Thromboxane Receptor Antagonist to Improve Endothelial Cell Function

Study Overview
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Brief Summary
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This study evaluates whether addition of the thromboxane receptor antagonist to chronic aspirin therapy improves endothelial function and reduces non-platelet thromboxane generation in patients with established cardiovascular disease. Half of participants will receive ifetroban and the other half will receive matchcing placebo for the 4 week study period.

Detailed Description
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Thromboxane is a prostaglandin produced in healthy individuals mainly in platelets, where it mediates platelet activation and vasoconstriction via binding to cellular thromboxane-prostanoid (TP) receptors. The cardioprotective effect of aspirin is due to suppression of platelet thromboxane generation and reactivity. Unfortunately 25-50% of patients with cardiovascular disease taking ASA continue to generate thromboxane from non-platelet sources, which significantly increases their risk of atherothrombosis and death. Evidence suggests that oxidative stress is a potent stimulus for thromboxane generation in endothelial cells that involves autocrine/paracrine signaling through the TP receptor. This clinical trial addresses the central hypothesis that vascular endothelial cells under oxidative stress are a major source of non-platelet thromboxane generation in patients with cardiovascular disease and that antagonism of the TP receptor will suppress its formation and improve endothelial function.

Official Title
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The Thromboxane Receptor Antagonist to Blunt the Effects of Non-Platelet Thromboxane Generation and Improve Endothelial Cell Function (TRAP) Trial

Conditions
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Cardiovascular Diseases, Vascular Dilation

Intervention / Treatment
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* Drug: Ifetroban Sodium
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females ≥18 years of age with established cardiovascular disease Take 81 mg daily of aspirin as part of their daily medical regimen Urine thromboxane B2 metabolites >1500 pg/mg creatinine on screening. Able to provide written consent and comply with protocol-specific procedures. Exclusion Criteria: Chronic oral anticoagulation. ST segment myocardial infarction within 1 month. Cardiac surgery within 1 month. Ongoing uncontrolled severe inflammatory condition. Pregnant or lactating. Ifetroban or aspirin sensitivity Inability to perform vascular testing.

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
Interventional Model Description: Single center, prospectively randomized, double-blinded, placebo-controlled clinical trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ifetroban<br>Ifetroban 250 mg oral capsule administered once daily for a minimum of 4 weeks. | Drug: Ifetroban Sodium<br>* Ifetroban sodium 250 mg capsule once daily for 4 weeks<br>|
| Placebo Comparator: Placebo<br>Matching placebo administered once daily for a minimum of 4 weeks. | Other: Placebo<br>* Placebo arm to match Ifetroban Sodium once daily for 4 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peripheral Arterial Tonometry | Change in Reactive Hyperemia Index (RHI) | Baseline to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brachial vasoractivity | Change in Percent flow-mediated vasodilation (FMD) | Baseline to 4 weeks | 
| Non-platelet thromboxane generation | Change in urine 11-dehydrothromboxane B2 | Baseline to 4 weeks |