Thromboxane Receptor Antagonist to Improve Endothelial Function (TRAP)

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

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 matching placebo for the 4 week study period.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Diseases; Vascular Dilation
• Intervention / Treatment: Drug: Ifetroban Sodium; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Medical School

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Males and females 18-80 years of age with established cardiovascular disease
• Take >=81 mg daily of aspirin as part of their daily medical regimen
• Urine thromboxane B2 metabolites >1145 pg/mg creatinine on screening.
• Able to provide written consent and comply with protocol-specific procedures.

Exclusion Criteria:

• Chronic oral anticoagulation with a non-vitamin K antagonist.
• Anticipated change or interruption in aspirin therapy during the study period.
• ST segment myocardial infarction within the past 30 days.
• Cardiac surgery within the past 30 days.
• Stage 4-5 renal failure or on renal replacement therapy.
• An ongoing uncontrolled severe inflammatory condition.
• Pregnant,intending to become pregnant or breast feeding.
• Known ifetroban or aspirin sensitivity Inability to perform vascular testing.
• Participation in another investigational drug trial within 30 days of randomization.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Reactive Hyperemia Index (RHI)	The change in Reactive Hyperemia Peripheral Index (RHI) as measured by Arterial Tonometry. The Reactive Hyperemia Index (RHI) is calculated as the ratio of post- to pre-occlusion peripheral arterial tone signals on the occluded side, normalized to the control side, and further adjusted for baseline vascular tone. RHI is automatically measured by the EndoPAT 2000 software. According to the manufacturer, an RHI value greater than 1.67 is considered normal, while a lower value indicates endothelial dysfunction and is associated with an increased risk of cardiovascular events.	Baseline to 4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Percent Flow-mediated Vasodilation (FMD)	The measure is the change in flow-mediated vasodilation (FMD) as measured by Brachial vasoractivity	Baseline to 4 weeks
Change in Urinary TXB2-M	Urinary urinary TXB2-M measured by 11-dhTXB2 ELISA	Baseline to 4 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oxidative stress	Change in urine 8-isoPGF2a	Baseline to 4 weeks
Renal Prostanoid Excretion	Change in urine TXB2, 6-ketoPGF1α and the ratio of TXB2 to 6-ketoPGF1α,	Baseline to 4 weeks
Prostacyclin Generation	Change in urine 2,3-dinor-6-ketoPGF1α and ratio of 11-dhTXB2 to 2,3-dinor-6-ketoPGF1α	Baseline to 4 weeks
Inflammatory Markers	Change in hs-CRP and ICAM-1	Baseline to 4 weeks
Coagulation Markers	Change in soluble tissue factor and activated protein C	Baseline to 4 weeks
Renal Function	Change in eGFR	Baseline to 4 weeks
Cardiac Function	Change in NT pro-BNP	Baseline to 4 weeks

Collaborators and Investigators

• Sponsor: Jeffrey Rade
• Collaborators: American Heart Association; Cumberland Pharmaceuticals
• Investigators: Principal Investigator: Jeffrey J Rade, MD, University of Massachusetts, Worcester

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2019
• Primary Completion (Actual): November 7, 2022
• Study Completion (Actual): November 15, 2022

Study Registration Dates

• First Submitted: May 21, 2019
• First Submitted That Met QC Criteria: May 21, 2019
• First Posted (Actual): May 24, 2019

Study Record Updates

• Last Update Posted (Actual): December 5, 2024
• Last Update Submitted That Met QC Criteria: November 18, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Platelet Aggregation Inhibitors; Ifetroban
• Other Study ID Numbers: UMMS-TPRA-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No