction, and baseline HbA1c as the fixed effects and participant as the random effect. | 26 weeks | 
| Change From Baseline to 52 Weeks in HbA1c | HbA1c is a test that measures a participant's average blood glucose level over a 2 to 3 month timeframe. LS means were calculated using MMRM adjusting for treatment, stratification factors (country, baseline LDL-C [<100 mg/dL (2.6 mmol/L) and ≥100 mg/dL (2.6 mmol/L)], baseline prior basal insulin therapy [insulin glargine/detemir/other]), visit, treatment-by-visit interaction, and baseline HbA1c as the fixed effects and participant as the random effect. | Baseline, 52 weeks | 
| Total Hypoglycemia Events | Hypoglycemic episodes are defined as events which are associated with reported signs and symptoms of hypoglycemia and/or documented blood glucose (BG) concentrations of ≤70 mg/dL (3.9 mmol/L). Group mean rates of total hypoglycemia (per 30 days) are presented and were calculated from negative binomial regression models (number of episodes = treatment + baseline total hypoglycemia rate, with log [exposure in days/30] as an offset variable). Group mean is estimated by taking the inverse link function on individual participant covariates first and then averages over all participants. | Baseline through 26 weeks, Baseline through 52 weeks | 
| Percentage of Participants With Total Hypoglycemic Events | Hypoglycemic episodes are defined as events that are associated with the reported signs and symptoms of hypoglycemia and/or documented BG concentrations of ≤70 mg/dL (3.9 mmol/L). 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 through 26 weeks, Baseline through 52 weeks | 
| Percentage of Participants With HbA1c Equal to or Less Than 6.5% and Less Than 7.0% | 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. | up to 26 weeks, up to 52 weeks | 
| Percentage of Participants With HbA1c Less Than 7.0% and Without Nocturnal Hypoglycemia | Hypoglycemic episodes are defined as events associated with reported signs and symptoms of hypoglycemia and/or a documented blood glucose concentration of ≤70 mg/dL (3.9 mmol/L). A nocturnal hypoglycemic event occurred between bedtime and waking and between the time points of 10:00 PM and 10:00 AM. The percentage of participants was calculated by dividing the number of participants with HbA1c <7.0% without nocturnal hypoglycemia by the total number of participants analyzed, multiplied by 100. | up to 26 weeks, up to 52 weeks | 
| Nocturnal Hypoglycemia Rates | Hypoglycemic episodes are defined as events that are associated with reported signs and symptoms of hypoglycemia and/or a documented BG concentration of ≤70 mg/dL (3.9 mmol/L). A nocturnal hypoglycemic event occurred between bedtime and waking and between the time points of 10:00 PM and 10:00 AM. Group mean rates of nocturnal hypoglycemia (per 30 days) are presented and were calculated from negative binomial regression models (number of episodes = treatment + baseline nocturnal hypoglycemia rate, with log [exposure in days/30] as an offset variable). Group mean is estimated by taking the inverse link function on individual participant covariates first and then averages over all participants. | Baseline through 26 weeks, Baseline through 52 weeks | 
| Percentage of Participants With Nocturnal Hypoglycemic Events | Hypoglycemic episodes are defined as events associated with the reported signs and symptoms of hypoglycemia and/or a BG concentration of ≤70 mg/dL (3.9 mmol/L). A nocturnal hypoglycemic event occurred between bedtime and waking and between the time points of 10:00 PM and 10:00 AM. The percentage of participants was calculated by dividing the number of participants with nocturnal hypoglycemic episodes by the total number of participants analyzed, multiplied by 100. | Baseline through 26 weeks, Baseline through 52 weeks | 
| Change in Body Weight | LS means were calculated using MMRM adjusting for treatment, stratification factors (baseline HbA1c [≤8.5% and >8.5%], country, baseline LDL-C [<100 mg/dL (2.6 mmol/L) and ≥100 mg/dL (2.6 mmol/L)], baseline prior basal insulin therapy [insulin glargine/detemir/other]), visit, treatment-by-visit interaction, and baseline body weight as fixed effects and participant as the random effect. | Baseline, 26 weeks, 52 weeks | 
