A Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes Mellitus

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy of the study drug tirzepatide in participants with type 2 diabetes mellitus.

Official Title
-----------------
A Phase 2 Study of Once-Weekly LY3298176 Compared With Placebo and Dulaglutide in Patients With Type 2 Diabetes Mellitus

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

Intervention / Treatment
-----------------
* Drug: tirzepatide
* Drug: Dulaglutide
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Have had type 2 diabetes (T2D) for ≥6 months according to the World Health Organization (WHO) classification. Have HbA1c of 7.0% to 10.5%, inclusive, as assessed by the central laboratory. If on metformin, have been treated with stable doses of metformin for at least 3 months. Have a body mass index (BMI) ≥23 and <50 kilograms per square meter. Exclusion Criteria: Have type 1 diabetes (T1D). Have used any glucose-lowering medication other than metformin within 3 months prior to study entry or during screening/lead-in period or have used any glucagon-like peptide-1 receptor agonists (GLP-1 RAs) at any time in the past. Have had any of the following cardiovascular conditions: acute myocardial infarction (MI), New York Heart Association Class III or Class IV heart failure, or cerebrovascular accident (stroke). Have acute or chronic hepatitis, signs and symptoms of any other liver disease other than nonalcoholic fatty liver disease (NAFLD), or alanine aminotransferase (ALT) level >2.5 times the upper limit of the reference range, as determined by the central laboratory at study entry; participants with NAFLD are eligible for participation in this trial. Have had chronic or acute pancreatitis any time prior to study entry. Have an estimated glomerular filtration rate (eGFR) <45 milliliters/minute/1.73 square meter, calculated by the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation. Have serum calcitonin ≥20 picograms per milliliter, as determined by the central laboratory at study entry. Have any condition that is a contraindication for use of the GLP-1 RA class (per country-specific labels) at study entry or develop such condition between study entry and randomization.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Tirzepatide placebo and dulaglutide placebo administered subcutaneously (SC) once weekly. | Drug: Placebo<br>* Administered SC<br>|
| Experimental: 1 mg Tirzepatide<br>1 milligrams (mg) tirzepatide administered SC once weekly. Dulaglutide placebo administered SC once weekly. | Drug: tirzepatide<br>* Administered SC<br>* Other names: LY3298176;Drug: Placebo<br>* Administered SC<br>|
| Experimental: 5 mg Tirzepatide<br>5 mg tirzepatide administered SC once weekly. Dulaglutide placebo administered SC once weekly. | Drug: tirzepatide<br>* Administered SC<br>* Other names: LY3298176;Drug: Placebo<br>* Administered SC<br>|
| Experimental: 10 mg Tirzepatide<br>10 mg tirzepatide administered SC once weekly. Dulaglutide placebo administered SC once weekly. | Drug: tirzepatide<br>* Administered SC<br>* Other names: LY3298176;Drug: Placebo<br>* Administered SC<br>|
| Experimental: 15 mg Tirzepatide<br>15 mg tirzepatide administered SC once weekly. Dulaglutide placebo administered SC once weekly. | Drug: tirzepatide<br>* Administered SC<br>* Other names: LY3298176;Drug: Placebo<br>* Administered SC<br>|
| Active Comparator: 1.5 mg Dulaglutide<br>1.5 mg Dulaglutide administered SC once weekly. Tirzepatide placebo administered SC once weekly. | Drug: Dulaglutide<br>* Administered SC<br>* Other names: LY2189265;Drug: Placebo<br>* Administered SC<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 26 in Hemoglobin A1c (HbA1c) Bayesian Dose Response | HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.This was a Bayesian dose response analysis of HbA1c (%) change from baseline. At baseline: Mean (SD = Standard Deviation) of baseline HbA1c (%). After baseline: Posterior Mean (SD = Posterior Standard Deviation) of HbA1c (%) change from baseline. The Least Squares Mean is Posterior mean. | Baseline, Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 12 in Hemoglobin A1c (HbA1c) Bayesian Dose Response | HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. This was a Bayesian dose response analysis of HbA1c (%) change from baseline. At baseline: Mean (SD = Standard Deviation) of baseline HbA1c (%). After baseline: Posterior Mean (SD = Posterior Standard Deviation) of HbA1c (%) change from baseline. The Least Squares Mean is Posterior mean. | Baseline, Week 12 | 
