A Study of LY2189265 Compared to Sitagliptin in Participants With Type 2 Diabetes Mellitus on Metformin

Study Overview
=================
Brief Summary
-----------------
This is an adaptive dose finding study and a Phase 3 efficacy study to evaluate the effects of once weekly injection of LY2189265 compared to Sitagliptin on glucose by measuring glycosylated hemoglobin (HbA1c) change from baseline after 52 weeks in participants with type 2 diabetes mellitus on Metformin.

Detailed Description
-----------------
This is a double blind study designed to select 1 or 2 LY2189265 doses for evaluation in Phase 3 studies (dose-finding portion) and to evaluate efficacy and safety of selected doses of LY2189265 in comparison to Sitagliptin (100 milligrams) up to 104 weeks and Placebo up to 26 weeks in participants with type 2 diabetes mellitus on Metformin (confirmatory, Phase 3 portion). The primary objective is to show non-inferiority of the higher LY2189265 dose (if 2 doses are selected) to Sitagliptin with respect to change in glycosylated hemoglobin (HbA1c) at 52 weeks. The final endpoint is 104 weeks. Participants are randomized to receive Placebo, Sitagliptin, or 1 of 7 initial LY2189265 doses until a dose decision is made based on quantitative analysis of the benefits and risks of each LY2189265 dose. A clinical utility index (CUI) that applies predicted values for change from baseline in HbA1c at 12 months and change from baseline in weight, diastolic blood pressure, and pulse rate at 6 months for each LY2189265 dose will be used toward this end. After the dose decision, participants in the selected LY2189265 arms and the comparator arms (Sitagliptin and Placebo/Sitagliptin arms) will continue the study, and additional participants will be randomized to the selected and comparator arms. Regardless of the timing of randomization relative to the dose decision point, all participants in the selected and comparator arms are planned to receive treatment for 104 weeks; participants in the Placebo/Sitagliptin arm will receive Placebo treatment for 26 weeks followed by Sitagliptin 100 mg for 78 weeks for blinding purposes only, and participants in the selected and Sitagliptin arms will receive the same treatment for 104 weeks. All participants will remain blinded to their study treatment throughout the study. Participants in the non-selected arms will discontinue from the study after the dose decision

Official Title
-----------------
A Phase 2/3, Placebo-Controlled, Efficacy and Safety Study of Once-Weekly, Subcutaneous LY2189265 Compared to Sitagliptin in Patients With Type 2 Diabetes Mellitus on Metformin

Conditions
-----------------
Diabetes Mellitus, Type 2

Intervention / Treatment
-----------------
* Drug: LY2189265
* Drug: Sitagliptin
* Drug: Placebo solution
* Drug: Placebo tablet
* Drug: Metformin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diabetes mellitus, type 2, for at least 6 months Treatment regimens: diet and exercise, metformin as monotherapy or in combination with another oral antihyperglycemic medication (OAM), or another OAM as monotherapy. Must be able to tolerate metformin at a dose of at least 1500 milligrams (mg) daily for 6 weeks prior to randomization. Glycosylated hemoglobin (HbA1c) value of ≥7.0% to ≤9.5%, except participants on diet and exercise therapy who must have had HbA1c value of >8.0% to ≤9.5% Body mass index (BMI) between 25 and 40 kilograms per meter squared (kg/m^2), inclusive Stable weight for 3 months prior to screening Females of childbearing potential must test negative for pregnancy and agree to use a reliable birth control method Exclusion Criteria: Diabetes mellitus, type 1 Use of a glucagon-like peptide-1 (GLP-1) analog (for example, exenatide) within 6 months prior to screening or are being treated with insulin Gastric emptying abnormality, history of bariatric surgery, or chronic use of drugs that affect gastrointestinal motility Use of medications to promote weight loss Clinically-relevant cardiovascular event within 6 months prior to screening Poorly controlled hypertension Electrocardiogram (ECG) reading considered outside the normal limits or indicating cardiac disease Liver disease, hepatitis, chronic pancreatitis, idiopathic acute pancreatitis, or alanine transaminase (ALT) levels >3.0 times the upper limit of normal Serum creatinine ≥1.5 milligrams per deciliter (mg/dL) or a creatinine clearance <60 milliliters per minute (mL/minute) Uncontrolled diabetes, defined as >2 episodes of ketoacidosis or hyperosmolar state requiring hospitalization in the 6 months prior to study entry. Uncontrolled endocrine or autoimmune abnormality History of a transplanted organ Chronic use of systemic glucocorticoid therapy Active or untreated malignancy Use of central nervous system (CNS) stimulants

