A Study Comparing the Effects and Safety of Dulaglutide With Insulin Glargine in Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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The purpose of this study is to examine if once-weekly dulaglutide is efficient and safe compared to once-daily insulin glargine in participants with type 2 diabetes mellitus who have inadequate glycemic control with 1 or 2 oral antihyperglycemic medications (OAM) (metformin and/or a sulfonylurea), in addition to any healthy lifestyle changes recommended by their healthcare providers.

Official Title
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The Efficacy and Safety of Once-Weekly, Subcutaneous Dulaglutide Compared to Once-Daily Insulin Glargine in Patients With Type 2 Diabetes Mellitus on Metformin and/or a Sulfonylurea

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Dulaglutide
* Drug: Insulin glargine
* Drug: Metformin
* Drug: Sulfonylureas


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have type 2 diabetes mellitus for at least 6 months Have been taking metformin and/or a sulfonylurea for at least 3 months before screening and have been on a stable therapeutic dose for at least 8 weeks Glycosylated hemoglobin (HbA1c) value of ≥7.0% to ≤11.0% Adult men or adult non-pregnant, non-breastfeeding women Body Mass Index (BMI) of ≥19.0 to ≤35.0 kilograms/square meter (kg/m^2) Stable weight (±5%) ≥3 months prior to screening Exclusion Criteria: Have type 1 diabetes mellitus Have previous treatment with a glucagon-like peptide-1 (GLP-1) receptor agonist, GLP-1 analog, or any other incretin mimetic Have treatment with dipeptidyl peptidase-IV (DPP-IV) inhibitor, an alpha-glucosidase inhibitor (AGI), thiazolidinedione (TZD), or glinide Have gastric emptying abnormality Have cardiac disorder defined as unstable angina, myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary intervention, heart failure, arrhythmia, transient ischemic attack, or stroke Have poorly controlled hypertension (systolic blood pressure above 160 millimeter of mercury[mmHg] or diastolic blood pressure above 95 mmHg) Have impaired liver function Have impaired kidney function Have history of chronic pancreatitis or acute pancreatitis Have a serum calcitonin ≥20 picograms per milliliter (pg/mL) Have a personal or family history of medullary C-cell hyperplasia, focal hyperplasia, carcinoma, or multiple endocrine neoplasia type 2 (MEN 2)

