A Study of Tirzepatide (LY3298176) Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes

Study Overview
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Brief Summary
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The reason for this study is to compare the effect of the study drug tirzepatide to semaglutide on blood sugar levels in participants with type 2 diabetes. The study will last approximately 47 weeks and may include about 12 visits.

Official Title
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A Phase 3, Randomized, Open-Label Trial Comparing Efficacy and Safety of Tirzepatide Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Patients With Type 2 Diabetes

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Tirzepatide
* Drug: Semaglutide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have been diagnosed with type 2 diabetes mellitus (T2DM) Have HbA1c between ≥7.0% and ≤10.5% Be on stable treatment with unchanged dose of metformin >1500 mg/day for at least 3 months prior to screening Be of stable weight (±5%) for at least 3 months before screening Have a body mass index (BMI) ≥25 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 acute or chronic hepatitis, signs and symptoms of any other liver disease, or blood alanine transaminase (ALT) enzyme level >3.0 times the upper limit of normal (ULN) for the reference range, as determined by the central laboratory. Participants with nonalcoholic fatty liver disease (NAFLD) are eligible for participation in this trial only if there ALT level is ≤3.0 the ULN for the reference range Have an estimated glomerular filtration rate <45 milliliters/minute/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 any other diabetes medicines other than metformin during the last 3 months Have been taking weight loss drugs, including over-the-counter medications during the last 3 months

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


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<br>* Other names: LY3298176;|
| Experimental: 10 mg Tirzepatide<br>10 mg tirzepatide administered SC once a week. | Drug: Tirzepatide<br>* Administered SC<br>* Other names: LY3298176;|
| Experimental: 15 mg Tirzepatide<br>15 mg tirzepatide administered SC once a week. | Drug: Tirzepatide<br>* Administered SC<br>* Other names: LY3298176;|
| Active Comparator: 1 mg Semaglutide<br>1 mg semaglutide administered SC once a week. | Drug: Semaglutide<br>* Administered SC<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) (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 + 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 + 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 + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + 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 (FSG) | Fasting serum glucose (FSG) is a test to determine sugar levels in serum sample after an overnight fast. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Treatment + Time + Treatment*Time (Type III sum of squares). | 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 + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Treatment + Time + Treatment*Time (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 | 
| Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score | DTSQc, an 8-item questionnaire, assesses relative change in treatment satisfaction perceived frequency of hyperglycemia, and perceived frequency of hypoglycemia from baseline to week 40 or early termination. The questionnaire consists of 8 items, 6 of which (1 and 4 through 8) assess treatment satisfaction. Each item is rated on a 7-point Likert scale. The scores from the 6 treatment satisfaction items are summed to a Total Treatment Satisfaction Score, which ranges from -18 to 18 where the higher the score the greater the improvement in satisfaction with treatment. The lower the score the greater the deterioration in satisfaction with treatment. The hyperglycemia and hypoglycemia scores range from -3 to 3 where negative scores indicate fewer problems with blood glucose levels and positive scores indicate more problems than before. LS Mean was determined by ANCOVA with Baseline DTSQs + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Treatment (Type III sum of squares). | 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 HbA1c Group (<=8.5%, >8.5%) + Treatment. | Baseline through Safety Follow-Up (Up to Week 44) | 
| Percentage of Participants Achieving an HbA1c Target Value of <5.7% | Percentage of Participants Achieving an HbA1c Target Value of <5.7%. | Week 40 | 

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