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The Impact of Factor Xa Inhibition on Thrombosis, Platelet Activation, and Endothelial Function in Peripheral Artery Disease

Primary Purpose

Peripheral Arterial Disease

Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Rivaroxaban 2.5 Mg Oral Tablet
Placebo
Aspirin 81Mg Ec Tab
Sponsored by
Vanderbilt University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Peripheral Arterial Disease focused on measuring Peripheral Artery Disease, PAD, Thrombosis, Rivaroxaban, Anticoagulant

Eligibility Criteria

40 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • History of peripheral artery disease (PAD) defined as:

    1. Previous aorto-femoral bypass surgery, limb bypass surgery, or percutaneous transluminal angioplasty revascularization of the iliac or infra-inguinal arteries, or
    2. Previous limb or foot amputation for arterial vascular disease, or

    3. History of intermittent claudication and one or more of the following:

      1. An ankle/arm blood pressure (BP) ratio < 0.90, or
      2. Significant peripheral artery stenosis (≥50%) documented by angiography, or by duplex ultrasound
  • Willing and able to provide written informed consent
  • Age ≥65, or
  • Age <65 and documented atherosclerosis or revascularization involving at least 2 vascular beds (lower extremity PAD, coronary artery disease, and/or carotid artery stenosis)
  • Receiving aspirin therapy prior to enrollment

Exclusion Criteria:

  • High risk of bleeding
  • Stroke within 1 month of any history of hemorrhagic or lacunar stroke
  • Severe heart failure with known ejection fraction <30% or New York Heart Association (NYHA) class III or IV symptoms
  • Estimated glomerular filtration rate <15 mL/min/1.73m2
  • Need for dual-antiplatelet therapy, other non-aspirin antiplatelet therapy, or oral anticoagulant therapy
  • Known non-cardiovascular disease that is associated with poor prognosis (e.g. metastatic cancer) or that increases the risk of an adverse reaction to study interventions
  • History of hypersensitivity or known contraindication to rivaroxaban or aspirin
  • Systemic treatment with strong inhibitors of both CYP 3A4 and p-glycoprotein (e.g. systemic azole antimycotics, such as ketoconazole, and human immunodeficiency virus [HIV]-protease inhibitors, such as ritonavir), or strong inducers of CYP 3A4, i.e. rifampicin, rifabutin, phenobarbital, phenytoin, and carbamazepine
  • Any known hepatic disease associated with coagulopathy
  • Subjects who are pregnant, breastfeeding, or are of childbearing potential, and sexually active and not practicing an effective method of birth control (e.g. surgically sterile, prescription oral contraceptives, contraceptive injections, intrauterine device, double- barrier method, contraceptive patch, male partner sterilization)
  • Concomitant participation in another study with investigational drug
  • Upcoming invasive procedure within 3 months
  • Invasive procedure within the prior 1 month
  • Being treated for an active infection
  • Acute or chronic limb-threatening ischemia
  • Known contraindication to any study related procedures

Sites / Locations

  • Vanderbilt University Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Control

Intervention

Arm Description

Participants will receive 81mg daily of aspirin + placebo for 30 days.

Participants will receive 81mg of aspirin + rivaroxaban 2.5mg twice daily for 30 days.

Outcomes

Primary Outcome Measures

Endothelium-dependent, flow-mediated dilation (FMD) of the brachial artery
FMD will be measured by forearm high-resolution ultrasonography after treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
Endogenous PAR-1 activation as measured by flow cytometry
Endogenous PAR-1 activation, a novel marker of platelet activation, will be measured by flow cytometry, following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. The unit of measure will be relative fluorescence.