| 9 Point Self-monitored Blood Glucose (SMBG) | 9-point SMBG profiles were obtained over 2 days within the week prior to Weeks 0, 4, 12, 26, 39, and 52. 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. LS means were calculated using MMRM adjusting for treatment, stratification factors (baseline HbA1c [≤8.5% and >8.5%], country, baseline LDL-C [<100 mg/dL (2.6 mmol/L) and ≥100 mg/dL (2.6 mmol/L)], baseline prior basal insulin therapy [insulin glargine/detemir/other]), visit, treatment-by-visit interaction, and baseline BG values as the fixed effects and participant as the random effect. | 26 weeks and 52 weeks | 
| Fasting Serum Glucose (by Laboratory Measurement) | Fasting serum glucose (FSG) is measured in blood before the morning meal. LS means were calculated using MMRM adjusting for treatment, stratification factors (baseline HbA1c [≤8.5% and >8.5%], country, baseline LDL-C [<100 mg/dL (2.6 mmol/L) and ≥100 mg/dL (2.6 mmol/L)], baseline prior basal insulin therapy [insulin glargine/detemir/other]), visit, treatment-by-visit interaction, and baseline HbA1c as the fixed effects and participant as the random effect. | 26 weeks and 52 weeks | 
| Fasting Blood Glucose (by Participant Self Monitored Blood Glucose Readings) | Fasting blood glucose (FBG) was measured by SMBG pre-morning meal. LS means were calculated using MMRM adjusting for treatment, stratification factors (baseline HbA1c [≤8.5% and >8.5%], country, baseline LDL-C [<100 mg/dL (2.6 mmol/L) and ≥100 mg/dL (2.6 mmol/L)], baseline prior basal insulin therapy [insulin glargine/detemir/other]), visit, treatment-by-visit interaction, and baseline FBG as the fixed effects and participant as the random effect. | 26 weeks and 52 weeks | 
| Intra-participant Variability of Fasting Blood Glucose (FBG) | FBG was measured by SMBG. Between-day glucose variability is measured by the standard deviation (SD) of FBG. LS means were calculated using MMRM adjusting for treatment, stratification factors (baseline HbA1c [≤8.5% and >8.5%], country, baseline LDL-C [<100 mg/dL (2.6 mmol/L) and ≥100 mg/dL (2.6 mmol/L)], baseline prior basal insulin therapy [insulin glargine/detemir/other]), visit, treatment-by-visit interaction, and baseline SD of FBG as the fixed effects and participant as the random effect. | 26 weeks and 52 weeks | 
| 0300 Hours Blood Glucose (BG) to Fasting BG Excursion | Results of a 0300-hour to pre-morning meal (FBG) excursion are presented (only excursions within a single SMBG profile are included). LS means were calculated using MMRM adjusting for treatment, stratification factors (baseline HbA1c [≤8.5% and >8.5%], country, baseline LDL-C [<100 mg/dL (2.6 mmol/L) and ≥100 mg/dL (2.6 mmol/L)], baseline prior basal insulin therapy [insulin glargine/detemir/other]), visit, treatment-by-visit interaction, and baseline excursion as the fixed effects and participant as the random effect. | 26 weeks and 52 weeks | 
| Triglycerides, Low Density Lipoprotein Cholesterol (LDL-C), High Density Lipoprotein Cholesterol (HDL-C), and Total Cholesterol | Concentrations of cholesterol, HDL-C, and LDL-C, and triglycerides are presented. LS means were calculated using MMRM adjusting for stratification factors (baseline HbA1c [≤8.5% and >8.5%], country, LDL-C [<100 mg/dL (2.6 mmol/L) and ≥100 mg/dL (2.6 mmol/L), except for the LDL-C outcome variable], prior basal insulin therapy [insulin glargine/detemir/other]), visit, treatment, treatment-by-visit interaction, and baseline value of corresponding lipid outcome variable as the fixed effects and participant as a random effect. | 26 weeks and 52 weeks | 
| Percentage of Participants With Change in Anti-LY2605541 Antibodies | The percentage of participants with anti-LY2605541 treatment-emergent antibody response (TEAR) is summarized. TEAR is defined as change from baseline to post-baseline in the anti-LY2605541 antibody level either from undetectable to detectable, or from detectable to the value with at least 130% relative increase from baseline. | 26 weeks, 52 weeks | 
