A Study in Participants With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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The purpose of this study is: To compare blood glucose (blood sugar) control on LY2605541 with insulin glargine after 26 weeks of treatment. To compare the rate of night time hypoglycemia (low blood glucose) on LY2605541 with insulin glargine during 26 weeks of treatment. To compare the number of participants on LY2605541 reaching blood glucose targets without hypoglycemia episodes at night to those taking insulin glargine after 26 weeks of treatment. To compare the rate of hypoglycemia over a 24-hour period on LY2605541 with insulin glargine during 26 weeks of treatment.

Official Title
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The Impact of LY2605541 Versus Insulin Glargine for Patients With Type 2 Diabetes Mellitus Advanced to Multiple Injection Bolus Insulin With Insulin Lispro: a Double-Blind, Randomized, 26-week Study - The IMAGINE 4 Study

Conditions
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Diabetes Mellitus, Type 2

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Have type 2 diabetes mellitus based on the World Health Organization (WHO) classification Had diabetes ≥1 year Have a hemoglobin A1c (HbA1c) value ≥7.0% and <12.0% at screening Have a body mass index (BMI) ≤45.0 kilograms per square meter (kg/m^2) Participants on any glucose lowering regimen that contains at least 1 daily insulin injection This inclusion criterion applies ONLY to women of childbearing potential Are not breastfeeding Test negative for pregnancy at screening and randomization Do not intend to become pregnant during the study Have practiced a reliable method of birth control 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) Have access to a method of communication with the site Have refrigeration in the home Capable of, and willing to do the following: adhere to a multiple daily injection regimen, inject insulin with a covered vial and syringe and prefilled pen, attend some appointments in the fasting state, and perform self blood glucose monitoring and record keeping as required by this protocol, as determined by the investigator. Caregiver may be responsible for all of the above Have given written informed consent to participate in this study in accordance with local regulations Exclusion Criteria Continuous subcutaneous insulin infusion therapy prior to screening Are using twice daily insulin glargine prior to screening Excessive insulin resistance defined as having received a daily dose of insulin ≥2.0 units per kilogram (units/kg) at the time of pre-randomization Glucagon-like peptide-1 (GLP-1) receptor agonist (eg, exenatide, exenatide once weekly, or liraglutide), thiazolidinedione (rosiglitazone, pioglitazone), or pramlintide, used concurrently or within 90 days prior to screening 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 ≥90 days prior to screening Have fasting hypertriglyceridemia (defined as >4.5 millimoles per liter [mmol/L], >400 milligrams per deciliter [mg/dL]) at screening Are currently taking, or have taken within the 90 days preceding screening, prescription or over-the-counter medications for weight loss Have had any episode of severe hypoglycemia (defined as requiring assistance due to neurologically disabling hypoglycemia) within 6 months prior to entry into the study Have had 2 or more emergency room visits or hospitalizations due to poor glucose control within the 6 months prior to screening Have had 1 or more episodes of ketoacidosis or hyperosmolar state/coma requiring hospitalization within 6 months prior to screening Have cardiac disease with functional status that is New York Heart Association Class III or IV (per New York Heart Association Cardiac Disease Classification) Are currently receiving renal dialysis or have a serum creatinine ≥2.0 mg/dL, except for participants taking metformin who will be required to follow local labeling restrictions regarding metformin use and serum creatinine 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 ≥2X the upper limit of normal (ULN) as defined by the central laboratory, or alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) >2.5X ULN as defined by the central laboratory, or aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) >2.5X 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 in the opinion of the investigator Have known or develop hypersensitivity or allergy to any of the study insulins or their excipients Have had a blood transfusion or severe blood loss within 3 months prior to screening or have known hemoglobinopathy, hemolytic anemia, or sickle cell anemia, or any other traits of hemoglobin abnormalities known to interfere with the HbA1c measurement 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 had an organ transplant 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Insulin Glargine + Insulin Lispro<br>Participant-specific dose of Insulin Glargine will be administered subcutaneously (SC) once daily at bedtime for 26 weeks. Participant-specific dose of Insulin Lispro will be administered SC for preprandial (pre-meal) and supplemental doses for 26 weeks. | Drug: Insulin Glargine<br> <br> Drug: Insulin Lispro<br> <br> * Other names: Humalog;|
| Experimental: LY2605541 + Insulin Lispro<br>Participant-specific dose of LY2605541 will be administered SC once daily at bedtime for 26 weeks. Participant-specific dose of Insulin Lispro will be administered SC for preprandial and supplemental doses for 26 weeks. | Drug: LY2605541<br> <br> * Other names: Insulin Peglispro;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 |
| --- | --- | --- |
