A Study in Patients 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 sugar control on LY2605541 with insulin glargine after 52 weeks of treatment. To compare the rate of night time 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 after 52 weeks of treatment

Official Title
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A Comparison of LY2605541 Versus Insulin Glargine as Basal Insulin Treatment in Combination With Oral Anti-Hyperglycemia Medications in Insulin-Naive Patients With Type 2 Diabetes Mellitus: A Double-Blind, Randomized Study

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Glargine
* Drug: LY2605541


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have type 2 diabetes mellitus, not treated with insulin, for at least 1 year prior to the study Have been receiving at least 2 OAMs for at least 3 months before entering the study Have a hemoglobin A1c (HbA1c) value between 7.0% and 11.0%, inclusive, at screening Are capable of and willing to inject insulin with a vial and syringe and perform self blood glucose monitoring Women of childbearing potential only: are not breastfeeding, have a negative pregnancy test at the time of screening and randomization, intend to not become pregnant during the trial, have practiced a reliable method of birth control for at least 6 weeks prior to screening, and agree to use a reliable method of birth control during the study and until 2 weeks following the last dose of study drug Exclusion Criteria: Have used insulin therapy (outside of pregnancy) anytime in the past 2 years, except for short-term treatment of acute conditions, and up to a maximum of 4 continuous weeks Use of rosiglitazone, pramlintide, or glucagon-like peptide 1 (GLP-1) receptor agonist (for example, exenatide, exenatide once weekly, or liraglutide) concurrently or within 3 months prior to screening Are currently taking, or have taken within the 3 months preceding screening, 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 ketoacidosis or hyperosmolar state/coma in the 6 months prior to the study Have cardiac disease with functional status that is New York Heart Association Class III or IV (per New York Heart Association [NYHA] Cardiac Disease Classification) Have a history of renal transplantation, or are currently receiving renal dialysis or have serum creatinine greater or equal than 2 milligrams per deciliter (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 at screening 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 malignancy or have been in remission from clinically significant malignancy for less than 5 years Have fasting or non-fasting triglycerides greater than 400 mg/dL (greater than 4.5 millimoles per liter [mmol/L]) at screening Are using lipid-lowering medication at a dose that has not been stable for 90 days prior to screening Are using niacin preparations as a lipid lowering medication and 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2605541<br>LY2605541 titrated based on blood glucose readings, administered subcutaneously (SC), once daily in combination with at least 2 pre-study oral antihyperglycemic medications (OAMs) prescribed by the personal physician, for 52 or 78 weeks | Drug: LY2605541<br> <br> |
| Active Comparator: Glargine<br>Glargine titrated based on blood glucose readings, administered SC, once daily in combination with at least 2 pre-study OAMs prescribed by the personal physician, for 52 or 78 weeks | Drug: Glargine<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 52 Week Endpoint in Hemoglobin A1c (HbA1c) | 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) with baseline HbA1c measurement, stratification factors (country, low density lipoprotein-cholesterol [LDL-C, < 100 milligrams per deciliter {mg/dL} and ≥ 100 mg/dL] and sulfonylurea [SU]/meglitinide use), visit, treatment, and visit-by-treatment interaction as fixed effects. | Baseline, 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Total and Nocturnal Hypoglycemia Events | Hypoglycemia is a condition that occurs when a person's blood glucose level is lower than the normal range (less than or equal to 70 milligrams per deciliter [mg/dL] or less than 3.9 millimoles per liter [mmol/L]). Total hypoglycemia refers to an event that meets the criteria for documented symptomatic hypoglycemia, asymptomatic hypoglycemia, probable symptomatic hypoglycemia, unspecified hypoglycemia, or severe hypoglycemia. Nocturnal hypoglycemia refers to any total hypoglycemic event that occurs between bedtime and waking. Group mean (listed as LS means below) rates of total and nocturnal hypoglycemia were calculated using a negative binomial regression model (number of episodes = treatment + SU/meglitinide use + baseline hypoglycemia event rate, with log [exposure per 30 days] as the offset variable in the model). | Baseline to 52 weeks | 