| Basal, Meal Time, and Total Insulin Dose Per Body Weight | Basal insulin dose, meal-time insulin dose (short-acting bolus dose), and total insulin dose were calculated based on the dose during the last 7 days prior to the post-treatment visit or last 3 days prior to the randomization visit. LS means were calculated using a constrained Longitudinal Data Analysis (cLDA) model adjusting for indicator variables of each treatment group at each postbaseline visit and stratification variables (baseline HbA1c [≤8.5% and> 8.5%], country, baseline LDL-C [<100 mg/dL (2.6 mmol/L) and ≥100 mg/dL (2.6 mmol/L)], and baseline prior basal insulin therapy [insulin glargine/detemir/ other]) as fixed effects. | 26 weeks and 52 weeks | 
| Insulin Treatment Satisfaction Questionnaire | Insulin Treatment Satisfaction Questionnaire (ITSQ) is a validated measure containing 22 items that assess treatment satisfaction for participants with diabetes and on insulin. The questionnaire measures satisfaction from the following 5 domains: Convenience of Regimen, Lifestyle Flexibility, Glycemic Control, Hypoglycemic Control, and Insulin Delivery Device. Data are transformed to a scale of 0-100, where higher scores indicate better treatment satisfaction. LS means were calculated using an ANCOVA model adjusting for treatment, baseline HbA1c (≤8.5% and >8.5%), country, and baseline prior basal insulin therapy (insulin glargine/detemir/other) as fixed effects and baseline ITSQ scores as a covariate. | up to 52 weeks | 
| European Quality of Life -5 Dimension (EQ-5D-3L) | The EQ-5D-3L is a generic, multidimensional, health-related, quality-of-life instrument. The profile allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression using a three-level scale of 1-3 (no problem, some problems, and extreme problems). These combinations of attributes are converted into a weighted health-state Index Score according to the United States population-based algorithm. Scores range from -0.11 to 1.0, where a score of 1.0 indicates perfect health. LS means were calculated using an ANCOVA adjusting for treatment, baseline HbA1c (≤8.5% and >8.5%), country, baseline prior basal insulin therapy (insulin glargine/detemir/other), and baseline EQ-5D-3L score as covariates. | up to 52 weeks | 
| Adult Low Blood Sugar Survey | Low Blood Sugar Survey (LBSS) (also referenced as Hypoglycemia Fear Survey - II [HFS-II]) is a questionnaire that measures 1) behaviors to avoid hypoglycemia and its negative consequences (15 items) and 2) worries about hypoglycemia and its negative consequences (18 items). Responses are made on a 5-point Likert-type scale where 0 = Never and 4 = Always. Total score is the sum of all items (range 0-132). Higher total scores reflect greater fear of hypoglycemia. LS means were calculated using MMRM adjusting for treatment, baseline HbA1c (≤8.5% and >8.5%), country, baseline prior basal insulin therapy (insulin glargine/detemir/other), visit, treatment-by-visit interaction, and baseline LBSS score as the fixed effects and participant as the random effect. | 26 weeks and 52 weeks | 
| Rapid Assessment of Physical Activity (RAPA) | The RAPA questionnaire assesses the level and intensity of physical activity of adult participants. It contains 2 subscales: RAPA 1 (Aerobic) and RAPA 2 (Strength and Flexibility). RAPA 1 contains 7 questions regarding the participant's amount and intensity of physical activity, allowing each participant's aerobic activity level to be categorized as sedentary, underactive, light activity, regular underactive, or active. RAPA 2 contains 2 questions regarding participants' physical activities that increase strength and improve flexibility. Each participant's strength and flexibility activity level is then categorized as neither strength nor flexibility activity, either strength or flexibility activity (not both), both strength and flexibility activity. The percentage of participants in each RAPA 1/2 category is presented and was calculated by dividing the number of participants in each RAPA 1/2 category by the total number of participants analyzed, multiplied by 100. | 52 weeks |