A Study in Participants With Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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The purpose of this study is: To compare the blood sugar control of LY2605541 with insulin glargine after 78 weeks of treatment. To compare the rate of night-time low blood sugar episodes on LY2605541 with insulin glargine during 78 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 78 weeks of treatment. To compare the rate of hypoglycemia episodes on LY2605541 with insulin glargine during 78 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: An Open-Label, Randomized, 78-Week Study - The IMAGINE 1 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: Have had diabetes mellitus for at least 1 year Have an hemoglobin A1c (HbA1c) value less than 12% according to the central laboratory at screening Have a body mass index (BMI) 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 the following: Insulin detemir, insulin glargine, or human insulin isophane suspension (NPH) insulin in combination with premeal insulin, Self-mixed or premixed insulin regimens with any basal and bolus insulin combination administered at least twice daily, or Continuous SC insulin infusion therapy This inclusion criterion applies to female participants: Are not breastfeeding Test negative for pregnancy at screening and randomization based on serum pregnancy tests Do not intend to become pregnant during the study Have practiced a reliable method of birth control (for example, use of oral contraceptives or levonorgestrel, diaphragms with contraceptive jelly, cervical caps with contraceptive jelly, condoms with contraceptive foam, intrauterine devices, partner with vasectomy, or abstinence) for at least 6 weeks prior to screening Agree to continue to use a reliable method of birth control during the study, as determined by the investigator (and for 2 weeks following the last dose of study drug) Capable of and willing and desirous to do the following: adhere to a multiple daily injection regimen, inject insulin with a prefilled pen and perform Self-Monitored Blood Glucose (SMBG) and record keeping as required by this protocol, as determined by the investigator. Caregiver may be responsible for all of the above. Exclusion Criteria: Are using twice-daily insulin glargine having been inadequately controlled on once-daily dosed glargine prior to screening Have excessive insulin resistance defined as having received a total daily dose of insulin greater than 1.5 units per kilogram (units/kg) at the time of randomization Receiving any oral or injectable medication (other than metformin for treatment of polycystic ovarian disease) intended for the treatment of diabetes mellitus other than insulins in the 90 days prior to screening Lipid-lowering medications: Are using niacin preparations as a 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 greater than or equal to 90 days prior to screening If a participant has not been on a stable dose of lipid-lowering medication for greater than or equal to 90 days prior to screening, the site should wait to screen the participant. If the results of the screening laboratory tests require a change to the participant's current lipid-lowering medication or initiation of lipid-lowering medication, it is acceptable to change the lipid-lowering medication for the participant and to have the participant return greater than or equal to 90 days later to complete some of the screening procedures again 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 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 Cardiovascular: have cardiac disease with functional status that is New York Heart Association Class III or IV (per New York Heart Association Cardiac Disease Classification) Renal: Have a history of renal transplantation or are currently receiving renal dialysis or have serum creatinine greater than 2.5 mg/dL Hepatic: 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 greater than or equal to 2 times the upper limit of normal (ULN) as defined by the central laboratory, Alanine aminotransferase (ALT)/(serum glutamic pyruvic transaminase (SGPT) greater than 2.5 times ULN as defined by the central laboratory, or Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) greater than 2.5 times ULN as defined by the central laboratory. Malignancy: 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 an increased risk for developing cancer or a recurrence of cancer in the opinion of the investigator Allergy: Have known hypersensitivity or allergy to any of the study insulins or their excipients Hematologic: 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 the HbA1c measurement Glucocorticoid therapy: Receiving chronic (lasting longer than 14 consecutive days) systemic glucocorticoid therapy (excluding topical , intraocular, intranasal, and inhaled preparations) or have received such therapy within 8 weeks immediately before screening with the exception of replacement therapy for adrenal insufficiency Diagnosed clinically significant diabetic autonomic neuropathy, in the opinion of the investigator Have any other condition (including known drug or alcohol abuse or psychiatric disorder including eating disorder) that precludes the participant from following and completing the protocol