| Percentage of Participants With Hemoglobin A1c Equal 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. | 52 weeks | 
| Fasting Serum Glucose (By Laboratory Measurement) | LS means were calculated using a MMRM with baseline fasting serum glucose measurement, stratification factors (country, HbA1c, LDL-C [< 100 mg/dL and ≥ 100 mg/dL], and SU/meglitinide use), treatment, visit, and treatment-by-visit interaction as fixed effects. | 52 weeks | 
| Fasting Blood Glucose (By Participant Self-monitored Blood Glucose Readings) | LS means were calculated using a MMRM with baseline fasting blood glucose measurement, stratification factors (country, HbA1c, LDL-C [< 100 mg/dL and ≥ 100 mg/dL], and SU/meglitinide use), treatment, visit, and treatment-by-visit interaction as fixed effects. | 52 weeks | 
| 6 Point Self-monitored Blood Glucose (SMBG) | Six-point SMBG profiles were obtained at pre-morning meal (fasting), pre-midday meal (lunch), pre-evening meal (dinner), bedtime, approximately 0300 hours, and pre-morning meal (fasting) the next day. Six-point SMBG profiles were obtained over 2 nonconsecutive days within the week prior to the next office visit. LS means were calculated using a MMRM with baseline blood glucose measurement, stratification factors (country, HbA1c, LDL-C [< 100 mg/dL and ≥ 100 mg/dL], and SU/meglitinide use), treatment, visit, and treatment-by-visit interaction as fixed effects. | 52 weeks | 
| Change From Baseline to 52 Weeks in Body Weight | LS means were calculated using a MMRM with baseline body weight measurement, stratification factors (country, HbA1c, LDL-C [< 100 mg/dL and ≥ 100 mg/dL], and SU/meglitinide use), treatment, visit, and treatment-by-visit interaction as fixed effects. | Baseline, 52 weeks | 
| Hemoglobin A1c | HbA1c is a test that measures a person's average blood glucose level over the past 2 to 3 months. LS means were calculated using a MMRM with baseline HbA1C measurement, stratification factors (country, HbA1c, LDL-C [< 100 mg/dL and ≥ 100 mg/dL], and SU/meglitinide use), treatment, visit, and treatment-by-visit interaction as fixed effects. | 52 weeks | 
| Insulin Dose Per Body Weight | LS means were calculated using a MMRM with baseline insulin dose measurement, stratification factors (country, HbA1c, LDL-C [< 100 mg/dL and ≥ 100 mg/dL], and SU/meglitinide use), treatment, visit, and treatment-by-visit interaction as fixed effects. | 52 weeks | 
| Number of Insulin Dose Adjustments to Steady-State | Insulin doses were adjusted according to an algorithm (adapted from Riddle et al. 2003) during the first 26 weeks of the study and thereafter according to investigator judgment. Steady-state was defined as the first local maximum dose (maximum of moving 4-week interval) of LY2605541 or glargine within the window of +/- 2 weeks. The number of dose adjustments to steady-state was the total number of dose changes until steady-state was reached. LS means were calculated using a MMRM with baseline insulin dose measurement, stratification factors (country, HbA1c, LDL-C [< 100 mg/dL and ≥ 100 mg/dL], and SU/meglitinide use), treatment, visit, and treatment-by-visit interaction as fixed effects. | Baseline to 52 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 to 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 a MMRM with baseline stratification factors (country, HbA1c, and SU/meglitinide use), treatment, visit, and treatment-by-visit interaction as fixed effects. | 52 weeks | 
