A Study Comparing the Effects and Safety of Dulaglutide With Glimepiride 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 glimepiride in participants with type 2 diabetes mellitus who have inadequate glycemic control with oral antihyperglycemic medication (OAM) or are OAM-naïve.

Official Title
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The Efficacy and Safety of Once-Weekly, Subcutaneous Dulaglutide Monotherapy Compared to Glimepiride in Patients With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Dulaglutide
* Drug: Glimepiride
* Drug: Placebo as Capsules
* Drug: Placebo as SC Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes mellitus OAM-naïve or have been taking OAM monotherapy for at least 3 months Glycosylated Hemoglobin (HbA1c) value of ≥7.0% to ≤10.5% for OAM-naïve participants or ≥6.5% to ≤10.0% for participants taking OAM monotherapy Adult men or adult non-pregnant, non-breastfeeding women Stable weight (±5%) ≥3 months prior to screening Body mass index (BMI) of ≥19.0 to ≤35.0 kilograms per square meter (kg/m^2) Exclusion Criteria: Have type 1 diabetes mellitus Have previously been treated with a glucagon-like peptide-1 (GLP-1) receptor agonist, GLP-1 analog, or any other incretin mimetic during the 3 months before screening Are currently taking dipeptidylpeptidase-IV (DPP-IV) inhibitor and thiazolidinediones (TZD) during the 3 months before screening 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 millimeters 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 picogram/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: Triple


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 plus one to three capsules of placebo each day for blinding purposes for up to 26 weeks. | Drug: Dulaglutide<br>* Administered SC<br>* Other names: LY2189265;Drug: Placebo as Capsules<br>* Placebo for glimepiride is administered orally as one to three capsules daily.<br>|
| Experimental: 0.75 mg Dulaglutide<br>0.75 mg dulaglutide administered as one SC injection once-weekly plus one to three capsules of placebo each day for blinding purposes for up to 26 weeks. | Drug: Dulaglutide<br>* Administered SC<br>* Other names: LY2189265;Drug: Placebo as Capsules<br>* Placebo for glimepiride is administered orally as one to three capsules daily.<br>|
| Active Comparator: Glimepiride<br>1 to 3 mg per day (mg/day) glimepiride administered orally as one to three capsules per day plus one SC injection of placebo once-weekly for blinding purposes for up to 26 weeks. | Drug: Glimepiride<br>* Administered orally<br>Drug: Placebo as SC Injection<br>* Placebo for dulaglutide is administered as one SC injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 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 Squares (LS) means were calculated using mixed model repeated measures (MMRM) analysis adjusting for treatment, country, pre-study therapy stratum, visit, and treatment-by-visit as fixed effects; baseline HbA1c as covariate; and participant as a random effect. | Baseline, 26 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Attaining HbA1c of <7% or ≤6.5% at 26 Weeks | Percentages of participants who achieved HbA1c levels of <7% or ≤6.5% were analyzed using a logistic regression model, controlling for treatment, pre-treatment, baseline HbA1c and country. | 26 Weeks | 
| Change From Baseline in Fasting Blood Glucose (FBG) at 26 Weeks | FBG is a test to determine how much glucose (sugar) is in a blood sample after an overnight fast. FBG was measured by a central laboratory. LS means were calculated using MMRM analysis adjusting for treatment, country, pre-study therapy stratum, visit, and treatment-by-visit as fixed effects; baseline FBG as covariate; and participant as a random effect. | Baseline, 26 Weeks | 
| Change From Baseline in 7-point Self-monitored Blood Glucose (SMBG) Profiles at 26 Weeks | Change from baseline in mean daily blood glucose (BG) values were measured with a 7-point SMBG profile. Participants recorded their 7-point SMBG profiles on 2 separate, non-consecutive days during the 2-week period immediately before randomization, Week 8, Week 16, and Week 26 (or the Early Discontinuation Visit). The 7-point SMBG profile consisted of pre-prandial BG measures before the morning (fasting), midday, and evening meals; BG measures 2 hours after the start (post-prandial) of the morning, midday, and evening meals; and BG measures at bedtime. Mean at 26 weeks was assessed in all treatment groups. LS means were calculated using MMRM analysis adjusting for treatment, country, pre-study therapy stratum, visit, and treatment-by-visit as fixed effects; baseline body weight as covariate; and participant as a random effect. | Baseline, 26 Weeks | 
| Rate of Hypoglycemic Episodes | Hypoglycemic episodes are defined as events that are associated with reported signs and symptoms of hypoglycemia and/or documented BG concentrations of ≤70 milligrams per deciliter (mg/dL) (≤3.9 mmol/L). A severe hypoglycemic episode was defined as any hypoglycemic event for which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs between bedtime and waking. Log mean rates of total hypoglycemia (per 30 days per participant) are presented and were calculated from negative binomial regression model. The model included country/region, prior medication group, treatment, visit, and treatment-by-visit interaction. The logarithm of days between visits was adjusted as an offset to account for possible unequal duration between visits and between participants. | Baseline through 26 Weeks | 