| Change From Baseline in 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 stratification factors (country, low-density lipoprotein cholesterol [LDL-C, <100 milligrams per deciliter (mg/dL) and ≥100 mg/dL], and number of insulin injections at baseline [1, 2, or ≥3]), visit, treatment, visit-by-treatment interaction, and baseline HbA1c. | Baseline, 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Hypoglycemia Rates (Adjusted for 30 Days) | 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 millimoles per liter [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 | 
| Percentage of Participants With Total Hypoglycemia Episodes | Hypoglycemic episodes are defined as events which 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, multiplied by 100. | Baseline through 26 weeks | 
| Nocturnal Hypoglycemia Rates (Adjusted for 30 Days) | Hypoglycemic episodes are defined as events which 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 | 
| Percentage of Participants With Nocturnal Hypoglycemia Episodes | Hypoglycemic episodes are defined as an event which 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, multiplied by 100. | Baseline through 26 weeks | 
| Body Weight Change From Baseline to 26 Weeks | 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], and number of insulin injections at baseline [1, 2, or ≥3]), treatment, visit, treatment-by-visit interaction, and baseline body weight as fixed effects, and participant as a random effect. | Baseline, 26 weeks | 
| Self-Monitored Blood Glucose (SMBG) 9-point Profiles at 26 Weeks | 9-point SMBG profiles were obtained over 2 nonconsecutive days within the week prior to Weeks 0, 4, 12, and 26. 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 stratification factors (baseline HbA1c [≤8.5% and >8.5%], country, LDL-C [<100 mg/dL and ≥100 mg/dL], and number of insulin injections at baseline [1, 2, or ≥3]), visit, treatment, visit-by-treatment interaction, and baseline BG values. | 26 weeks | 
| Percentage of Participants With HbA1c <7.0% and ≤6.5% at 26 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. | up to 26 weeks | 
| Percentage of Participants With HbA1c <7.0% Without Nocturnal Hypoglycemia at 26 Weeks | Hypoglycemic episodes are defined as an event which is 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 | 
| Basal, Bolus, and Total Insulin Dose by Weight at 26 Weeks | 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 a constrained Longitudinal Data Analysis (cLDA) model adjusting for indicator variables of each treatment group at each post-baseline visit and stratification variables (baseline HbA1c [≤8.5% and >8.5%], country, baseline LDL-C [<100 mg/dL and ≥100 mg/dL], and baseline number of insulin injections [1, 2, or ≥3]). | 26 weeks | 
| Fasting Serum Glucose (FSG) From Laboratory at 26 Weeks | 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], and number of insulin injections at baseline [1, 2, or ≥3]), treatment, visit, treatment-by-visit interaction, and baseline FSG. | 26 weeks | 
| Fasting Blood Glucose (FBG) (by SMBG) Intra-participant Variability at 26 Weeks | 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 the stratification factors (baseline HbA1c [≤8.5% and >8.5%], country, baseline LDL-C [<100 mg/dL and ≥100 mg/dL], and number of insulin injections at baseline [1, 2, or ≥3]), treatment, visit, treatment-by-visit interaction, and baseline FBG variability. | 26 weeks | 
| 0300-hour Blood Glucose to FBG Excursion at 26 Weeks | 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 stratification factors (baseline HbA1c [≤8.5% and >8.5%], country, baseline LDL-C [<100 mg/dL and ≥100 mg/dL], and number of insulin injections at baseline [1, 2, or ≥3]), treatment, visit, treatment-by-visit interaction, and baseline excursion. | 26 weeks | 
| HbA1c at 26 Weeks | 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 stratification factors (country, LDL-C [<100 mg/dL and ≥100 mg/dL], and number of insulin injections at baseline [1, 2, or ≥3]), treatment, visit, treatment, visit-by-treatment interaction, and baseline HbA1c. | 26 weeks | 
| Lipid Profile at 26 Weeks | 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], number of insulin injections at baseline [1, 2, or ≥3]), visit, treatment, visit-by-treatment interaction, and baseline value of corresponding lipid outcome variable. | 26 weeks | 
| Number of Participants With Change in Anti-LY2605541 Antibodies From Baseline to 26 Weeks | The number 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 | 
| Insulin Treatment Satisfaction Questionnaire (ITSQ) at 26 Weeks | 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, 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 factors (baseline HbA1c [≤8.5% and >8.5%], country, and baseline number of insulin injections [1, 2, or ≥3]) as fixed effects and baseline value of the ITSQ scores as a covariate. | up to 26 weeks | 
| Low Blood Sugar Survey (LBSS) at 26 Weeks | 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 including stratification factors (baseline HbA1c [≤8.5% and >8.5%], country, baseline number of insulin injections [1, 2, or ≥3]), visit, treatment, visit-by-treatment interaction, and baseline LBSS score. | 26 weeks | 
| EuroQoL-5D (EQ-5D) at 26 Weeks | 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 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 ANCOVA adjusting for treatment, stratification factors (baseline HbA1c [≤8.5% and >8.5%], country, and baseline number of insulin injections [1, 2, or ≥ 3]), and baseline EQ-5D score. | up to 26 weeks | 
| Rapid Assessment of Physical Activity (RAPA) at 26 Weeks | 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 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. | up to 26 weeks |