A Study in Participants With Type 2 Diabetes Mellitus (AWARD-2)

Study Overview
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Brief Summary
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The purpose of this study is to determine if LY2189265 is effective in reducing hemoglobin A1c (HbA1c) and safe, as compared to Insulin Glargine in participants with Type 2 Diabetes. Participants must also be taking metformin and glimepiride.

Detailed Description
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Rescue therapy refers to 1 of 2 types of additional therapy, each given for a different reason: any additional therapeutic intervention in participants who developed persistent, severe hyperglycemia despite full compliance with the assigned therapeutic regimen, or initiation of an alternative antihyperglycemic medication following study drug discontinuation. Participants who received rescue therapy were included in the analysis population, but only measurements obtained prior to the beginning of rescue therapy were included in specified efficacy analyses.

Official Title
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A Randomized, Open-Label, Parallel-Arm, Noninferiority Comparison of the Effects of Two Doses of LY2189265 and Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes on Stable Doses of Metformin and Glimepiride

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Insulin Glargine
* Drug: LY2189265
* Drug: Metformin
* Drug: Glimepiride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 Diabetes not well controlled on 1, 2, or 3 oral antidiabetic medications (at least one of them must be metformin and/or a sulfonylurea) Glycosylated hemoglobin (HbA1c) greater than or equal to 7 and less than or equal to 11 if taking 1 oral antidiabetic medication HbA1c greater than or equal to 7 and less than or equal to 10 if on 2 or 3 oral antidiabetic medications Accept treatment with metformin and glimepiride throughout the study, as per protocol Willing to inject subcutaneous medication once weekly for LY2189265 or once daily for Insulin Glargine. Stable weight for 3 months prior to screening Body mass index (BMI) between 23 and 45 kilograms per square meter (kg/m^2) Females of child bearing potential must test negative for pregnancy at screening by serum pregnancy test and be willing to use a reliable method of birth control during the study and for 1 month following the last dose of study drug Exclusion Criteria: Type 1 Diabetes HbA1c equal to or less than 6.5 at randomization Chronic insulin use Taking drugs to promote weight loss by prescription or over the counter Taking systemic steroids for greater than 14 days except for topical, eye, nasal, or inhaled History of Heart Failure New York Heart Classification III or IV, or acute myocardial infarction, or stroke within 2 months of screening Gastrointestinal (GI) problems such as diabetic gastroparesis or bariatric surgery (stomach stapling) or chronically taking drugs that directly affect GI motility Hepatitis or liver disease or ALT (alanine transaminase) greater than 3.0 of upper normal limit Acute or chronic pancreatitis of any form Renal disease (kidney) with a serum creatinine of greater than or equal to 1.5 milligrams per deciliter (mg/dL) for males and greater than or equal to 1.4 mg/dL for females, or a creatinine clearance of less than 60 milliliters per minute (ml/min) History (includes family) of type 2A or 2B Multiple Endocrine Neoplasia (MEN 2A or 2B) or medullary c-cell hyperplasia or thyroid cancer A serum calcitonin greater than or equal to 20 picograms per milliliter (pcg/ml) at screening Significant active autoimmune disease such as Lupus or Rheumatoid Arthritis History of or active malignancy except skin or in situ cervical or prostate cancer for within last 5 years Sickle cell, hemolytic anemia, or other hematological condition that may interfere with HbA1c testing Organ transplant except cornea Have enrolled in another clinical trial within the last 30 days Have previously signed an informed consent or participated in a LY2189265 study Have taken a glucagon-like peptide 1 (GLP-1) receptor agonist within the 3 months 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2189265 1.5 mg<br>LY2189265 (Dulaglutide): 1.5 milligrams (mg), subcutaneous (SC), once weekly for 78 weeks Metformin: at least 1500 milligrams per day (mg/day), oral, for 78 weeks Glimepiride: at least 4 mg/day, oral, for 78 weeks | Drug: LY2189265<br> <br> * Other names: Dulaglutide;Drug: Metformin<br> <br> Drug: Glimepiride<br> <br> |
| Experimental: LY2189265 0.75 mg<br>LY2189265 (Dulaglutide): 0.75 milligrams (mg), subcutaneous (SC), once weekly for 78 weeks Metformin: at least 1500 milligrams per day (mg/day), oral, for 78 weeks Glimepiride: at least 4 mg/day, oral, for 78 weeks | Drug: LY2189265<br> <br> * Other names: Dulaglutide;Drug: Metformin<br> <br> Drug: Glimepiride<br> <br> |
