Cardiovascular Diseases, Vascular Dilation
Conditions
Brief summary
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.
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.
Interventions
DRUGIfetroban Sodium
Ifetroban sodium 250 mg capsule once daily for 4 weeks
DRUGPlacebo
Placebo arm to match Ifetroban Sodium once daily for 4 weeks.
Sponsors
American Heart Association
Cumberland Pharmaceuticals
Jeffrey Rade
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Single center, prospectively randomized, double-blinded, placebo-controlled clinical trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Reactive Hyperemia Index (RHI) | Baseline to 4 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Percent Flow-mediated Vasodilation (FMD) | Baseline to 4 weeks | The measure is the change in flow-mediated vasodilation (FMD) as measured by Brachial vasoractivity |
| Change in Urinary TXB2-M | Baseline to 4 weeks | Urinary urinary TXB2-M measured by 11-dhTXB2 ELISA |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ifetroban Ifetroban 250 mg oral capsule administered once daily for a minimum of 4 weeks.
Ifetroban Sodium: Ifetroban sodium 250 mg capsule once daily for 4 weeks | 29 |
| Placebo Matching placebo administered once daily for a minimum of 4 weeks.
Placebo: Placebo arm to match Ifetroban Sodium once daily for 4 weeks. | 28 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 0 | 2 |
Baseline characteristics
| Characteristic | Ifetroban | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 63.3 Years STANDARD_DEVIATION 10.2 | 63 Years STANDARD_DEVIATION 8.62 | 62.4 Years STANDARD_DEVIATION 9.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 26 Participants | 52 Participants | 26 Participants |
| Region of Enrollment United States | 29 participants | 57 participants | 28 participants |
| Sex: Female, Male Female | 10 Participants | 19 Participants | 9 Participants |
| Sex: Female, Male Male | 19 Participants | 38 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 1 / 28 |
| other Total, other adverse events | 18 / 29 | 17 / 28 |
| serious Total, serious adverse events | 0 / 29 | 3 / 28 |
Outcome results
Primary
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.
Time frame: Baseline to 4 weeks
Population: 5 participants were withdrawn from the placebo group
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ifetroban | Change in Reactive Hyperemia Index (RHI) | -0.01 percentage index change |
| Placebo | Change in Reactive Hyperemia Index (RHI) | 0.21 percentage index change |
Secondary
Change in Percent Flow-mediated Vasodilation (FMD)
The measure is the change in flow-mediated vasodilation (FMD) as measured by Brachial vasoractivity
Time frame: Baseline to 4 weeks
Population: 5 participants from the placebo group were withdrawn from the study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ifetroban | Change in Percent Flow-mediated Vasodilation (FMD) | 11.36 percentage |
| Placebo | Change in Percent Flow-mediated Vasodilation (FMD) | -15.83 percentage |
Secondary
Change in Urinary TXB2-M
Urinary urinary TXB2-M measured by 11-dhTXB2 ELISA
Time frame: Baseline to 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ifetroban | Change in Urinary TXB2-M | 370.7 pg/mg creatinine |
| Placebo | Change in Urinary TXB2-M | -210.9 pg/mg creatinine |