A Study of LY2605541 in Participants With Type 2 Diabetes Mellitus

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to compare LY2605541 and insulin glargine using the following measures after participants have been treated for 26 weeks: Change in participants' overall blood sugar control The rate of night time low blood sugar episodes The number of participants that reach blood sugar targets without low blood sugar episodes at night The rate of low blood sugar episodes reported over a 24-hour period

Official Title
-----------------
A Comparison of LY2605541 Versus Insulin Glargine Alone or in Combination With Pre-study Oral Antihyperglycemic Medications in Patients With Type 2 Diabetes Mellitus Previously Treated With Basal Insulin: An Open-Label, Randomized Study The IMAGINE 5 Study

Conditions
-----------------
Diabetes Mellitus, Type 2

Intervention / Treatment
-----------------
* Drug: LY2605541
* Drug: Insulin glargine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Have had type 2 diabetes mellitus for at least 1 year Have been receiving basal insulin (neutral protamine Hagedorn [NPH], detemir, or glargine) and a stable dose of 0 to 3 oral antihyperglycemic medications (OAMs) used as specified in the local prescribing information for at least 90 days prior to screening. At least 1 of the OAMs must be dosed at, or above, half the maximum daily dose allowed by local regulations or at the maximally tolerated dose Have a hemoglobin A1c (HbA1c) less than or equal to 9.0% at screening Have a body mass index (BMI) less than or equal to 45.0 kilograms per square meter (kg/m^2) Women of childbearing potential who are not breastfeeding, have a negative pregnancy test at screening and randomization, do not plan to become pregnant during the study, and have practiced reliable birth control for at least 6 weeks prior to screening and will continue to do so during the study and until 2 weeks after the last dose of study drug Exclusion Criteria: Have routinely used insulin glargine twice daily in the 90 days prior to the study or have used routine, mealtime insulin therapy (outside of pregnancy) anytime in the past 6 months, except for short-term treatment up to a maximum of 4 continuous weeks Have used rosiglitazone, pramlintide, glucagon-like peptide 1 (GLP-1) receptor agonist concurrently or within 90 days prior to screening For participants on OAMs: have any restrictions for cardiac, renal, and hepatic diseases in the local product regulations Are taking, or have taken within the 90 days preceding screening, prescription or over-the-counter medications to promote weight loss Have had any episodes of severe hypoglycemia within 6 months prior to screening Have had 1 or more episodes of diabetic ketoacidosis or hyperosmolar state/coma in the 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 or equal to 2 milligrams per deciliter (mg/dL) (177 micromoles per liter [µmol/L]) 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 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 measurement of HbA1c Have active or untreated cancer, have been in remission from clinically significant cancer(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 Are receiving chronic (lasting longer than 14 consecutive days) systemic glucocorticoid therapy (excluding topical, intranasal, intraocular, and inhaled preparations) or have received such therapy within the 8 weeks immediately preceding screening Have fasting triglycerides greater than 400 mg/dL (4.5 millimoles per liter [mmol/L]) at screening Have an irregular sleep/wake cycle (for example, participants who sleep during the day and work during the night) in the investigator's opinion Lipid-lowering medication: Are using or have used any of the following: niacin preparations as a lipid-lowering medication and/or bile acid sequestrants within 90 days prior to screening or lipid-lowering medication at a dose that has not been stable for at least 90 days prior to screening