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 Dulaglutide<br>1.5 milligrams (mg) dulaglutide administered as one subcutaneous (SC) injection once-weekly added to participant's pre-study prescribed dose of metformin and/or a sulfonylurea for up to 52 weeks. Participants are blinded to the dulaglutide dose. | Drug: Dulaglutide<br>* Administered SC<br>* Other names: LY2189265;Drug: Metformin<br>* Administered orally at pre-study prescribed dose, and is not being provided as part of the trial.<br>Drug: Sulfonylureas<br>* Administered orally at pre-study prescribed dose, and is not being provided as part of the trial.<br>|
| Experimental: 0.75 mg Dulaglutide<br>0.75 mg Dulaglutide administered as one SC injection once-weekly added to participant's pre-study prescribed dose of metformin and/or a sulfonylurea for up to 52 weeks. Participants are blinded to the dulaglutide dose. | Drug: Dulaglutide<br>* Administered SC<br>* Other names: LY2189265;Drug: Metformin<br>* Administered orally at pre-study prescribed dose, and is not being provided as part of the trial.<br>Drug: Sulfonylureas<br>* Administered orally at pre-study prescribed dose, and is not being provided as part of the trial.<br>|
| Active Comparator: Insulin Glargine<br>Insulin glargine administered based on fasting blood glucose concentrations per the dosing titration schedule as once daily SC injection at bedtime added to participant's pre-study prescribed dose of metformin and /or a sulfonylurea for up to 52 weeks. | Drug: Insulin glargine<br>* Administered SC per dosing titration schedule<br>Drug: Metformin<br>* Administered orally at pre-study prescribed dose, and is not being provided as part of the trial.<br>Drug: Sulfonylureas<br>* Administered orally at pre-study prescribed dose, and is not being provided as part of the trial.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at 26 Weeks | HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. Least square (LS) means of change from baseline in HbA1c were calculated using a mixed-effects model for repeated measures (MMRM) with the change in HbA1c as the dependent variable and treatment, baseline HbA1c, country, oral antihyperglycemic medication (OAM) , visit, and treatment-by-visit interaction as fixed effects, and participant was the random effect. | Baseline, 26 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HbA1c at 52 Weeks | HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. LS means of change from baseline in HbA1c were calculated using a MMRM with the change in HbA1c as the dependent variable and treatment, baseline HbA1c, country, OAM, visit, and treatment-by-visit interaction as fixed effects, and participant was as the random effect. | Baseline, 52 Weeks | 
| Percentage of Participants Attaining HbA1c of <7% or ≤6.5% at 26 Weeks and 52 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 and 52 weeks | 
| Change From Baseline in Fasting Blood Glucose (FBG) at 26 Weeks and 52 Weeks | LS means of change from baseline were calculated using MMRM with the change in FBG as the dependent variable and treatment, baseline value, country, OAM, visit, and treatment-by-visit interaction as fixed effects, and participant was the random effect. | Baseline, 26 Weeks, 52 Weeks | 
| Change From Baseline in 7-point Self-monitored Blood Glucose (SMBG) Profiles at 26 Weeks and 52 Weeks | Participants were required to perform 7-point SMBG profiles on 2 separate, nonconsecutive days during the 2 weeks before randomization and Weeks 8, 14, 20, 26, 39, and 52 (or the Early Discontinuation Visit). SMBG measurements were taken using a plasma-equivalent blood glucose (BG) meter at 7 time points: morning pre-meal, morning 2 hours post-meal, mid-day pre-meal, mid-day 2 hours post-meal, evening pre-meal, evening 2 hours post-meal, and at bedtime. Mean and Week 26 and Week 52 was assessed in all treatment groups. LS means of change from baseline were calculated using MMRM with the change in 7-point SMBG as the dependent variable and treatment, baseline value, country, OAM, visit, and treatment-by-visit interaction as fixed effects, and participant was the random effect. | Baseline, 26 Weeks, 52 Weeks | 
| Change From Baseline in Homeostasis Model Assessment 2 Steady-state Beta (β)- Cell Function (HOMA2-%B) at 26 Weeks and 52 Weeks | The updated Homeostasis Model Assessment (HOMA2) was used to quantify steady state beta-cell function (%B). HOMA2-%B is a computer model that uses fasting plasma insulin and glucose concentrations to estimate %B as a percentage of a normal reference population. LS means were calculated using a homeostasis model assessment with change from baseline in HOMA-%B as a covariate and country, baseline measurement, OAM, and treatment as fixed effects. | Baseline, 26 weeks, 52 weeks | 
| Change From Baseline in Homeostasis Model Assessment 2 Insulin Sensitivity - Cell Function (HOMA2-%S) at 26 Weeks and 52 Weeks | The HOMA2 was used to estimate the steady-state insulin sensitivity (%S). HOMA2-S is a computer model that uses fasting plasma insulin and glucose concentrations to estimate insulin sensitivity (%S) as a percentage of the normal reference population. LS means were calculated using an homeostasis model assessment with change from baseline in HOMA-%S as a covariate and country, baseline measurement, OAM, and treatment as fixed effects. | Baseline, 26 Weeks, 52 Weeks | 
| Rate of Hypoglycemic Events | Hypoglycemic events (HE) were classified as documented symptomatic hypoglycemia, asymptomatic hypoglycemia, severe hypoglycemia, and probable symptomatic hypoglycemia. The 1-year adjusted rate of HEs was summarized cumulatively at 26 weeks and 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 26 weeks and 52 weeks | 
| Number of Self-reported Hypoglycemic Events | 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 felt that he/she was experiencing symptoms and/or signs associated with hypoglycemia, and had a plasma glucose level of less than or equal to 3.9 millimoles/liter [mmol/L]), asymptomatic (defined as events not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose of less than or equal to 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 was 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 26 Weeks and 52 Weeks | 
| Change From Baseline to 26 Weeks and 52 Weeks on Blood Pressure (BP) | Seated systolic blood pressure (SBP) and seated diastolic blood pressure (DBP) were measured. LS means of change from baseline were calculated using a MMRM with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. | Baseline, 26 Weeks, 52 Weeks | 
| Change From Baseline at 26 Weeks and 52 Weeks on Pulse Rate | Seated pulse rate was measured. LS means of change from baseline were calculated using a MMRM with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. | Baseline, 26 Weeks, 52 Weeks | 
| Change From Baseline 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. | Baseline, 26 Weeks, 52 Weeks | 
| Change From Baseline in Electrocardiogram Parameters, Heart Rate (HR) |  | Baseline, 26 Weeks, 52 Weeks | 
| Change From Baseline in Pancreatic Enzymes | Amylase (total and pancreas-derived) and lipase concentrations were measured | Baseline, 26 Weeks, 52 Weeks | 
| Change From Baseline in Serum Calcitonin |  | Baseline, 26 Weeks, 52 Weeks | 
| Number of Participants With Adjudicated Cardiovascular (CV) Events | Deaths and nonfatal cardiovascular adverse events were adjudicated by a committee of physicians with cardiology expertise external to the Sponsor. The nonfatal cardiovascular events subjected to adjudication included 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 Adjudicated Pancreatitis | The number of participants with pancreatitis confirmed by adjudication is summarized. Events of pancreatitis (including suspected pancreatitis and severe or serious abdominal pain) were adjudicated by a committee of expert physicians external to the Sponsor. 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 | 
| Change From Baseline in Body Weight |  | Baseline, 26 Weeks, 52 Weeks | 
| Change in Body Mass Index | Body mass index is an estimate of body fat based on body weight divided by height squared. | Baseline, 26 Weeks, 52 Weeks | 
| Percentages of Participants Developing Treatment-Emergent Dulaglutide Anti-drug Antibody (ADA) | Number of participants with treatment emergent (TE) dulaglutide anti-drug antibodies from postbaseline to follow up were summarized. A participant was considered to have TE dulaglutide 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 52 Weeks | 
| EQ-5D Health State Score Responses | The EQ-5D questionnaire is a widely used, generic questionnaire that assesses health-related quality of life. It consists of 2 parts. The first part assesses 5 dimensions associated with quality of life (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has 3 possible levels of response: no problem, some problem, and extreme problem. Additional categories of response include ambiguous and missing. The number of participants per each of the 3 response categories is summarized for each of the 5 dimensions. | Baseline, 26 Weeks, 52 Weeks | 
| Change From Baseline in EQ-5D Visual Analog Scale Score | The EQ-5D is a generic, multidimensional, health-related, quality-of-life instrument. Overall health state score was self-reported using a visual analogue scale (VAS) marked on a scale of 0 to 100 with 0 representing worst imaginable health state and 100 representing best imaginable health state. LS means of change from baseline were calculated using ANCOVA and adjusted by treatment, country, and baseline. | Baseline, 26 weeks, 52 weeks |