A Study to Compare a New Drug for Type 2 Diabetes to Placebo and to a Treatment Already Available for Type 2 Diabetes

Study Overview
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Brief Summary
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The main purpose of this study is to compare the safety and effectiveness of the study drug known as LY2944876 to exenatide extended-release and placebo in participants with type 2 diabetes mellitus. All drugs will be given by an injection under the skin. Participants remain on stable doses of metformin, as prescribed by their personal investigator if they were on metformin at study entry. Participants' involvement in the study is expected to last about 30 weeks.

Detailed Description
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The study will include a 12 week blinded treatment period, where neither the participant nor the investigator will know to which treatment each individual is assigned. Thereafter follows a 12 week period where participants and the investigator will know which treatment they are assigned to. Participants' on LY2944876 and on exenatide extended-release continue treatment in this period, those who received placebo will be followed without treatment.

Official Title
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Comparison of the Oxyntomodulin Analog, LY2944876, to Once-Weekly Exenatide and to Placebo in Patients With Type 2 Diabetes

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: LY2944876
* Drug: Exenatide extended-release
* Drug: Placebo
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women with diabetes mellitus Type 2 Have screening HbA1c ≥7.0% and ≤10.5% either on diet and exercise alone or on a stable dose of metformin (≥1000 mg/day) for 3 months prior to screening Have body mass index (BMI) ≥23 and ≤45 kilograms per meter squared at screening Exclusion Criteria: Women of child bearing potential Participants who have used thiazolidinediones within 3 months prior to screening, or any other drugs for treatment of hyperglycemia (except metformin) within the prior 2 months Participants who have used insulin for diabetic control for more than 6 consecutive days within the prior year Participants with impaired renal function (serum creatinine >124 micromole per liter (µmol/L) [1.4 milligrams per deciliter (mg/dL)] in women, >133 µmol/L [1.5 mg/dL] in men)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10 mg LY2944876<br>10 milligrams (mg) LY2944876 given subcutaneously (SC) once weekly for 24 weeks. Participants remain on stable doses of metformin, as prescribed by their personal investigator if they were on metformin at study entry. | Drug: LY2944876<br>* Administered SC<br>Drug: Metformin<br>* Oral<br>|
| Experimental: 15 mg LY2944876<br>15 mg LY2944876 given SC once weekly for 24 weeks. Participants remain on stable doses of metformin, as prescribed by their personal investigator if they were on metformin at study entry. | Drug: LY2944876<br>* Administered SC<br>Drug: Metformin<br>* Oral<br>|
| Experimental: 30 mg LY2944876<br>30 mg LY2944876 given SC once weekly for 24 weeks. Participants remain on stable doses of metformin, as prescribed by their personal investigator if they were on metformin at study entry. | Drug: LY2944876<br>* Administered SC<br>Drug: Metformin<br>* Oral<br>|
| Experimental: 50 mg LY2944876<br>50 mg LY2944876 given SC once weekly for 24 weeks. Participants remain on stable doses of metformin, as prescribed by their personal investigator if they were on metformin at study entry. | Drug: LY2944876<br>* Administered SC<br>Drug: Metformin<br>* Oral<br>|
| Experimental: Exenatide extended-release<br>2 mg exenatide extended-release given SC once weekly for 24 weeks. Participants remain on stable doses of metformin, as prescribed by their personal investigator if they were on metformin at study entry. | Drug: Exenatide extended-release<br>* Administered SC<br>Drug: Metformin<br>* Oral<br>|
| Placebo Comparator: Placebo<br>Placebo for LY2944876 and Exenatide given SC once weekly for 12 weeks. Participants assigned to placebo will have no injections during the second 12 weeks of the study. Participants remain on stable doses of metformin, as prescribed by their personal investigator if they were on metformin at study entry. | Drug: Placebo<br>* Administered SC<br>Drug: Metformin<br>* Oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin A1c (HbA1c) at Week 12 | HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HbA1c at Week 24 | HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. | Baseline, Week 24 | 