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2605541 + Insulin Lispro<br>LY2605541 titrated based on blood glucose readings, administered by subcutaneous (SC) injection via pen device once daily at bedtime for 78 weeks in combination with Insulin Lispro. Insulin Lispro titrated based on blood glucose readings, administered by SC injection via pen device at meal times for 78 weeks. | Drug: LY2605541<br>* Administered by SC injection with a pen device.<br>Drug: Insulin Lispro<br>* Administered by SC injection with a pen device.<br>* Other names: Humalog;|
| Active Comparator: Glargine + Insulin Lispro<br>Glargine dose titrated based on blood glucose readings, administered by SC injection via pen device once daily at bedtime for 78 weeks in combination with Insulin Lispro. Insulin Lispro dose titrated based on blood glucose readings, administered by SC injection via pen device at meal times for 78 weeks. | Drug: Glargine<br>* Administered by SC injection via a pen device.<br>Drug: Insulin Lispro<br>* Administered by SC injection with a pen device.<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) at 26 Weeks | 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 (baseline low-density lipoprotein cholesterol [LDL-C] [<100 milligrams per deciliter (mg/dL) and ≥100 mg/dL] and country), visit, treatment-by-visit interaction, and baseline HbA1c as the fixed effects and participant as the random effect. | 26 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 a 2- to 3-month timeframe. LS means were calculated using MMRM, adjusting for treatment, stratification factors (baseline LDL-C [<100 mg/dL and ≥100 mg/dL] and country), visit, treatment-by-visit interaction, and baseline HbA1c as the fixed effects. | 52 weeks and 78 weeks | 
| Change From Baseline in Hemoglobin A1c (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 (baseline LDL-C [<100 mg/dL and ≥100 mg/dL] and country), visit, treatment-by-visit interaction, and baseline HbA1c as the fixed effects. | Baseline, 26 weeks, 52 weeks, 78 weeks | 
| Percentage of Participants With Hemoglobin A1c (HbA1c) Less Than 7.0% or Less Than or Equal to 6.5% Using Last Observation Carried Forward (LOCF) | HbA1c is a test that measures a participant's average blood glucose level over a 2- to 3-month timeframe. The percentage of participants was calculated by dividing the number of participants reaching target HbA1c by the total number of participants analyzed, then multiplying by 100. | 26 weeks and 52 weeks and 78 weeks | 
| Proportion of Participants With Hemoglobin A1c (HbA1c) Less Than 7.0% Without Nocturnal Hypoglycemia | Hypoglycemic episodes are defined as an event that is associated with reported signs and symptoms of hypoglycemia and/or a documented blood glucose concentration of ≤70 mg/dL (3.9 millimoles per liter [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, then multiplying by 100. | 26 weeks and 52 weeks and 78 weeks | 
| Total Hypoglycemia Rates (Adjusted by 30 Days) | Hypoglycemic episodes are defined as events that 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 and Baseline through 52 weeks and Baseline through 78 weeks | 
| Percentage of Participants With Total Hypoglycemia Events | Hypoglycemic events are defined as events that are associated with 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, then multiplying by 100. | Baseline through 26 weeks and Baseline through 52 weeks and Baseline through 78 weeks | 
| Nocturnal Hypoglycemia Rates (Adjusted by 30 Days) | 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 and Baseline through 52 weeks and Baseline through 78 weeks | 
| Percentage of Participants With Nocturnal Hypoglycemic Events | Hypoglycemic episodes are defined as an event that is associated with 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, then multiplying by 100. | Baseline through 26 weeks and Baseline through 52 weeks and Baseline through 78 weeks | 
| Fasting Serum Glucose (FSG) by Laboratory Measurement | LS means were calculated using MMRM, adjusting for treatment, stratification factors (baseline HbA1c [≤8.5% and >8.5%], baseline LDL-C level [<100 mg/dL and ≥100 mg/dL], and country), visit, treatment-by-visit interaction, and corresponding baseline dependent variable as the fixed effects, and participants as the random effect. | 26 weeks and 52 weeks and 78 weeks | 
| Fasting Blood Glucose (FBG) Intra-participant Variability | FBG was measured by self-monitored blood glucose (SMBG). Between-day glucose variability is measured by the standard deviation of FBG. LS means were calculated using MMRM, adjusting for treatment, stratification factors (baseline HbA1c [≤8.5% and >8.5%], baseline LDL-C level [<100 mg/dL and ≥100 mg/dL], and country), visit, treatment-by-visit interaction, and corresponding baseline dependent variable as the fixed effects, and participants as the random effect. | 26 weeks and 52 weeks and 78 weeks | 