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 3.0 mg LY2189265<br>LY2189265 (Dulaglutide): 3.0 milligrams (mg), subcutaneous (SC) injection, once weekly for up to 104 weeks Placebo: tablet, administered orally, once daily for up to 104 weeks Metformin: at least 1500 milligrams per day (mg/day), administered orally for up to 104 weeks | Drug: LY2189265<br> <br> * Other names: Trulicity;Drug: Placebo tablet<br> <br> Drug: Metformin<br> <br> |
| Experimental: 2.0 mg LY2189265<br>LY2189265 (Dulaglutide): 2.0 milligrams (mg), subcutaneous (SC) injection, once weekly for up to 104 weeks Placebo: tablet, administered orally, once daily for up to 104 weeks Metformin: at least 1500 milligrams per day (mg/day), administered orally for up to 104 weeks | Drug: LY2189265<br> <br> * Other names: Trulicity;Drug: Placebo tablet<br> <br> Drug: Metformin<br> <br> |
| Experimental: 1.5 mg LY2189265<br>LY2189265 (Dulaglutide): 1.5 milligrams (mg), subcutaneous (SC) injection, once weekly for up to 104 weeks Placebo: tablet, administered orally, once daily for up to 104 weeks Metformin: at least 1500 milligrams per day (mg/day), administered orally for up to 104 weeks | Drug: LY2189265<br> <br> * Other names: Trulicity;Drug: Placebo tablet<br> <br> Drug: Metformin<br> <br> |
| Experimental: 1.0 mg LY2189265<br>LY2189265 (Dulaglutide): 1.0 milligrams (mg), subcutaneous (SC) injection, once weekly for up to 104 weeks Placebo: tablet, administered orally, once daily for up to 104 weeks Metformin: at least 1500 milligrams per day (mg/day), administered orally for up to 104 weeks | Drug: LY2189265<br> <br> * Other names: Trulicity;Drug: Placebo tablet<br> <br> Drug: Metformin<br> <br> |
| Experimental: 0.75 mg LY2189265<br>LY2189265 (Dulaglutide): 0.75 milligrams (mg), subcutaneous (SC) injection, once weekly for up to 104 weeks Placebo: tablet, administered orally, once daily for up to 104 weeks Metformin: at least 1500 milligrams per day (mg/day), administered orally for up to 104 weeks | Drug: LY2189265<br> <br> * Other names: Trulicity;Drug: Placebo tablet<br> <br> Drug: Metformin<br> <br> |
| Experimental: 0.5 mg LY2189265<br>LY2189265 (Dulaglutide): 0.5 milligrams (mg), subcutaneous (SC) injection, once weekly for up to 104 weeks Placebo: tablet, administered orally, once daily for up to 104 weeks Metformin: at least 1500 milligrams per day (mg/day), administered orally for up to 104 weeks | Drug: LY2189265<br> <br> * Other names: Trulicity;Drug: Placebo tablet<br> <br> Drug: Metformin<br> <br> |
| Experimental: 0.25 mg LY2189265<br>LY2189265 (Dulaglutide): 0.25 milligrams (mg), subcutaneous (SC) injection, once weekly for up to 104 weeks Placebo: tablet, administered orally, once daily for up to 104 weeks Metformin: at least 1500 milligrams per day (mg/day), administered orally for up to 104 weeks | Drug: LY2189265<br> <br> * Other names: Trulicity;Drug: Placebo tablet<br> <br> Drug: Metformin<br> <br> |
| Active Comparator: Sitagliptin<br>Sitagliptin: 100-milligrams (mg) tablet, administered orally, once daily for 104 weeks Placebo: solution, subcutaneous (SC) injection, once weekly for 104 weeks Metformin: at least 1500 milligrams per day (mg/day), administered orally for 104 weeks | Drug: Sitagliptin<br> <br> Drug: Placebo solution<br> <br> Drug: Metformin<br> <br> |