| Change From Baseline to Week 26 in HbA1c | HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. The Least Squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included the independent variables: Baseline + Baseline BMI Group + Baseline Metformin Flag + Treatment + Time + Treatment*Time. | Baseline, Week 26 | 
| Change From Baseline to Week 12 in HbA1c | HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. The Least Squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included the independent variables: Baseline + Baseline BMI Group + Baseline Metformin Flag + Treatment + Time + Treatment*Time. | Baseline, Week 12 | 
| Change From Baseline in Body Weight | Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with independent variables: Baseline + Baseline HbA1C Group + Baseline BMI Group + Baseline Metformin Flag + Treatment + Time + Treatment*Time. | Baseline, Week 26 | 
| Percentage of Participants With 5% or Greater Body Weight Loss From Baseline | Percentage of participants with 5% or greater body weight loss from baseline last observation carried forward (LOCF) analyses using Logistic regression model with Baseline value + Baseline HbA1C Group + Baseline BMI Group + Baseline Metformin + Treatment as factors. | Week 26 | 
| Percentage of Participants With 10% or Greater Body Weight Loss From Baseline | Percentage of participants with 10% or greater body weight loss from baseline LOCF analyses using Logistic regression model with Baseline value + Baseline HbA1C Group + Baseline BMI Group + Baseline Metformin + Treatment as factors. | Week 26 | 
| Percentage of Participants Reaching the HbA1c Target of ≤6.5% | Percentage of participants with HbA1c ≤6.5% at Week 26 using a logistic regression model for endpoint used last observation carried forward (LOCF) method including baseline value, baseline BMI Group, baseline Metformin and treatment as factors. | Week 26 | 
| Percentage of Participants Reaching the HbA1c Target of <7.0% | Percentage of participants with HbA1c <7.0% at Week 26 using a logistic regression model for endpoint used last observation carried forward (LOCF) method including baseline value, baseline BMI Group, baseline Metformin and treatment as factors. | Week 26 | 
| Change From Baseline in Fasting Blood Glucose | Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with covariates: Baseline + Baseline HbA1C Group + Baseline BMI Group + Baseline Metformin Flag + Treatment + Time + Treatment*Time. | Baseline, Week 26 | 
| Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) | LS means were calculated using MMRM model with independent variables: Baseline, Baseline HbA1C Group, Baseline BMI Group, Baseline Metformin Flag,Treatment, time, treatment*time. | Baseline, Week 26 | 
| Change From Baseline in Total Cholesterol | LS means were calculated using MMRM model with independent variables: Baseline, Baseline HbA1C Group, Baseline BMI Group, Baseline Metformin Flag, Treatment, Time, Treatment*Time. | Baseline, Week 26 | 
| Change From Baseline in Triglycerides | LS means were calculated using MMRM model with independent variables: Baseline, Baseline HbA1C Group, Baseline BMI Group, Baseline Metformin Flag, Treatment, Time, Treatment*Time. | Baseline, Week 26 | 
| Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) | LS means were calculated using MMRM model with independent variables: Baseline, Baseline HbA1C Group, Baseline BMI Group, Baseline Metformin Flag, Treatment, Time, Treatment*Time. | Baseline, Week 26 | 
| Change From Baseline in Waist Circumference | LS means were calculated using MMRM model with independent variables: Baseline, Baseline HbA1C Group, Baseline BMI Group, Baseline Metformin Flag, Treatment, Time, Treatment*Time. | Baseline, Week 26 | 
| Number of Participants With Anti-Drug Antibodies | Number of Participants With Anti-Drug Antibodies. | Baseline through Week 30 | 
| Pharmacokinetics (PK): Model Predicted Concentration at Steady State (Css) of Tirzepatide | Pharmacokinetics (PK): Model Predicted Concentration at Steady State (Css) of Tirzepatide | Predose: Week 1,8,12 and 26; Postdose: Week 1,2,4 and 12 |