Effect of Tirzepatide on Progression of Coronary Atherosclerosis Using MDCT

Study Overview
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Brief Summary
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A multi-center, randomized, double-blind, placebo-controlled, parallel-group phase IV Study evaluating the effects of tirzepatide on atherosclerotic plaque progression assessed by coronary computed tomography angiography (CCTA) in participants with a diagnosis of type II Diabetes (T2DM) and atherosclerosis.

Detailed Description
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This is a multi-center study in which 120 male and female participants who meet the eligibility criteria will be randomized. Study will assess changes in coronary atheroma volume comparing tirzepatide 15 mg/week plus Standard of Care (SOC), as compared to placebo plus SOC. Potential eligible participants may be prescreened for eligibility prior to the screening visit and must have a diagnosis of atherosclerosis (as assessed by >10% atheroma on CCTA) and T2DM. Patients must be on a stable medical regiment (>4 weeks on statin therapy and diabetes medications) and undergo screening CCTA to demonstrate coronary plaque. Participant eligibility will be assessed by the Imaging Core Lab. If the participant meets all entry criteria during baseline visit, then consenting participants will be randomized 1:1 to receive tirzepatide on top of standard of care for treatment period of 12 months. Participants will be asked to maintain stable doses of statins and diabetes medications. Persistent hyperglycemia will be treated by primary physician or endocrinologist,

Official Title
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Effect of Tirzepatide on Progression of Coronary Atherosclerosis Using MDCT

Conditions
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Type II Diabetes, Atherosclerosis

Intervention / Treatment
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* Drug: Tirzepatide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female 40 years to 80 years of age at signing of informed consent Type 2 DM of minimum 5 years duration with HbA1c ≥7.0% to ≤10.5% Body mass index (BMI) ≥25 kilograms per meter squared (kg/m²) Presence of two discrete coronary artery plaques with visual diameter stenosis >20% on CCTA At the baseline visit, participants must be on a stable (>4 weeks) regiment of diabetes medications. Patients using oral hormonal contraceptives must switch to a non-oral contraceptive method, or add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation Exclusion Criteria: Have had a major cardiovascular event within the last 60 days Have type 1 diabetes mellitus Current use of GLP1-RA Have a history of severe hypoglycemia and/or hypoglycemia unawareness within the last 6 months Are currently planning treatment for diabetic retinopathy and/or macular edema Have history of, or currently planning a coronary, carotid, or peripheral artery revascularization (ie - stent, bypass) Have a history of pancreatitis Have a history of ketoacidosis or hyperosmolar state/coma Have a known clinically significant gastric emptying abnormality, have undergone or currently planning any gastric outlet obstruction, or have undergone or currently planning any gastric bypass (bariatric) surgery or restrictive bariatric surgery Have a history of an active or untreated malignancy or are in remission from a clinically significant malignancy for less than 5 years Have a family or personal history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN-2) Have had a blood transfusion or severe blood loss within 90 days prior to screening or have known hematological conditions that may interfere with HbA1c measurement Planned or Prior Bypass surgery Contradiction for CCTA (e.g. serious allergic reaction to the contrast dye) or CCTA not meeting entry standards after two attempts during the Baseline CCTA visit as assessed by the imaging core lab. Uncontrolled severe hypertension: systolic blood pressure > 180 mmHg or diastolic BP > 100 mm Hg prior to randomization (assessed at the screening visit) despite antihypertensive therapy Heart Failure NYHA Class III or IV at the screening visit Renal insufficiency (eGFR <40 ml/min/1.73m2) as measured by the Modification of Diet in Renal Disease (MDRD) formula at the screening visit. Hospitalization for major cardiovascular event including heart failure in the past 2 months

Ages Eligible for Study
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Minimum Age: 40 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: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double blind Placebo controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tirzepatide<br>Tirzepatide 15mg Prefilled pen for weekly subcutaneous injection over 52 weeks | Drug: Tirzepatide<br>* Tirzepatide 15mg Subcutaneous Solution<br>* Other names: Mounjaro;|
| Placebo Comparator: Placebo<br>Placebo Prefilled pen (volume matched) for weekly subcutaneous injection over 52 weeks | Drug: Placebo<br>* Volume matched Subcutaneous Solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of total non-calcified coronary plaque volume | Reduction of total non-calcified coronary plaque volume from baseline (start of the study) till the final visit will be measured using Coronary Computed Tomography Angiography (CCTA). | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of low attenuation plaque volume | Reduction change in low attenuation plaque volume from baseline (start of the study) till the final visit will be measured using Coronary Computed Tomography Angiography (CCTA) | 12 months | 
| Reduction of total plaque volume, fibrous, lipid-rich and calcified plaque volumes using CCTA | Reduction change of total plaque volume, fibrous, lipid-rich and calcified plaque volumes will be compared between baseline and at the end of the study. | 12 months | 
| Change in HgA1c lab values in the blood. | Change in HgA1c lab values in the blood will be compared between baseline and at the end of the study. | 12 months |