| Percent Change From Baseline in Body Weight |  | Baseline, Week 12; Baseline, Week 24 | 
| Change From Baseline in Fasting Blood Glucose | Least square means (LSM) was calculated from mixed-effects model with repeated measures (MMRM) analysis using restricted maximum likelihood (REML) with metformin use, baseline body mass index (BMI) category, baseline HbA1c category, country, treatment, visit, and treatment-by-visit interaction as fixed effects, baseline fasting blood glucose as a covariate, and participant as a random effect. | Baseline, Week 12; Baseline, Week 24 | 
| Change From Baseline in 7-point Self-Monitored Blood Glucose (SMBG) Values | SMBG 7-point profiles were measured at 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. LSM were calculated from MMRM analysis using REML with metformin use, baseline BMI category, baseline HbA1c category, country, treatment, visit, and treatment-by-visit interaction as fixed effects, baseline fasting blood glucose as a covariate, and participant as a random effect. | Baseline, Week (Wk) 12; Baseline, Week 24 | 
| Change From Baseline in Lipids | Change from baseline in high-density lipoprotein cholesterol (HDL-C), total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C). LSM was calculated from MMRM analysis using REML with metformin use, baseline BMI category, baseline HbA1c category, country, treatment, visit, and treatment-by-visit interaction as fixed effects, baseline parameter result as a covariate, and participant an a random effect. | Baseline, Week 24 | 
| Change From Baseline in Fasting Fibroblast Growth Factor 21 | LSM was calculated from MMRM analysis using REML with metformin use, baseline BMI category, baseline HbA1c category, country, treatment, visit, and treatment-by-visit interaction as fixed effects, baseline parameter result as a covariate, and participant as a random effect. | Baseline, Week 12; Baseline, Week 24 | 
| Percentage of Participants Requiring Rescue Therapy | Participants who received rescue medication with non-study antihyperglycemic medications or change their stable dose of metformin. | Baseline through Therapy Completion (Week 24) | 
| Percentage of Participants Developing Anti-Drug Antibodies to LY2944876 | Percentage of participants developing anti-drug antibodies to LY2944876. | Week 12 and Week 24 | 
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2944876 | Evaluable pharmacokinetic concentrations from the specified timepoints were combined and utilized in a population approach to determine the population mean estimate and standard deviation at steady-state. | Baseline, Week 8, Week 12, Week 16, Week 20, Week 24 | 
| Pharmacokinetics: Area Under the Concentration Curve (AUC) of LY2944876 | Evaluable pharmacokinetic concentrations from the specified timepoints were combined and utilized in a population approach to determine the population mean estimate and standard deviation at steady-state. | Baseline, Week 8, Week 12, Week 16, Week 20, Week 24 | 
| Change From Baseline in Adiponectin Levels | LSM are calculated from MMRM analysis using REML with metformin use, baseline BMI category, baseline HbA1c category, country, treatment, visit, and treatment-by-visit interaction as fixed effects, baseline parameter result as a covariate, and participant as a random effect. | Baseline, Week 12; Baseline, Week 24 | 
| Change From Baseline in Beta-Hydroxy Butyrate Levels | LSM are calculated from MMRM analysis using REML with metformin use, baseline BMI category, baseline HbA1c category, country, treatment, visit, and treatment-by-visit interaction as fixed effects, baseline parameter result as a covariate, and participant as a random effect. | Baseline, Week 12; Baseline, Week 24 | 
| Change From Baseline in Glucagon Levels | LSM are calculated from MMRM analysis using REML with metformin use, baseline BMI category, baseline HbA1c category, country, treatment, visit, and treatment-by-visit interaction as fixed effects, baseline parameter result as a covariate, and participant as a random effect. | Baseline, Week 12; Baseline, Week 24 | 
| Change From Baseline in Insulin Levels | LSM are calculated from MMRM analysis using REML with metformin use, baseline BMI category, baseline HbA1c category, country, treatment, visit, and treatment-by-visit interaction as fixed effects, baseline parameter result as a covariate, and participant as a random effect. | Baseline, Week 12; Baseline, Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Weight loss