| Active Comparator: Insulin Glargine<br>Insulin Glargine: dose titration based on blood glucose measures, subcutaneous (SC), once daily for 78 weeks Metformin: at least 1500 milligrams per day (mg/day), oral, for 78 weeks Glimepiride: at least 4 mg/day, oral, for 78 weeks | Drug: Insulin Glargine<br> <br> Drug: Metformin<br> <br> Drug: Glimepiride<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 Weeks Endpoint in Glycosylated Hemoglobin (HbA1c) | Least Squares (LS) means were calculated using analysis of covariance (ANCOVA) with country and treatment as fixed effects and baseline HbA1c as a covariate. | Baseline, 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 26 Weeks and 78 Weeks Endpoint in Glycosylated Hemoglobin (HbA1c) | Least Squares (LS) means were calculated using analysis of covariance (ANCOVA) with country and treatment as fixed effects and baseline HbA1c as a covariate. | Baseline, 26 weeks, and 78 weeks | 
| Number of Participants Achieving Glycosylated Hemoglobin (HbA1c) Less Than 7% at 26, 52 and 78 Weeks | Number of participants achieving HbA1c levels less than 7.0% was analyzed with a logistic regression model with baseline, country, and treatment as factors included in the model. | 26, 52, and 78 weeks | 
| Number of Participants Achieving Glycosylated Hemoglobin (HbA1c) Less Than or Equal to 6.5% at 26, 52 and 78 Weeks | Number of participants achieving HbA1c levels less than or equal to 6.5% was analyzed with a logistic regression model with baseline, country, and treatment as factors included in the model. | 26, 52, and 78 weeks | 
| Change From Baseline to 26, 52 and 78 Weeks for Daily Mean Blood Glucose Values From the 8-point Self-monitored Blood Glucose (SMBG) Profiles | The self-monitored blood glucose (SMBG) data were collected at the following 8 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; and 3 AM or 5 hours after bedtime. Least Squares (LS) means of the mean of the 8 time points (Daily Mean) were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. | Baseline, 26, 52, and 78 weeks | 
| Change From Baseline to 52 and 78 Weeks in Updated Homeostasis Model Assessment of Beta-cell Function (HOMA2-%B) and Updated Homeostasis Model Assessment of Insulin Sensitivity (HOMA2-%S) | The homeostatic model assessment (HOMA) is a method used to quantify insulin resistance and beta (β)-cell function. HOMA2-B is a computer model that uses fasting plasma insulin and glucose concentrations to estimate steady state beta cell function (%B) as a percentage of a normal reference population (normal young adults). HOMA2-S is a computer model that uses fasting plasma insulin and glucose concentrations to estimate insulin sensitivity (%S), as percentages of a normal reference population (normal young adults). The normal reference population for both HOMA2-B and HOMA-2S were set at 100%. Least Squares (LS) means of change from baseline of C-peptide based HOMA2-%B and HOMA2-%S were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. | Baseline, 52, and 78 weeks | 
| Change From Baseline to 52 and 78 Weeks in Glucagon Concentration | Least Squares (LS) means of change from baseline were calculated using analysis of covariance (ANCOVA) with country and treatment as fixed effects and baseline as a covariate. | Baseline, 52, and 78 weeks | 
| Change From Baseline to 26, 52 and 78 Weeks for Body Weight | Least Squares (LS) means of change from baseline were calculated using analysis of covariance (ANCOVA) with country and treatment as fixed effects and baseline as a covariate. | Baseline, 26, 52, and 78 weeks | 
| Change From Baseline to 26, 52 and 78 Weeks for Body Mass Index | Body mass index (BMI) is an estimate of body fat based on body weight divided by height squared. Least Squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. | Baseline, 26, 52, and 78 weeks | 
| Change From Baseline to 26, 52 and 78 Weeks in the EuroQol 5 Dimension | The European Quality of Life - 5 dimensions (EQ-5D) questionnaire is a generic, multidimensional, health-related, quality-of-life instrument. It consists of 2 parts: the first part assesses 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) that have 3 possible levels of response (no problem, some problem, or extreme problem). These dimensions are converted into a weighted health-state Index Score. The EQ-5D United Kingdom (UK) score ranges from -0.59 to 1.0, where a score of 1.0 indicates perfect health and negative values are valued as worse than dead. The second part of the questionnaire consists of a 100-mm visual analog scale (VAS) on which the participants rated their perceived health state on that day from 0 (worst imaginable health state) to 100 (best imaginable health). Least Squares (LS) means of change from baseline were calculated using analysis of covariance (ANCOVA) and adjusted by treatment, country, and baseline. | Baseline, 26, 52, and 78 weeks | 