| Number of Participants With Self-Reported Hypoglycemic Episodes | The overall number of participants with self-reported hypoglycemic episodes is presented. | Baseline through 26 Weeks | 
| Change From Baseline in Homeostasis Model Assessment 2 Steady-state Beta (β) - Cell Function (HOMA2-%B) at 26 Weeks | Change from baseline in HOMA2-%B was assessed by using the homeostasis model assessment (HOMA) to quantify β-cell function. HOMA2-%B is a computer model that uses FBG, insulin, and C-peptide concentrations to estimate steady state β-cell function (%B) as a percentage of a normal reference population (normal young adults). The normal reference population was set at 100%. LS means were calculated using an analysis of covariance (ANCOVA) model with country, baseline, pre-treatment, and treatment as fixed effects. | Baseline, up to 26 Weeks | 
| Change From Baseline in Homeostasis Model Assessment 2 Insulin Sensitivity - Cell Function (HOMA2-%S) at 26 Weeks | Change from baseline in HOMA2-%S was assessed by using the HOMA to quantify insulin sensitivity. HOMA2-%S is a computer model that uses fasting plasma insulin and glucose concentrations to estimate steady state insulin sensitivity (%S) as a percentage of a normal reference population (normal young adults). The normal reference population was set at 100%. LS means were calculated using an ANCOVA model with country, baseline, pre-treatment, and treatment as fixed effects. | Baseline, up to 26 Weeks | 
| Change From Baseline in Pancreatic Enzymes at 26 Weeks | Amylase (total and pancreas-derived) and lipase concentrations were measured. | Baseline, 26 Weeks | 
| Change From Baseline in Serum Calcitonin at 26 Weeks |  | Baseline, 26 Weeks | 
| Change From Baseline in Sitting Blood Pressure at 26 Weeks | Sitting systolic blood pressure (SBP) and sitting diastolic blood pressure (DBP) were measured. LS means were calculated using MMRM analysis adjusting for treatment, country, pre-study therapy stratum, visit, and treatment-by-visit as fixed effects; baseline blood pressure as covariate; and participant as a random effect. | Baseline, 26 Weeks | 
| Change From Baseline in Sitting Pulse Rate at 26 Weeks | LS means were calculated using MMRM analysis adjusting for treatment, country, pre-study therapy stratum, visit, and treatment-by-visit as fixed effects; baseline pulse rate as covariate; and participant as a random effect. | Baseline, 26 Weeks | 
| Change From Baseline in Electrocardiogram (ECG) Parameters, Fridericia Corrected QT (QTcF) Interval and P-R Wave (PR) Interval at 26 Weeks | 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: QTcF = QT/RR^0.33. Corrected QT (QTc) is the QT interval corrected for heart rate and R-R wave (RR), which is the interval between two R waves. PR is the interval between the P wave and the ventricular depolarization wave (QRS) complex. | Baseline, 26 Weeks | 
| Change From Baseline in Heart Rate From ECG at 26 Weeks |  | Baseline, 26 Weeks | 
| Change From Baseline in Body Weight at 26 Weeks | LS means were calculated using MMRM analysis adjusting for treatment, country, pre-study therapy stratum, visit, and treatment-by-visit as fixed effects; baseline body weight as covariate; and participant as a random effect. | Baseline, 26 Weeks | 
| Change From Baseline in Body Mass Index (BMI) at 26 Weeks | BMI is an estimate of body fat based on body weight divided by height squared. LS means were calculated using MMRM analysis adjusting for treatment, country, pre-study therapy stratum, visit, and treatment-by-visit as fixed effects; baseline body weight as covariate; and participant as a random effect. | Baseline, 26 Weeks | 
| Percentage of Participants Developing Antibodies to Dulaglutide | Dulaglutide anti-drug antibodies (ADA) were assessed at baseline and 26 weeks. A participant was considered to have treatment-emergent dulaglutide ADA if the participant had at least 1 titer that was treatment-emergent relative to baseline, defined as a 4-fold or greater increase in titer from baseline measurement. | Baseline through 26 Weeks | 
| Number of Participants With Adjudicated Cardiovascular Events | 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 that were adjudicated 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 AEs regardless of causality, is located in the Reported Adverse Events module. | Baseline through 26 Weeks | 
| Number of Participants With Adjudicated Pancreatitis | The number of adjudicated (by an independent committee of expert physicians) pancreatic events is summarized at 26 weeks. A summary of serious and other non-serious AEs regardless of causality is located in the Reported Adverse Events module. | Baseline through 26 Weeks | 
| European Quality of Life Questionnaire-5 Dimensions (EQ-5D) Health State Score Responses at 26 Weeks | The EQ-5D questionnaire is a widely used, generic questionnaire that 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 5 response categories is summarized for each of the 5 dimensions. | Week 26 | 
| Visual Analog Scale (VAS) Score at 26 Weeks | The EQ-5D questionnaire is a widely used, generic questionnaire that assesses health-related quality of life and consists of a 100-milliliter (mm) visual analog scale (VAS) on which the participant rated their perceived health state on that day from 0-mm (worst imaginable health state) to 100-mm (best imaginable health state). | Week 26 |