A Study in Participants With Type 2 Diabetes Mellitus (AWARD-4)

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy and safety of LY2189265 in comparison to Insulin Glargine, both in combination with Insulin Lispro (plus or minus Metformin), in participants with Type 2 Diabetes treated with 1 or 2 injections of insulin.

Detailed Description
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The term rescue therapy in this trial was defined as therapy for participants who met criteria for persistent severe hyperglycemia and therapy for participants who required new intervention for any other reason. The latter included participants who discontinued study drug due to adverse events, participant decision, or any other reason. For efficacy analyses, participants who received rescue medication were included in the analysis population, but only measurements obtained prior to taking rescue therapy were included in the efficacy analysis. For safety analyses, with the exception of hypoglycemia, all measurements including those obtained after taking rescue therapy were included in the analysis.

Official Title
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The Impact of LY2189265 Versus Insulin Glargine in Combination With Insulin Lispro for the Treatment to Target of Type 2 Diabetes Mellitus (AWARD-4: Assessment of Weekly AdministRation of LY2189265 in Diabetes - 4)

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Insulin Glargine
* Drug: LY2189265
* Drug: Insulin Lispro


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes Currently using insulin for at least 3 months with a conventional insulin regimen with or without oral medications Glycosylated hemoglobin (HbA1c) greater than or equal to 7% and less than or equal to 11% Willing to inject subcutaneous medication Willing to monitor blood glucose levels and adjust insulin dose Willing to maintain a study diary Body mass index (BMI) between 23 and 45 kilograms per square meter (kg/m^2) Stable weight for 3 months prior to screening Females of child bearing potential must test negative for pregnancy at screening 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 Previous therapy with glucagon-like peptide 1 (GLP-1) agonists within 3 months prior to screening 1 or more episodes of ketoacidosis within 6 months prior to screening Have been treated with prescription or over the counter medication to promote weight loss within 3 months prior to screening Estimated glomerular filtration rate (eGFR) less than or equal to 30 milliliters per minute per 1.73 square meters (mL/min/1.73 m^2) at screening Taking steroids for greater than 14 days except for topical, eye, nasal, or inhaled History of heart failure, New York Heart Classification III or IV within 2 months prior to screening Gastrointestinal (GI) problems such as diabetic gastroparesis or bariatric surgery (stomach stapling) or chronically taking medications that directly affect GI motility Acute or chronic hepatitis or pancreatitis Self or family history of 2A or type 2B multiple endocrine neoplasia or medullary C-Cell hyperplasia Serum calcitonin greater than or equal to 20 picograms per milliliter (pcg/mL) at screening Organ transplant except cornea Significant active autoimmune disease such as Lupus or Rheumatoid Arthritis History of or active malignancy except skin or in situ cervical or prostate cancer within the last 5 years Known drug or alcohol abuse Have enrolled in another clinical trial within the last 30 days Have previously signed an informed consent or participated in a LY2189265 study