| Change From Baseline to 26, 52 and 78 Weeks in the Impact of Weight on Activities of Daily Living | The Impact of Weight on Activities of Daily Living questionnaire (renamed the Ability to Perform Physical Activities of Daily Living Questionnaire [APPADL]) contains 7 items that assess how difficult it is for participants to engage in certain activities considered to be integral to normal daily life, such as walking, standing and climbing stairs. Items are scored on a 5-point numeric rating scale where 5 = not at all difficult and 1 = unable to do. The individual scores from all 7 items are summed and a single total score is calculated and may range between 7 and 35. A higher score indicates better ability to perform activities of daily living. Least Squares (LS) means of change from baseline were calculated using analysis of covariance (ANCOVA) with country and treatment as fixed effects and baseline as a covariate. | Baseline, 26, 52, and 78 weeks | 
| Change From Baseline to 26, 52 and 78 Weeks in the Impact of Weight on Self-Perception | The Impact of Weight on Self-Perception (IW-SP) questionnaire contains 3 items that assess how often the participants' body weight affects how happy they are with their appearance and how often they feel self-conscious when out in public. Items are scored on a 5-point numeric rating scale where 5 = never and 1 = always. A single total score is calculated by summing the scores for all 3 items. Total score ranges between 3 and 15, where a higher score is indicative of better self-perception. Least Squares (LS) means of change from baseline were calculated using analysis of covariance (ANCOVA) with country and treatment as fixed effects and baseline as a covariate. | Baseline, 26, 52, and 78 weeks | 
| Change From Baseline to 26, 52 and 78 Weeks in the Low Blood Sugar Survey | The Low Blood Sugar Survey (LBSS) contains 33 items comprised of 2 subscales (behavior and worry), each of which is rated on a 5-point numeric rating scale from 0 (never) to 4 (almost always). It captures behavioral changes associated with the concerns and experiences of hypoglycemia and the degree to which participants are worried about certain aspects associated with hypoglycemia during the previous 4 weeks. The behavior (or avoidance) subscale has 15 items, and the worry (or affect) subscale has 18 items. Subscale scores are calculated by summing participant responses to items (behavior range 0-60; worry range 0-72). A total score is calculated as the sum of both subscales (range 0-132). Higher scores indicate greater negative impact on subscales and total score. Least Squares (LS) means of change from baseline were calculated using analysis of covariance (ANCOVA) with country and treatment as fixed effects and baseline as a covariate. | Baseline, 26, 52, and 78 weeks | 
| Number of Participants With Treatment Emergent Adverse Events at 26, 52 and 78 Weeks | A treatment-emergent adverse event (TEAE) was defined as an event that first occurs or worsens (increases in severity) after baseline regardless of causality or severity. The number of participants with one or more TEAE is summarized cumulatively at 26, 52, and 78 weeks. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | 26, 52, and 78 weeks | 
| Number of Self-reported Hypoglycemic Events at 26, 52 and 78 Weeks | Hypoglycemic events (HE) were classified as severe (defined as episodes requiring the assistance of another person to actively administer resuscitative actions), documented symptomatic (defined as any time a participant feels that he/she is experiencing symptoms and/or signs associated with hypoglycemia, and has a plasma glucose level of =<3.9 mmol/L), asymptomatic (defined as events not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose of =<3.9 mmol/L), nocturnal (defined as any hypoglycemic event that occurred between bedtime and waking), or probable symptomatic (defined as events during which symptoms of hypoglycemia were not accompanied by a plasma glucose determination). The number of self-reported hypoglycemic events is summarized cumulatively at 26, 52, and 78 weeks. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through 26, 52, and 78 weeks | 
