A Study of Tirzepatide (LY3298176) on the Reduction on Morbidity and Mortality in Adults With Obesity

Study Overview
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Brief Summary
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This study will investigate the effect of tirzepatide on the reduction of morbidity and mortality in adults living with obesity and provide additional evidence for the potential clinical benefits of tirzepatide in this population.

Official Title
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A Phase 3, Randomized, Double-blind, Placebo-Controlled Study to Investigate the Effect of Tirzepatide on the Reduction of Morbidity and Mortality in Adults With Obesity

Conditions
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Obesity, Overweight

Intervention / Treatment
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* Drug: Tirzepatide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a body mass index (BMI) ≥27.0 kilogram/square meter (kg/m ²) Are either individuals ≥40 years of age with established cardiovascular disease (CVD). CVD is defined as meeting at least one of the following: Coronary artery disease Cerebrovascular disease Peripheral arterial disease OR individuals without established CVD but have the presence of cardiovascular (CV) risk factors (primary prevention) women 55-69 years of age or men 50-64 years of age with at least 3 risk factors like tobacco use, dyslipidemia, hypertension at screening, or women ≥70 years of age or men, ≥65 years of age with at least 2 risk factors at screening. Exclusion Criteria: Have type 1 diabetes (T1D) or (T2D), history of ketoacidosis, or hyperosmolar state/coma Have laboratory evidence diagnostic of diabetes mellitus at screening of HbA1c ≥6.5% (≥48 millimole/mole (mmol/mol) or fasting glucose (FG) ≥126 milligram/deciliter (≥7.0 millimole/liter (mmol/L). Any one of the following CV conditions within 90 days prior to screening MI acute coronary syndrome stroke coronary or peripheral arterial revascularization procedure, which may also include carotid artery revascularization, or acute decompensated heart failure Have a known clinically significant gastric emptying abnormality such as severe gastroparesis or gastric outlet obstruction or have undergone or currently planning any gastric bypass (metabolic) surgery or restrictive bariatric surgery. Note: Liposuction or abdominoplasty are not considered as gastric bypass procedures. Have a history of chronic or acute pancreatitis Have a family or personal history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Have acute or chronic hepatitis, or clinical signs or symptoms of any other liver disease, or have elevated liver enzyme measurements, determined by the central laboratory at screening Have a presence or history of malignant neoplasms within the past 5 years prior to screening.

Ages Eligible for Study
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Minimum Age: 40 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: Tirzepatide<br>Participants will receive escalated doses of tirzepatide subcutaneously (SC) up to a maximum tolerated dose. | Drug: Tirzepatide<br>* Administered SC<br>* Other names: LY3298176;|
| Placebo Comparator: Placebo<br>Participants will receive tirzepatide matched placebo. | Drug: Placebo<br>* Administered SC<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Occurrence of Any Component Event of Composite (All-Cause Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Coronary Revascularization, or Heart Failure Events) | Time to first occurrence of any component event of composite, all-cause death, nonfatal MI, nonfatal stroke, coronary revascularization, or heart failure events that results in hospitalization or urgent visits. | Up to 5 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Onset of Type 2 Diabetes (T2D) |  | Up to 5 Years | 
| Hierarchical Composite of Renal Death or End-Stage Renal Disease (ESRD), Sustained Decline in Estimated Glomerular Filtration Rate (eGFR), and eGFR Slope | Hierarchical composite of time to first occurrence of renal death or ESRD, ≥57% sustained decline in eGFR, ≥40% sustained decline in eGFR, and eGFR slope difference >0.5 milliliter/minute/1.73 square meter/year (mL/min/1.73 m²/year) will be assessed by the win ratio. The reported unit will be the total wins for each treatment group from performing a hierarchical comparison of components. | Estimated from Baseline (Week 0) to Study Completion Up to 5 Years | 
| Time to First Occurrence of Any Component Event of Major Adverse Cardiovascular Events-3 (MACE-3) (CV Death, Nonfatal MI or Nonfatal Stroke) | Time to first occurrence of any component event of MACE-3 (CV death, nonfatal MI or nonfatal stroke) | Up to 5 Years | 
| Mean Change from Baseline Short Form-36 Version 2 (SF-36 v2) Acute Form Physical Functioning Domain Score | The SF-36 v2 acute, 1-week recall version is a 36-item generic, participant-administered measure designed to assess the following 8 domains (Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role - Emotional, and Mental Health. Each domain is scored individually and further aggregated into 2 health component summary scores, physical component and mental component summary. Scoring of each domain and both summary scores are norm-based and presented in the form of T-scores, with a mean of 50 and standard deviation of 10; higher scores indicate better levels of function and/or better health. | Baseline, 2 Years | 
| Time to the Occurrence of All-cause Death |  | Up to 5 Years | 
| Time to First Occurrence of CV Death |  | Up to 5 Years | 
| Time to First Occurrence of MI |  | Up to 5 Years | 
| Time to First Occurrence of Stroke |  | Up to 5 Years | 
| Time to First Occurrence of Coronary Revascularization |  | Up to 5 Years | 
| Time to First Occurrence Heart Failure (HF) Events | Time to first occurrence heart failure (HF) events that result in hospitalization or urgent visits | Up to 5 Years | 
| Time to First Occurrence of Hospitalization for Unstable Angina |  | Up to 5 Years | 
| Time to first occurrence of Hospitalization or Urgent Visit | Time to first occurrence of hospitalization or urgent visit due to atrial fibrillation, or cardioversion or ablation for atrial fibrillation | Up to 5 Years | 
| Time to First Occurrence of Any Component Event of the Composite Endpoint (eGFR, ESRD, or Renal Death) | Time to first occurrence of any component event of the composite endpoint ≥40% sustained decline in eGFR, ESRD, or renal death. | Up to 5 Years | 
| eGFR Slope |  | Up to 5 Years | 
| Percent Change from Baseline in Body Weight |  | Baseline, 156 Weeks | 
| Change from Baseline in Systolic Blood Pressure (SBP) in Millimeter Mercury (mmHg) |  | Baseline, 156 Weeks | 
| Change from Baseline Diastolic Blood Pressure (DBP) (mmHg) |  | Baseline, 156 Weeks | 
| Percentage of Participants with Hemoglobin A1c (HbA1c) <39 Millimole/Mole (mmol/mol) (5.7%) | Percentage of participants with HbA1c <39 mmol/mol (5.7%) at each time where HbA1c is assessed for participants with a screening HbA1c ≥39 mmol/mol. | Up to 5 Years |