| Placebo Comparator: Placebo/Sitagliptin (Baseline Through 104 Weeks)<br>Placebo: solution, subcutaneous (SC) injection, once weekly for 104 weeks Placebo: tablet, administered orally, once daily for 26 weeks Sitagliptin: after 26 weeks, 100-milligrams (mg) tablet, administered orally, once daily for 78 weeks Metformin: at least 1500 milligrams per day (mg/day), administered orally for 104 weeks | Drug: Placebo solution<br> <br> Drug: Placebo tablet<br> <br> Drug: Metformin<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glycosylated Hemoglobin (HbA1c) Change From Baseline | Least squares (LS) means were calculated using analysis of covariance (ANCOVA) and last observation carried forward (LOCF) imputation 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 in Glycosylated Hemoglobin (HbA1c) at the Dose Decision Point | Change from baseline in HbA1c was 1 of the 4 measures included in the clinical utility index (CUI) used to evaluate the dose decision. The maximum duration of exposure to LY2189265, Sitagliptin, or Placebo (across all treatment arms) at the decision point was 27.4 weeks. | Baseline up to 27.4 weeks | 
| Glycosylated Hemoglobin (HbA1c) Change From Baseline | Least squares (LS) means were calculated using analysis of covariance (ANCOVA) and last observation carried forward (LOCF) imputation with country and treatment as fixed effects and baseline HbA1c as a covariate. | Baseline, 26 weeks, 104 weeks | 
| Durability of Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Durability of effect on HbA1c was assessed by comparing the differences in mean change from baseline in HbA1c at 1 time point versus an earlier time point. Least squares (LS) means of change from baseline HbA1c data were calculated using a mixed-effects model for repeated measures (MMRM) analysis with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. | Baseline, 13, 26, 52, and 104 weeks | 
| Fasting Blood Glucose Change From Baseline | Least squares (LS) means of change from baseline were calculated using 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 104 weeks | 
| Fasting Insulin Change From Baseline | Least squares (LS) means of change from baseline fasting insulin data were calculated using a mixed-effects model for repeated measures (MMRM) analysis with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. | Baseline, 26, 52, and 104 weeks | 
| Change From Baseline in Body Weight at Dose Decision Point | Change from baseline in body weight was 1 of the 4 measures included in the clinical utility index (CUI) used to evaluate the dose decision. The maximum duration of exposure to LY2189265, Sitagliptin, or Placebo (across all treatment arms) at the decision point was 27.4 weeks. | Baseline up to 27.4 weeks | 
| Body Weight Change From Baseline | Least squares (LS) means of change from baseline body weight were calculated using analysis of covariance (ANCOVA) and last observation carried forward (LOCF) imputation with country and treatment as fixed effects and baseline as a covariate. | Baseline, 26, 52, and 104 weeks | 
| Durability of Change From Baseline Body Weight | Durability of effect on body weight was assessed by comparing the differences in mean change from baseline in body weight at 1 time point versus an earlier time point. Least squares (LS) means of change from baseline body weight data were calculated using a mixed-effects model for repeated measures (MMRM) analysis with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. | Baseline, 13, 26, 52, and 104 weeks | 
| Waist Circumference Change From Baseline | 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 104 weeks | 
| Percentage of Participants Who Achieve Glycosylated Hemoglobin (HbA1c) <7% or ≤6.5% | The percentage of participants achieving HbA1c levels <7.0% and ≤6.5% was analyzed using a logistic regression model and last observation carried forward (LOCF) imputation with baseline, country, and treatment as factors included in the model. | Baseline, 26, 52, and 104 weeks | 
| Incidence of Hypoglycemic Episodes | Hypoglycemic episodes (HE) were classified as severe (defined as episodes requiring assistance from 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 millimoles per liter [mmol/L]), asymptomatic (defined as episodes not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose of ≤3.9 mmol/L), nocturnal (defined as any episode that occurred between bedtime and waking), or probable symptomatic (defined as episodes during which symptoms of hypoglycemia were not accompanied by a plasma glucose determination). The number of participants with self-reported hypoglycemic events is summarized cumulatively. | Baseline through 26 and 104 weeks | 
