A Study of Tirzepatide (LY3298176) Versus Placebo in Participants With Type 2 Diabetes Inadequately Controlled on Insulin Glargine With or Without Metformin

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to compare the safety and efficacy of the study drug tirzepatide to placebo in participants with type 2 diabetes that are already on insulin glargine, with or without metformin. Participants will administer tirzepatide or placebo along with their previous glucose lowering medications. The study will last approximately 47 weeks and may include about 23 visits.

Official Title
-----------------
Randomized, Phase 3, Double-blind Trial Comparing the Effect of the Addition of Tirzepatide Versus Placebo in Patients With Type 2 Diabetes Inadequately Controlled on Insulin Glargine With or Without Metformin

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

Intervention / Treatment
-----------------
* Drug: Tirzepatide
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Have been diagnosed with type 2 diabetes mellitus (T2DM) and have been treated with insulin glargine (U100), once daily with or without metformin ≥3 months prior to screening visit. Have HbA1c between ≥7.0% and ≤10.5%. Have a stable weight (± 5%) for at least 3 months before screening. Have a body mass index (BMI) ≥23 kilograms per meter squared (kg/m²) at screening. Exclusion Criteria: Have type 1 diabetes mellitus. Have had chronic or acute pancreatitis any time prior to study entry. Have proliferative diabetic retinopathy or diabetic maculopathy or nonproliferative diabetic retinopathy requiring acute treatment. Have disorders associated with slowed emptying of the stomach, or have had any stomach surgeries for the purpose of weight loss. Have an estimated glomerular filtration rate <30 mL/minute/1.73 m² [for participants on metformin, estimated glomerular filtration rate <45 mL/min/1.73 m2 (or lower than the country-specific threshold for using the protocol-required dose of metformin per local label)] Have had a heart attack, stroke, or hospitalization for congestive heart failure in the past 2 months. Have a personal or family history of medullary thyroid carcinoma or personal history of multiple endocrine neoplasia syndrome type 2. Have been taking weight loss drugs, including over-the-counter medications during the last 3 months.

Ages Eligible for Study
-----------------
Minimum Age: 18 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 |
| --- | --- |
| Experimental: 5 mg Tirzepatide<br>5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week. | Drug: Tirzepatide<br>* Administered SC as add-on to the pre-trial background medication.<br>* Other names: LY3298176;|
| Experimental: 10 mg Tirzepatide<br>10 mg tirzepatide administered SC once a week. | Drug: Tirzepatide<br>* Administered SC as add-on to the pre-trial background medication.<br>* Other names: LY3298176;|
| Experimental: 15 mg Tirzepatide<br>15 mg tirzepatide administered SC once a week. | Drug: Tirzepatide<br>* Administered SC as add-on to the pre-trial background medication.<br>* Other names: LY3298176;|
| Placebo Comparator: Placebo<br>Placebo administered SC once a week. | Drug: Placebo<br>* Administered SC as add-on to the pre-trial background medication.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg) | HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Baseline Metformin Use (Yes, No) + Pooled Country + Treatment + Time + Treatment*Time (Type III sum of squares). | Baseline, Week 40 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HbA1c (5 mg) | HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Baseline Metformin Use (Yes, No) + Pooled Country + Treatment + Time + Treatment*Time (Type III sum of squares). | Baseline, Week 40 | 
| Change From Baseline in Body Weight | Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Baseline HbA1c Group (<= 8.0%, >8.0%) + Baseline Metformin Use (Yes, No) + Pooled Country + Treatment + Time + Treatment*Time (Type III sum of squares). | Baseline, Week 40 | 
| Percentage of Participants Achieving an HbA1c Target Value of <7% | Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A.HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. | Week 40 | 
| Change From Baseline in Fasting Serum Glucose | Fasting serum glucose (FSG) is a test to determine sugar levels in serum sample after an overnight fast. LS Mean was determined by MMRM model with Baseline + Pooled Country + Baseline Metformin Use (Yes, No) + Baseline HbA1c Group (<= 8.0%, >8.0%) + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. | Baseline, Week 40 | 
| Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values | The self-monitored plasma glucose (SMBG) data were collected at the following 7 time points: Morning Premeal - Fasting, Morning 2-hour Postmeal, Midday Premeal, Midday 2-hour Postmeal, Evening Premeal, Evening 2-hour Postmeal and Bedtime. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Baseline HbA1c Group (<= 8.0%, >8.0%) + Baseline Metformin Use (Yes, No) + Pooled Country + Treatment (Type III sum of squares). | Baseline, Week 40 | 
| Percentage of Participants Who Achieved Weight Loss ≥5% | Percentage of Participants who Achieved Weight Loss ≥5%. | Week 40 | 
| Percentage Change From Baseline in Daily Mean Insulin Glargine Dose | LS mean was calculated using MMRM model with log (Baseline) + Baseline Metformin Use (Yes, No) + Pooled Country + Baseline HbA1c Group (<= 8.0%, >8.0%) + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. | Baseline, Week 40 | 
| Rate of Hypoglycemia With Blood Glucose <54 Milligram/Deciliter (mg/dL) [<3.0 Millimole/Liter (mmol/L)] or Severe Hypoglycemia | The hypoglycemia events were defined by participant reported events with blood glucose <54mg/dL) (<3.0 mmol/L] or severe hypoglycemia. Severe hypoglycemia is defined as an episode with severe cognitive impairment requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. The rate of postbaseline hypoglycemia was estimated by negative binomial model: number of episodes = Pooled Country + Baseline Metformin Use (Yes, No) + Baseline HbA1c Group (<= 8.0%, >8.0%) + Treatment, with log (exposure in days/365.25) as an offset variable. | Baseline through Safety Follow-Up (Up to Week 44) | 
| Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve (AUC) of Tirzepatide | AUC is a combined measure obtained from Week 7, 15, 23 and 39 and a single averaged measure of AUC was reported. | Week 7, 15, 23 and 39 post dose | 
| Percentage of Participants Achieving an HbA1c Target Value of <5.7% | Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. | Week 40 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), GIP/GLP-1 dual receptor agonist, T2DM