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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<br>Administered by subcutaneous (SQ) injection once daily at bedtime. Initial dose based on dose of prestudy basal insulin and adjusted based on fasting blood glucose (FBG). LY2605541 will be given alone or in combination with up to 3 pre-study oral antihyperglycemic medications (OAMs) whose use is not excluded in combination with insulin. Treatment may last up to 52 weeks. | Drug: LY2605541<br> <br> * Other names: Insulin peglispro;|
| Active Comparator: Insulin glargine<br>Administered by SQ injection once daily at bedtime. Initial dose based on dose of prestudy basal insulin and adjusted based on FBG. Insulin glargine will be used alone or in combination with up to 3 pre-study OAMs whose use is not excluded in combination with insulin. Treatment may last up to 52 weeks. | Drug: Insulin glargine<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 26-week Endpoint in 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 stratification factors (country, baseline low-density lipoprotein cholesterol [LDL-C, <100 milligrams per deciliter (mg/dL) and ≥100 mg/dL], and sulfonylurea (SU) or meglitinide use), visit, treatment, visit-by-treatment interaction, and baseline HbA1c. | Baseline, 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 52 Weeks in HbA1c | LS means were calculated using MMRM adjusting for stratification factors (country, baseline LDL-C [<100 mg/dL and ≥100 mg/dL], and SU or meglitinide use), visit, treatment, visit-by-treatment interaction, and baseline HbA1c. | Baseline, 52 weeks | 
| Rate of Total and Nocturnal Hypoglycemia Events (Adjusted by 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]). A nocturnal hypoglycemic event occurred between bedtime and waking. Group mean rates of total and nocturnal hypoglycemia (per 30 days) are presented and were calculated from negative binomial regression models (number of episodes = treatment + baseline hypoglycemia rate + baseline SU or meglitinide use, 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 | 
| Percentage of Participants That Have Total and Nocturnal Hypoglycemic Events | 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). A nocturnal hypoglycemic event 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 through 26 weeks and 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. | 26 and 52 weeks | 
| Percentage of Participants With HbA1c <7.0% and Without Nocturnal Hypoglycemia | 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. 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. | 26 and 52 weeks | 
| Fasting Serum Glucose (FSG) (by Laboratory) | LS means were calculated using MMRM adjusting for stratification factors (country, baseline HbA1c [≤8.0% and >8.0%], baseline LDL-C [<100 mg/dL and ≥100 mg/dL], and SU or meglitinide use), visit, treatment, visit-by-treatment interaction, and baseline FSG. | 26 and 52 weeks | 
| Fasting Blood Glucose (FBG) (by Self Monitoring) | LS means were calculated using MMRM adjusting for stratification factors (country, baseline HbA1c [≤8.0% and >8.0%], baseline LDL-C [<100 mg/dL and ≥100 mg/dL], and SU or meglitinide use), visit, treatment, visit-by-treatment interaction, and baseline FBG. | 26 and 52 weeks | 
| Intra-participant Variability in Fasting Blood Glucose (FBG) | 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 (country, baseline HbA1c [≤8.5% and >8.5%], baseline LDL-C [<100 mg/dL and ≥100 mg/dL], and SU or meglitinide use), treatment, visit, treatment-by-visit interaction, and baseline FBG intra-participant variability. | 26 and 52 weeks | 
| 6-point Self-monitored Blood Glucose (SMBG) | SMBG measurements were taken at 6 time points (pre-morning meal [fasting], pre-midday meal, pre-evening meal, bedtime, approximately 0300 hours, and pre-morning meal [fasting] on the next day) and were performed on 2 non-consecutive days in the week prior to next office visit. 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 SU or meglitinide use), visit, treatment, visit-by-treatment interaction, and baseline BG values. | 26 and 52 weeks | 
| HbA1c | LS means were calculated using MMRM adjusting for stratification factors (country, baseline LDL-C [<100 mg/dL and ≥100 mg/dL], and SU or meglitinide use), visit, treatment, visit-by-treatment interaction, and baseline HbA1c. | 26 and 52 weeks | 
| Insulin Dose Per Kilogram of Body Weight | Daily basal insulin dose is presented. LS means were calculated using MMRM adjusting for the stratification factors (country, baseline HbA1c [≤8.5% and >8.5%], baseline LDL-C [<100 mg/dL and ≥100 mg/dL], and SU or meglitinide use), treatment, visit, treatment-by-visit interaction, and baseline insulin dose. | 26 and 52 weeks | 
| Number of Insulin Dose Adjustments to Steady-state | The number of dose adjustments required to reach a steady dose is presented. LS means were calculated from negative binomial regression models, where the number of dose adjustments = treatment + stratification factors (country, baseline HbA1c [≤8.5% and >8.5%], baseline LDL-C [<100 mg/dL and ≥100 mg/dL], and SU or meglitinide use). | Baseline through 26 weeks | 
| European Quality of Life - 5 Dimension (EuroQol-5D) Score | The EuroQol-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 an analysis of covariance (ANCOVA) model adjusting for treatment, stratification factors (country, baseline HbA1c [≤8.5% and >8.5%], and SU or meglitinide use), and baseline EuroQol-5D score. | 26 weeks | 
| Insulin Treatment Satisfaction Questionnaire (ITSQ) Score | 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 a higher score indicate better treatment satisfaction. LS means were calculated using ANCOVA with treatment and stratification factors (country, baseline HbA1c [≤8.5% and >8.5%], and SU or meglitinide use) as fixed effects and baseline value of the ITSQ score as a covariate. | 26 weeks | 
| Adult Low Blood Sugar Survey (LBSS) Score | 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 ANCOVA with treatment and stratification factors (country, baseline HbA1c [≤8.5% and >8.5%], and SU or meglitinide use) as fixed effects and baseline value of the LBSS score as a covariate. | 26 weeks | 
| Change From Baseline in Body Weight | LS means were calculated using MMRM adjusting for stratification factors (country, baseline HbA1c [≤8.5% and >8.5%], LDL-C [<100 mg/dL and ≥100 mg/dL, except for the LDL-C outcome variable], and SU or meglitinide use), visit, treatment, visit-by-treatment interaction, and baseline body weight. | Baseline, 26 weeks, 52 weeks | 
| Change From Baseline in 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 (country, baseline HbA1c [≤8.5% and >8.5%], LDL-C [<100 mg/dL and ≥100 mg/dL, except for the LDL-C outcome variable], and SU or meglitinide use), visit, treatment, visit-by-treatment interaction, and baseline value of corresponding lipid outcome variable. | Baseline, 26 weeks, 52 weeks | 
| Number of Participants With Change in Anti-LY2605541 Antibodies | 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 52 weeks |