| Insulin Treatment Satisfaction Questionnaire | The Insulin Treatment Satisfaction Questionnaire (ITSQ) is a validated instrument containing 22 items that assess treatment satisfaction for participants with diabetes who are receiving 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 total score on a scale of 0 to 100, where higher scores indicate better treatment satisfaction. LS means were calculated using a MMRM with stratification factors (country, HbA1c, and SU/meglitinide use), treatment, visit, and treatment-by-visit interaction as fixed effects. | Up to 52 weeks | 
| Adult Low Blood Sugar Survey | The adult Low Blood Sugar Survey (LBSS) is a validated, participant-reported 33-item questionnaire with items rated on a 5-point Likert scale, where 0 = never and 4 = always. The LBSS measures behaviors to avoid hypoglycemia and its negative consequences (15 items) and worries about hypoglycemia and its negative consequences (18 items). Total score is the sum of all items (range of 0 to 132). Higher total scores reflect greater fear of hypoglycemia. LS means were calculated using an analysis of covariance model (ANCOVA) with baseline LBSS score, stratification factors (country, HbA1c, and SU/meglitinide use), and treatment as fixed effects. | Up to 52 weeks | 
| Change From Baseline to 52 Weeks in Triglycerides, Low Density Lipoprotein Cholesterol (LDL-C), and High Density Lipoprotein Cholesterol (HDL-C) | LS means were calculated using a MMRM with baseline lipid measurement, stratification factors (country, HbA1c, LDL-C [< 100 mg/dL and ≥ 100 mg/dL], and SU/meglitinide use), treatment, visit, and treatment-by-visit interaction as fixed effects. | Baseline, 52 weeks | 
| Percentage of Participants With Equal or Above 2-, and 3-fold Upper Limits of Normal (ULN) for Total Bilirubin |  | Up to 52 weeks | 
| Overall Treatment-Emergent Anti-LY2065541 Antibody Response (TEAR) | The percentage of participants with a TEAR is summarized. TEAR is defined as a change in the anti-LY2605541 antibody level from undetectable at baseline to detectable at baseline, or, for those participants with detectable antibodies at baseline, change to a value with at least a 130% relative increase from baseline. Overall TEAR is defined as one or more TEAR during the specified period. | Baseline to 78 weeks | 
| Intra-participant Variability of the Fasting Blood Glucose (FBG) | Intra-participant variability of FBG, which was measured by SMBG, was assessed by the standard deviation of the FBG measurement at the Week 52 visit. LS means were calculated using a MMRM with baseline fasting blood glucose measurement, stratification factors (country, HbA1c, LDL-C [< 100 mg/dL and ≥ 100 mg/dL], and SU/meglitinide use), treatment, visit, and treatment-by-visit interaction as fixed effects. | 52 weeks | 
| Percentage of Participants With Total and Nocturnal Hypoglycemic Events | A hypoglycemic event is defined by a blood glucose value ≤70 mg/dL (3.9mmol/L). Total hypoglycemic events include documented symptomatic hypoglycemia, asymptomatic hypoglycemia, probable symptomatic hypoglycemia, unspecified hypoglycemia, or severe hypoglycemia. Nocturnal hypoglycemic events refer to any total hypoglycemic event that occurs between bedtime and waking. The percentage of participants was calculated by dividing the number of participants with hypoglycemic or nocturnal hypoglycemic events by the total number of participants analyzed, multiplied by 100. | Baseline to 52 weeks | 
| Percentage of Participants With HbA1C Equal or Less Than 6.5% and Less Than 7.0 % and Without Nocturnal Hypoglycemia | The percentage of participants with HbA1C ≤ 6.5% or < 7.0% without nocturnal hypoglycemia is presented. Percentage was calculated by dividing the number of participants with the indicated HbA1c values over the total number of participants and multiplying by 100. | Up to 52 weeks | 
| Percentage of Participants With Equal or Above 2- and 3-fold ULN for Alanine Transaminase/Serum Glutamic Pyruvic Transaminase (ALT/SGPT) and Aspartate Transaminase/Serum Glutamic Oxaloacetic Transaminase (AST/SGOT) | The percentage of participants was calculated by dividing the number of participants equal or above 2- or 3-fold ULN for ALT/SGPT or AST/SGOT by the total number of participants analyzed, multiplied by 100. | Up to 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes mellitus, type 2 diabetes mellitus, insulin naive, insulin treatment