Secondary Outcome Measures

Prothrombin time
Prothrombin time will be measured using turbidimetric assays following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. The unit of measure will be in seconds.
Partial thromboplastin time
Partial thromboplastin time will be measured using turbidimetric assays following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. The unit of measure will be seconds.
von Willebrand factor (vWF)
Blood levels of von Willebrand factor will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
D-Dimer
Blood levels of D-dimer will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
High-sensitivity C-reactive protein.
Blood levels of high-sensitivity C-reactive protein will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. The unit of measure will be mg/L.
Tumor necrosis factor-alpha
Blood levels of tumor necrosis factor-alpha will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
Interleukin-1beta
Blood levels of interleukin-1beta will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
Interleukin-6
Blood levels of interleukin-6 will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
Soluble intercellular adhesion molecule-1 (slCAM-1)
Blood levels of soluble intercellular adhesion molecule-1 (slCAM-1) will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
Monocyte chemoattractant protein-1 (MCP-1)
Blood levels of monocyte chemoattractant protein-1 (MCP-1) will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
Plasminogen activator inhibitor 1 (PAI-1)
Blood levels of plasminogen activator inhibitor 1 (PAI-1) will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
CD41a (Integrin alpha-II-beta)
CD41a, a marker of platelet activation, will be measured by flow cytometry following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
CD62p (P-Selectin)
CD62p, a marker of platelet activation, will be measured by flow cytometry following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.

Full Information

First Posted
July 9, 2021
Last Updated
October 16, 2023
Sponsor
Vanderbilt University Medical Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT05009862
Brief Title
The Impact of Factor Xa Inhibition on Thrombosis, Platelet Activation, and Endothelial Function in Peripheral Artery Disease
Official Title
The Impact of Factor Xa Inhibition on Thrombosis, Platelet Activation, and Endothelial Function in Peripheral Artery Disease
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 19, 2022 (Actual)
Primary Completion Date
March 1, 2025 (Anticipated)
Study Completion Date
March 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University Medical Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to understand how the drug rivaroxaban improves symptoms associated with peripheral artery disease.
Detailed Description
The Primary Investigator's central hypothesis is that activation of thrombotic pathways and downstream effectors of factor Xa signaling contribute to the development of PAD and its complications. Aim 1: To assess the impact of rivaroxaban on macrovascular endothelial function in a randomized, double-blind, placebo-controlled crossover intervention in humans with PAD. Aim 2: To assess the impact of rivaroxaban on PAR-1-mediated platelet activation in addition to its pleiotropic effects on thrombosis, thrombolysis, and inflammation in a randomized, double-blind, placebo-controlled crossover intervention in humans with PAD.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Peripheral Arterial Disease
Keywords
Peripheral Artery Disease, PAD, Thrombosis, Rivaroxaban, Anticoagulant