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: 1.5 mg LY2189265<br>LY2189265 (Dulaglutide): 1.5 milligrams (mg), subcutaneous (SC), once weekly for 52 weeks Insulin Lispro: dose titration based on blood glucose measures, subcutaneous (SC), thrice daily (after each meal) for 52 weeks | Drug: LY2189265<br> <br> * Other names: Dulaglutide;Drug: Insulin Lispro<br> <br> |
| Experimental: 0.75 mg LY2189265<br>LY2189265 (Dulaglutide): 0.75 milligrams (mg), subcutaneous (SC), once weekly for 52 weeks Insulin Lispro: dose titration based on blood glucose measures, subcutaneous (SC), thrice daily (after each meal) for 52 weeks | Drug: LY2189265<br> <br> * Other names: Dulaglutide;Drug: Insulin Lispro<br> <br> |
| Active Comparator: Insulin Glargine<br>Insulin Glargine: dose titration based on blood glucose measures, subcutaneous (SC), once daily for 52 weeks Insulin Lispro: dose titration based on blood glucose measures, subcutaneous (SC), thrice daily (after each meal) for 52 weeks | Drug: Insulin Glargine<br> <br> Drug: Insulin Lispro<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 26-week Endpoint in Glycosylated Hemoglobin (HbA1c) | Least Squares (LS) means of change from baseline were calculated using analysis of covariance (ANCOVA) adjusted by treatment, country, baseline metformin, and baseline HbA1c. | Baseline, 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 52-week Endpoint in Glycosylated Hemoglobin (HbA1c) | Least Squares (LS) means of change from baseline were calculated using analysis of covariance (ANCOVA) adjusted by treatment, country, baseline metformin, and baseline HbA1c. | Baseline, 52 weeks | 
| Percentage of Participants Attaining Glycosylated Hemoglobin (HbA1c) Less Than 7% and Less Than or Equal to 6.5% at Weeks 26 and 52 | The percentage of participants achieving HbA1c level less than 7.0% and less than or equal to 6.5% was analyzed with a repeated logistic regression model (generalized estimating equation model) with baseline HbA1c, baseline metformin, country, and treatment as factors included in the model. | 26 weeks and 52 weeks | 
| Change From Baseline to 26 and 52 Weeks in the Percentage of Participants Achieving Glycosylated Hemoglobin (HbA1c) Less Than 7% Without Nocturnal or Severe Hypoglycemia | The percentage of participants achieving HbA1c less than 7.0% without nocturnal (defined as any hypoglycemic event that occurred between bedtime and waking) or severe (episodes requiring the assistance of another person to actively administer resuscitative actions) hypoglycemia was analyzed with a repeated logistic regression model (generalized estimating equation model) with baseline HbA1c, baseline metformin, country, and treatment as factors included in the model. | Baseline, 26 weeks, and 52 weeks | 
| Change From Baseline to 26 and 52 Weeks in Blood Glucose Values From the 8-point Self-monitored Plasma Glucose (SMPG) Profiles | The self-monitored plasma glucose (SMPG) 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 3AM or 5 hours after bedtime. The mean of the 8 time points (Daily Mean) was also calculated. Least Squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, metformin, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. | Baseline, 26 weeks, and 52 weeks | 
| Change From Baseline to 26 and 52 Weeks in Fasting Serum Glucose | Fasting serum glucose was measured by the central laboratory. Least Squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, country, visit, metformin use, and treatment-by-visit interaction as fixed effects and baseline fasting blood glucose as a covariate. | Baseline, 26 weeks, and 52 weeks | 
| Total Daily Insulin Dose Overall and by Components (Insulin Lispro and Insulin Glargine) | Total daily insulin (TDI) dose was reported at baseline, 26 weeks, and 52 weeks. Daily Insulin Lispro and Insulin Glargine doses were reported at 26 and 52 weeks. | Baseline and 26 weeks and 52 weeks | 
| Change From Baseline to 26 and 52 Weeks in Body Weight | Least Squares (LS) means of change from baseline were calculated using analysis of covariance (ANCOVA) with country, treatment, and metformin use as fixed effects and baseline body weight as a covariate. | Baseline, 26 weeks, and 52 weeks | 
| Body Weight at Baseline, 52 Weeks, and 4 Weeks After Last Dose |  | Baseline and 52 weeks and 4 weeks after last dose | 
| Change From Baseline to 26 Weeks, 52 Weeks, and 4 Weeks After Last Dose in Body Mass Index (BMI) | Body mass index 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, metformin use, and treatment-by-visit interaction as fixed effects and baseline BMI as a covariate. | Baseline, 26 weeks, and 52 weeks | 
| Change From Baseline to 26 and 52 Weeks in the EQ-5D | The 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 consists of a 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) adjusted by treatment, country, metformin use, and baseline. | Baseline, 26 weeks, and 52 weeks | 
| Change From Baseline to 26 and 52 Weeks in the Impact of Weight on Activities of Daily Living (IW-ADL) | 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, treatment, and metformin use as fixed effects and baseline score as a covariate. | Baseline, 26 weeks, and 52 weeks | 