| 0300-hour Blood Glucose (BG) to Fasting Blood (FBG) Glucose Excursion | Results of a 0300-hour to pre-morning meal (FBG) excursion are presented (only SMBG profiles with both 0300 hours and the next day pre-morning measurements are included for the calculation of such excursion). LS means were calculated using MMRM, adjusting for treatment, stratification factors (baseline HbA1c [≤8.5% and >8.5%], baseline LDL-C level [<100 mg/dL and ≥100 mg/dL], and country), visit, treatment-by-visit interaction, and corresponding baseline dependent variable as the fixed effects and participants as the random effect. | 26 weeks and 52 weeks and 78 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, 52, 65, and 78. 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 pre-morning meal the next day. LS means were calculated using MMRM, adjusting for treatment, stratification factors (baseline HbA1c [≤8.5% and >8.5%], baseline LDL-C level [<100 mg/dL and ≥100 mg/dL], and country), visit, treatment-by-visit interaction, and corresponding baseline dependent variable as the fixed effects and participants as the random effect. | 26 weeks and 52 weeks and 78 weeks | 
| Change From Baseline in Body Weight | LS means were calculated using MMRM, adjusting for treatment, stratification factors (baseline HbA1c [≤8.5% and >8.5%], baseline LDL-C level [<100 mg/dL and ≥100 mg/dL], and country), visit, treatment-by-visit interaction, and corresponding baseline dependent variable as the fixed effects, and participants as the random effect. | Baseline and 26 weeks and 52 weeks and 78 weeks | 
| Basal, Bolus, and Total Insulin Dose | Basal insulin dose, short-acting bolus insulin dose (each meal and overall), 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 MMRM, adjusting for treatment, stratification factors (baseline HbA1c [≤8.5% and >8.5%], baseline LDL-C level [<100 mg/dL and ≥100 mg/dL], and country), visit, treatment-by-visit interaction, and corresponding baseline dependent variable as the fixed effects and participants as the random effect. | 26 weeks and 52 weeks and 78 weeks | 
| Lipid Profile | Concentrations of cholesterol, high-density lipoprotein cholesterol (HDL-C), LDL-C, and triglycerides are summarized. LS means were calculated using MMRM, adjusting for stratification factors (baseline HbA1c [≤8.5% and >8.5%], country, LDL-C [<100 mg/dL and ≥100 mg/dL] except for the LDL-C outcome variable), visit, treatment, treatment-by-visit interaction, and baseline value of corresponding lipid outcome variable. | 26 weeks and 52 weeks and 78 weeks | 
| Percentage of Participants With Change in Anti-LY2605541 Antibodies | The percentage of participants with a treatment-emergent anti-LY2605541 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. | Baseline through 26 weeks and Baseline through 52 weeks and Baseline through 78 weeks | 
| Insulin Treatment Satisfaction Questionnaire (ITSQ) | ITSQ is a validated instrument containing 22 items that assess treatment satisfaction for participants with diabetes and on insulin. The questionnaire measures satisfaction from the following 5 domains: Inconvenience of Regimen, Lifestyle Flexibility, Glycemic Control, Hypoglycemic Control, and Insulin Delivery Device. Data presented are the transformed overall score on a scale of 0-100, where higher scores indicate better treatment satisfaction. LS means were calculated using an analysis of covariance (ANCOVA) model with treatment and stratification (baseline HbA1c [≤8.5% or >8.5%] and country) as fixed effects and baseline value of the dependent variable as a covariate. | 26 weeks | 
| Low Blood Sugar Survey (LBSS) | LBSS (also referenced as Hypoglycemia Fear Survey - II [HFS-II]) is a 33-item 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 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, stratification factors (baseline HbA1c [≤8.5% and >8.5%] and country), visit, treatment-by-visit interaction , and corresponding baseline dependent variable as the fixed effects and participants as the random effect. | 26 weeks and 52 weeks and 78 weeks | 
| European Quality of Life-5 Dimension (EQ-5D) | The EQ-5D 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 3-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 ANCOVA, adjusting for treatment and stratification factors (baseline HbA1c [≤8.5% or >8.5%] and country) as fixed effects and baseline EQ-5D score as a covariate. | 26 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 activities, 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 (flex) activity, either strength or flex (not both), both strength and flex 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, then multiplying by 100. | 26 weeks and 78 weeks |