| Rate of Hypoglycemic Episodes | Hypoglycemic episodes (HE) were classified as severe (defined as episodes requiring assistance from 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 millimoles per liter [mmol/L]), asymptomatic (defined as episodes not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose of ≤3.9 mmol/L), nocturnal (defined as any episode that occurred between bedtime and waking), or probable symptomatic (defined as episodes during which symptoms of hypoglycemia were not accompanied by a plasma glucose determination). The 1-year adjusted rate of HE is summarized cumulatively. | Baseline through 26 and 104 weeks | 
| Beta Cell Function and Insulin Sensitivity (HOMA2) | 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 HOMA2-%S 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, 26, 52, and 104 weeks | 
| Number of Participants With Treatment-emergent Adverse Events at 26 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 1 or more TEAEs 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 | 
| Number of Participants With Treatment-emergent Adverse Events at 52 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 1 or more TEAEs 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 52 weeks | 
| Number of Participants With Treatment-emergent Adverse Events at 104 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 1 or more TEAEs 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 104 weeks | 
| Number of Participants With Treatment-emergent Abnormal Laboratory Tests at 26 Weeks | The number of participants with treatment-emergent abnormal laboratory results (defined as abnormalities that first occur after baseline) was summarized cumulatively for alkaline phosphatase, alanine aminotransferase or serum glutamic pyruvic transaminase (ALT/SGPT), amylase (pancreatic and total), aspartate aminotransferase or serum glutamic oxaloacetic transaminase (AST/SGOT), basophils, bilirubin (direct and total), calcitonin, chloride, creatine phosphokinase (CPK), creatinine, creatinine clearance, eosinophils, erythrocytes, gamma glutamyltransferase (GGT), hematocrit, hemoglobin, leukocytes, lipase, lymphocytes, mean cell hemoglobin concentration (MCHC), mean cell volume (MCV), monocytes, neutrophils, platelets, potassium, sodium, urea nitrogen, and urine microalbumin-to-creatinine ratio (UMCR). | Baseline through 26 weeks | 
| Number of Participants With Treatment-emergent Abnormal Laboratory Tests at 52 Weeks | The number of participants with treatment-emergent abnormal laboratory results (defined as abnormalities that first occur after baseline) was summarized cumulatively for alkaline phosphatase, alanine aminotransferase or serum glutamic pyruvic transaminase (ALT/SGPT), amylase (pancreatic and total), aspartate aminotransferase or serum glutamic oxaloacetic transaminase (AST/SGOT), basophils, bilirubin (direct and total), calcitonin, chloride, creatine phosphokinase (CPK), creatinine, creatinine clearance, eosinophils, erythrocytes, gamma glutamyltransferase (GGT), hematocrit, hemoglobin, leukocytes, lipase, lymphocytes, mean cell hemoglobin concentration (MCHC), mean cell volume (MCV), monocytes, neutrophils, platelets, potassium, sodium, urea nitrogen, and urine microalbumin-to-creatinine ratio (UMCR) . | Baseline through 52 weeks | 
| Number of Participants With Treatment-emergent Abnormal Laboratory Tests at 104 Weeks | The number of participants with treatment-emergent abnormal laboratory results (defined as abnormalities that first occur after baseline) was summarized cumulatively for alkaline phosphatase, alanine aminotransferase or serum glutamic pyruvic transaminase (ALT/SGPT), amylase (pancreatic and total), aspartate aminotransferase or serum glutamic oxaloacetic transaminase (AST/SGOT), basophils, bilirubin (direct and total), calcitonin, chloride, creatine phosphokinase (CPK), creatinine, creatinine clearance, eosinophils, erythrocytes, gamma glutamyltransferase (GGT), hematocrit, hemoglobin, leukocytes, lipase, lymphocytes, mean cell hemoglobin concentration (MCHC), mean cell volume (MCV), monocytes, neutrophils, platelets, potassium, sodium, urea nitrogen, and urine microalbumin-to-creatinine ratio (UMCR). | Baseline through 104 weeks | 