| Rate of Self-reported Hypoglycemic Events at 26, 52 and 78 Weeks | Hypoglycemic events (HE) were classified as severe (defined as episodes requiring the assistance of another person to actively administer resuscitative actions), documented symptomatic (defined as any time a participant feels that he/she is experiencing symptoms and/or signs associated with hypoglycemia, and has a plasma glucose level of =<3.9 mmol/L), asymptomatic (defined as events not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose of =<3.9 mmol/L), nocturnal (defined as any hypoglycemic event that occurred between bedtime and waking), or probable symptomatic (defined as events during which symptoms of hypoglycemia were not accompanied by a plasma glucose determination). The 1-year adjusted rate of hypoglycemic events is summarized cumulatively at 26, 52, and 78 weeks. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through 26, 52, and 78 weeks | 
| Number of Participants Requiring Additional Intervention Due to Hyperglycemia at 26, 52 and 78 Weeks | Additional intervention was defined as any additional therapeutic intervention in participants who developed persistent, severe hyperglycemia despite full compliance with the assigned therapeutic regimen, or initiation of an alternative antihyperglycemic medication following study drug discontinuation. The number of participants requiring additional intervention due to hyperglycemia is summarized cumulatively at 26, 52, and 78 weeks. | 26, 52, and 78 weeks | 
| Change From Baseline to 26, 52 and 78 Weeks on Pancreatic Enzymes | Amylase (total and pancreas-derived) and lipase concentrations were measured. | Baseline, 26, 52, and 78 weeks | 
| Number of Participants With Adjudicated Pancreatitis at 26, 52 and 78 Weeks | The number of participants with pancreatitis confirmed by adjudication is summarized cumulatively at 26, 52, and 78 weeks. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through 26, 52, and 78 weeks | 
| Change From Baseline to 26, 52 and 78 Weeks on Serum Calcitonin |  | Baseline, 26, 52, and 78 weeks | 
| Number of Participants With Adjudicated Cardiovascular Events at 26, 52 and 78 Weeks | Information on cardiovascular (CV) risk factors was collected at baseline. Data on any new CV event was prospectively collected using a CV event electronic case report form. At prespecified visits, participants were asked about any new CV event. Deaths and nonfatal cardiovascular adverse events (AEs) were adjudicated by a committee of physicians with cardiology expertise external to the Sponsor. The nonfatal cardiovascular AEs to be adjudicated include myocardial infarction, hospitalization for unstable angina, hospitalization for heart failure, coronary interventions (such as coronary artery bypass graft or percutaneous coronary intervention), and cerebrovascular events including cerebrovascular accident (stroke) and transient ischemic attack. The number of participants with adjudicated CV events is summarized cumulatively at 26, 52, and 78 weeks. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through 26, 52, and 78 weeks | 
| Change in Baseline to 26, 52 and 78 Weeks on Pulse Rate | Sitting pulse rate was measured. Least Squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. | Baseline, 26, 52, and 78 weeks | 
| Change From Baseline to 26, 52, and 78 Weeks on Blood Pressure | Sitting systolic blood pressure (SBP) and sitting diastolic blood pressure (DBP) were measured. Least Squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. | Baseline, 26, 52, and 78 weeks | 
| Change From Baseline to 26, 52 and 78 Weeks on Electrocardiogram Parameters, Heart Rate | Electrocardiogram (ECG) heart rate was measured. Least Squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. | Baseline, 26, 52, and 78 weeks | 
| Change From Baseline to 26, 52 and 78 Weeks on Electrocardiogram Parameters, Fridericia Corrected QT (QTcF) Interval and PR Interval | The QT interval is a measure of the time between the start of the Q wave and the end of the T wave and was calculated from electrocardiogram (ECG) data using Fridericia's formula: QTc = QT/RR^0.33. Corrected QT (QTc) is the QT interval corrected for heart rate and RR, which is the interval between two R waves. PR is the interval between the P wave and the QRS complex. Least Squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. | Baseline, 26, 52, and 78 weeks | 
| Number of Participants With LY2189265 Antibodies at 26, 52, 78 Weeks and 4 Weeks After Last Dose of Study Drug (83 Weeks Maximum) | LY2189265 (Dulaglutide) anti-drug antibodies (ADA) were assessed at baseline, 26, 52, and 78 weeks, and at the safety follow-up visit 30 days after study drug discontinuation (83 weeks). The number of participants with initial postbaseline detection of treatment emergent (defined as a 4-fold increase in the ADA titer from baseline) LY2189265 ADA at each time point were summarized. | Baseline, 26, 52, 78, and 83 weeks |