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
75 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Control
Arm Type
Placebo Comparator
Arm Description
Participants will receive 81mg daily of aspirin + placebo for 30 days.
Arm Title
Intervention
Arm Type
Experimental
Arm Description
Participants will receive 81mg of aspirin + rivaroxaban 2.5mg twice daily for 30 days.
Intervention Type
Drug
Intervention Name(s)
Rivaroxaban 2.5 Mg Oral Tablet
Intervention Description
rivaroxaban 2.5 milligrams twice daily
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
placebo
Intervention Type
Drug
Intervention Name(s)
Aspirin 81Mg Ec Tab
Intervention Description
aspirin 81 milligrams
Primary Outcome Measure Information:
Title
Endothelium-dependent, flow-mediated dilation (FMD) of the brachial artery
Description
FMD will be measured by forearm high-resolution ultrasonography after treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
Time Frame
Baseline to 37 days
Title
Endogenous PAR-1 activation as measured by flow cytometry
Description
Endogenous PAR-1 activation, a novel marker of platelet activation, will be measured by flow cytometry, following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. The unit of measure will be relative fluorescence.
Time Frame
Baseline to 37 days
Secondary Outcome Measure Information:
Title
Prothrombin time
Description
Prothrombin time will be measured using turbidimetric assays following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. The unit of measure will be in seconds.
Time Frame
Baseline to 37 days
Title
Partial thromboplastin time
Description
Partial thromboplastin time will be measured using turbidimetric assays following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. The unit of measure will be seconds.
Time Frame
Baseline to 37 days
Title
von Willebrand factor (vWF)
Description
Blood levels of von Willebrand factor will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
Time Frame
Baseline to 37 days
Title
D-Dimer
Description
Blood levels of D-dimer will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
Time Frame
Baseline to 37 days
Title
High-sensitivity C-reactive protein.
Description
Blood levels of high-sensitivity C-reactive protein will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. The unit of measure will be mg/L.
Time Frame
Baseline to 37 days
Title
Tumor necrosis factor-alpha
Description
Blood levels of tumor necrosis factor-alpha will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
Time Frame
Baseline to 37 days
Title
Interleukin-1beta
Description
Blood levels of interleukin-1beta will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
Time Frame
Baseline to 37 days
Title
Interleukin-6
Description
Blood levels of interleukin-6 will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
Time Frame
Baseline to 37 days
Title
Soluble intercellular adhesion molecule-1 (slCAM-1)
Description
Blood levels of soluble intercellular adhesion molecule-1 (slCAM-1) will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
Time Frame
Baseline to 37 days
Title
Monocyte chemoattractant protein-1 (MCP-1)
Description
Blood levels of monocyte chemoattractant protein-1 (MCP-1) will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
Time Frame
Baseline to 37 days
Title
Plasminogen activator inhibitor 1 (PAI-1)
Description
Blood levels of plasminogen activator inhibitor 1 (PAI-1) will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
Time Frame
Baseline to 37 days
Title
CD41a (Integrin alpha-II-beta)
Description
CD41a, a marker of platelet activation, will be measured by flow cytometry following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
Time Frame
Baseline to 37 days
Title
CD62p (P-Selectin)
Description
CD62p, a marker of platelet activation, will be measured by flow cytometry following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo.
Time Frame
Baseline to 37 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: History of peripheral artery disease (PAD) defined as: Previous aorto-femoral bypass surgery, limb bypass surgery, or percutaneous transluminal angioplasty revascularization of the iliac or infra-inguinal arteries, or Previous limb or foot amputation for arterial vascular disease, or History of one or more of the following: An ankle/arm blood pressure (BP) ratio < 0.90, or Significant peripheral artery stenosis (≥50%) documented by angiography, or by duplex ultrasound Willing and able to provide written informed consent Receiving aspirin therapy prior to enrollment Exclusion Criteria: High risk of bleeding Stroke within 1 month of any history of hemorrhagic or lacunar stroke Severe heart failure with known ejection fraction <30% or New York Heart Association (NYHA) class III or IV symptoms Estimated glomerular filtration rate <15 mL/min/1.73m2 Need for dual-antiplatelet therapy, other non-aspirin antiplatelet therapy, or oral anticoagulant therapy Known non-cardiovascular disease that is associated with poor prognosis (e.g. metastatic cancer) or that increases the risk of an adverse reaction to study interventions History of hypersensitivity or known contraindication to rivaroxaban or aspirin Systemic treatment with strong inhibitors of both CYP 3A4 and p-glycoprotein (e.g. systemic azole antimycotics, such as ketoconazole, and human immunodeficiency virus [HIV]-protease inhibitors, such as ritonavir), or strong inducers of CYP 3A4, i.e. rifampicin, rifabutin, phenobarbital, phenytoin, and carbamazepine Any known hepatic disease associated with coagulopathy Subjects who are pregnant, breastfeeding, or are of childbearing potential, and sexually active and not practicing an effective method of birth control (e.g. surgically sterile, prescription oral contraceptives, contraceptive injections, intrauterine device, double- barrier method, contraceptive patch, male partner sterilization) Concomitant participation in another study with investigational drug Upcoming invasive procedure within 3 months Invasive procedure within the prior 1 month Being treated for an active infection Acute or chronic limb-threatening ischemia Known contraindication to any study related procedures
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Paige V Yates, BS
Phone
(615) 322-0930
Email
paige.v.yates@vumc.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Aaron W Aday, MD
Organizational Affiliation
VUMC Cardiovascular Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

The Impact of Factor Xa Inhibition on Thrombosis, Platelet Activation, and Endothelial Function in Peripheral Artery Disease

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