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

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

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.

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

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