| Number of Participants With Treatment-emergent Abnormal Lipid Tests | The number of participants with treatment-emergent abnormal lipid test (cholesterol, high density lipoprotein cholesterol [HDL-C], low density lipoprotein cholesterol [LDL-C], and triglycerides [TG]) results (defined as lipid test abnormalities that first occurred after baseline) is summarized cumulatively. | Baseline through 26 and 104 weeks | 
| Change From Baseline in Pulse Rate at Dose Decision Point | Sitting pulse rate was measured at the time that the dose decision was made (dose decision point). Change from baseline in pulse rate was 1 of the 4 measures included in the clinical utility index (CUI) used to evaluate the dose decision. The maximum duration of exposure to LY2189265, Sitagliptin, or Placebo (across all treatment arms) at the decision point was 27.4 weeks. | Baseline up to 27.4 weeks | 
| Change From Baseline in Blood Pressure at Dose Decision Point | Sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured at the dose decision point. Change from baseline in DBP was 1 of the 4 measures included in the clinical utility index (CUI) used to evaluate the dose decision. The maximum duration of exposure to LY2189265, Sitagliptin, or Placebo (across all treatment arms) at the time of the decision point was 27.4 weeks. | Baseline up to 27.4 weeks | 
| Change From Baseline in Pulse Rate | Sitting and standing pulse rate 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 covariate. | Baseline, 26 weeks, 104 weeks | 
| Change From Baseline in Blood Pressure | Sitting and standing systolic blood pressure (SBP) and 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 weeks, 104 weeks | 
| Change From Baseline in Electrocardiogram (ECG) Parameters, Fridericia-corrected QT (QTcF) 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 weeks, 104 weeks | 
| Participant-reported Outcomes, Impact of Weight on Quality of Life-Lite (IWQoL-Lite) | The Impact of Weight on Quality of Life-Lite (IWQoL-Lite questionnaire) is an obesity-specific, 31-item questionnaire designed to measure the impact of weight on participants' quality of life. Items are scored on a 5-point numeric rating scale where 5 = always true and 1 = never true. Items are summed into 6 scales (physical function [11 items], self-esteem [7 items], sexual life [4 items], public distress [5 items], work [4 items], and total score [31 items]) based on the average for the valid responses on that scale multiplied by the number of items on that scale (rounded to the nearest whole integer). Higher scores indicate lower levels of functioning (negative effects). Scores are linearly transformed to a 0 to 100 scale. | Baseline, 52 weeks, and 104 weeks | 
| Participant-reported Outcomes, EQ-5D | The EQ-5D questionnaire is a generic, multidimensional, health-related, quality-of-life instrument. It consists of 2 parts. The first part allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and mood using a three level scale of 1-3 (no problem, some problems, and major problems). These combinations of attributes were converted into a weighted health-state Index Score according to the United Kingdom (UK) population-based algorithm. The possible values for the Index Score ranged from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension). The second part of the questionnaire consists of a 100-millimeter 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 state). | Baseline, 52 weeks, and 104 weeks | 
| Resource Utilization | The number of visits to the emergency room (ER) is summarized cumulatively. | Baseline through 52 and 104 weeks | 
| Pharmacokinetics of LY2189265: Area Under the Concentration-Time Curve | Pharmacokinetic (PK) parameter estimates from LY2189265 concentration data were obtained using a 2-compartment population PK model with first order absorption. Area under the plasma-concentration curve from 0 to 168 hours, steady state (AUC0-168h, ss) of LY2189265 is summarized. | Baseline through 52 weeks | 
| Antibodies to LY2189265 | The number of participants with postbaseline detection of treatment-emergent antidrug LY2189265 antibodies (ADA) is summarized. | Baseline through 104 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diabetes, type 2 diabetes