| Change From Baseline to 26 and 52 Weeks in the Impact of Weight on Self-Perception (IW-SP) | 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, treatment, and metformin use as fixed effects and baseline score as a covariate. | Baseline, 26 weeks, and 52 weeks | 
| Change From Baseline to 26 and 52 Weeks in the Low Blood Sugar Survey (LBSS) | 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, treatment and metformin use as fixed effects and baseline score as a covariate. | Baseline, 26 weeks, and 52 weeks | 
| Change From Baseline to 26 and 52 Weeks in Pancreatic Enzymes | Amylase (total and pancreas-derived [PD]) and lipase concentrations were measured. | Baseline, 26 weeks, and 52 weeks | 
| Pancreatic Enzymes at Baseline, 52 Weeks, and 4 Weeks After Last Dose | Amylase (total and pancreas-derived [PD]) and lipase concentrations were measured at baseline and at 4 weeks after last dose (ALD). | Baseline and 52 weeks and 4 weeks after last dose | 
| Change From Baseline to 26 and 52 Weeks in Serum Calcitonin |  | Baseline, 26 weeks, and 52 weeks | 
| Serum Calcitonin at Baseline, 52 Weeks, and 4 Weeks After Last Dose |  | Baseline and 52 weeks and 4 weeks after last dose | 
| Change From Baseline to 26 and 52 Weeks in Blood Pressure | Seated systolic blood pressure (SBP) and seated 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, metformin use, and treatment-by-visit interaction as fixed effects and baseline blood pressure as a covariate. | Baseline, 26 weeks, and 52 weeks | 
| Blood Pressure at Baseline, 52 Weeks, and 4 Weeks After Last Dose | Seated systolic blood pressure (SBP) and seated diastolic blood pressure (DBP) were measured. | Baseline and 52 weeks and 4 weeks after last dose | 
| Change From Baseline to 26 and 52 Weeks in Pulse Rate | Seated 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, metformin use, and treatment-by-visit interaction as fixed effects and baseline as a covariate | Baseline, 26 weeks, and 52 weeks | 
| Pulse Rate at Baseline, 52 Weeks, and 4 Weeks After Last Dose | Seated pulse rate was measured. | Baseline and 52 weeks and 4 weeks after last dose | 
| Change From Baseline to 26 and 52 Weeks in 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, metformin use, and treatment-by-visit interaction as fixed effects and baseline value as a covariate. | Baseline, 26 weeks, and 52 weeks | 
| Change From Baseline to 26 and 52 Weeks in 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, metformin use, and treatment-by-visit interaction as fixed effects and baseline value as a covariate. | Baseline, 26 weeks, and 52 weeks | 
| Number of Events of Adjudicated Pancreatitis up to 26 Weeks, 52 Weeks, and 4 Weeks After Last Dose | The number of adjudicated (by an independent Clinical Endpoint Committee [CEC]) pancreatic events is summarized at 52 weeks. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through 52 weeks | 
| Number of Participants With Self-reported Hypoglycemic Events up to 26 Weeks, 52 Weeks, and 4 Weeks After Last Dose | Hypoglycemic events (HE) were classified as severe (episodes requiring the assistance of another person to actively administer resuscitative actions and had a plasma glucose [PG] of ≤ 70 milligrams per deciliter [mg/dL]), documented symptomatic (any time a participant felt that he/she was experiencing symptoms and/or signs associated with hypoglycemia and had a PG of ≤ 70 mg/dL), or asymptomatic (events not accompanied by typical symptoms of hypoglycemia but with a measured PG of ≤ 70 mg/dL). The number of participants with self-reported hypoglycemic events is summarized cumulatively. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through 26 weeks and 52 weeks | 
| Rate of Self-reported Hypoglycemic Events up to 52 Weeks | Hypoglycemic events (HE) were classified as severe (episodes requiring the assistance of another person to actively administer resuscitative actions and had a plasma glucose [PG] of ≤ 70 milligrams per deciliter [mg/dL]), documented symptomatic (any time a participant felt that he/she was experiencing symptoms and/or signs associated with hypoglycemia and had a PG of ≤ 70 mg/dL), or asymptomatic (events not accompanied by typical symptoms of hypoglycemia but with a measured PG of ≤ 70 mg/dL). The 1-year adjusted rate of hypoglycemic events is summarized cumulatively at 52 weeks. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through 52 weeks | 
| Number of Participants With Adjudicated Cardiovascular Events up to 52 Weeks | 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. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through 52 weeks | 
| Number of Participants With Treatment Emergent LY2189265 Antibodies up to 26 Weeks, 52 Weeks, and 4 Weeks After Last Dose | A participant was considered to have treatment emergent LY2189265 anti-drug antibodies (ADA) if the participant had at least one titer that was treatment-emergent relative to baseline, defined as a 4-fold or greater increase in titer from baseline measurement. | Baseline through 4 weeks after last dose | 
| Number of Participants With Treatment Emergent Adverse Events up to 26 Weeks, 52 Weeks, and 4 Weeks After Last Dose | 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 weeks, 52 weeks, and 4 weeks after last dose. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through 26 weeks, 52 weeks, and 4 weeks after last dose |