Peripheral Artery DiseasePhase 4NCT02975583
Vorapaxar and Lower Extremity Bypass Grafts
A Phase 4 study testing Vorapaxar in people with Peripheral Artery Disease, run by Vanderbilt University.
Trial summary
There are no medical therapies indicated for reduction of limb ischemic events. Studies of dual-antiplatelet therapy with aspirin and clopidogrel versus aspirin alone (CASPAR) as well as studies of systemic anticoagulation (WAVE) have shown no benefit for either strategy in the reduction in limb vascular events. Read more about this study
- Who is it for?
- Ages 35 to 75 yearsHealthy volunteers can take part
- Conditions the study is for
- Peripheral Artery Disease
- What is being tested?
- Vorapaxar
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- 1 Oct 2017to 10 Jan 2018
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 35 to 75 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Male or female, age 35 years or older
- Atherosclerotic, infrainguinal PAD
- Rutherford classes 3-5 planned for lower extremity bypass grafting
- Adequate inflow into the index femoral artery
- Adequate popliteal, tibial, or pedal revascularization target
- Willing to comply with protocol, attend follow-up appointments, complete all study assessments, and provide informed consent
Who cannot join
- Complete occlusion of the iliac artery
- Aortoiliac occlusive disease or severe common femoral artery disease
- Presence of a femoral, popliteal or tibial aneurysm of the index limb
- Life expectancy less than 2 years
- A vascular disease prognosis that includes an anticipated above ankle amputation on index limb within 4 weeks of index procedure
- Renal dysfunction defined as MDRD eGFR ≤ 30ml/min/173 m2 at the time of screening
Show all 14Show fewer
- Currently on dialysis or history of a renal transplant
- A documented hypercoagulable state
- Nonatherosclerotic occlusive disease
- Any prior infrainguinal revascularization
- Current immunosuppressive medication, chemotherapy or radiation therapy
- Absolute contraindication to iodinated contrast
- Women who are pregnant
- Women who are nursing
About this study
Official title: A Double-blind, Randomized, Parallel Design Two Center Study to Compare the Effect of Vorapaxar vs. Placebo on Lower Extremity Vein Graft Maturation, Remodeling, and Function
There are no medical therapies indicated for reduction of limb ischemic events. Studies of dual-antiplatelet therapy with aspirin and clopidogrel versus aspirin alone (CASPAR) as well as studies of systemic anticoagulation (WAVE) have shown no benefit for either strategy in the reduction in limb vascular events. Surgical bypass grafting involves harvesting of the vein, warm ischemia with disruption of vaso vasorum, ischemia-reperfusion, and finally heightened hemodynamic stress in the new arterial environment. Vein grafts rapidly remodel in response to the increase in blood flow and pressure in an attempt to normalize them into physiological range. The investigators have previously identified 3 distinct temporal phases of the remodeling process: During the first 30 days following implantation is a critical period of luminal enlargement which appears to be an endothelium-independent process. The second phase occurs between 1 and 3 months and represents a period of stiffening of the vein graft indicating synthesis of fibrous proteins. The third period is referred to as biochemical remodeling wherein the vein recovers clinically measureable endothelial function. It is likely diabetes mellitus impacts each of these phases. TRA2°P-TIMI 50 demonstrated a reduction in acute limb ischemic (ALI) events (42% reduction) and urgent peripheral arterial revascularizations (35% reduction), a finding unique among medical therapies. While the temporal trend in reduction in ALI events occurred early and late after exposure suggestion an antithrombotic mechanism, the reduction in elective revascularization occurred later suggested beneficial effects beyond platelet inhibition. The purpose of this trial is to study the physiological impact of vorapaxar on lower extremity bypass graft maturation and function.
Read the detailed description
Peripheral artery disease (PAD) is characterized by atherosclerotic occlusive disease of the lower extremities. More than 8 million Americans and 200 million people globally have PAD. Recent data reveal a prevalence of 15% in the MEDICARE population. In populations at risk, patients with a history of diabetes or cigarette smoking, the risk may rise as high as 30%. In addition to the heightened risk of myocardial infarction and stroke, PAD increases the risk of lower extremity claudication and critical limb ischemia. Lower extremity bypass grafting is an important method of restoring blood flow to the distal limb, reducing symptoms of claudication, and preventing amputation in patients with severe PAD.
Vorapaxar is a protease activated receptor (PAR)-1 antagonist that inhibits thrombin activation of the PAR-1 receptor. Vorapaxar has been FDA approved for patients with PAD to reduce the rate of cardiovascular death, MI, stroke, and urgent coronary revascularization. It is prohibited in patients with a previous stroke. In addition, patients treated with vorapaxar were noted to have a significant reduction in the rates of acute limb ischemia. This study will be a randomized, double blind, placebo-controlled randomized study of vorapaxar vs. placebo in 80 patients undergoing femoral-popliteal bypass grafting for Rutherford 3 - 5 disease.
Baseline visit: Informed consent will be signed. Vital signs will be taken and blood drawn fasting for baseline values.
First visit, pre-surgery: Blood will be drawn for platelet activation testing. A 6 minute walk test will be performed. Brachial artery reactivity testing will be performed. An ankle-brachial index will be performed.
30 days: Platelet testing will be performed. 90 days: Limited history and physical exam. 180 days: Limited history and exam, blood draw for biomarkers, brachial artery reactivity testing. Vein bypass graft reactivity testing.
360 days: 6 minute walk test and ankle brachial index will be performed.
Randomization: The Investigational Pharmacy will create a block randomization. Patients in the active treatment group will receive vorapaxar 2.08 mg daily or matching placebo. Treatment will continue for 1 year.
In addition, 20 healthy subjects to serve as a control population to define normal parameters during a single visit day. The healthy subjects will not be administered vorapaxar or placebo.
- Conditions
- Peripheral Artery Disease
- Being tested
- Vorapaxar, Placebos
- Keywords
- Atherosclerosis
- Medical subject headings
- Peripheral Arterial Disease, Atherosclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VorapaxarDrug
Also called Zontivity
2.08 mg oral tablet daily
PlacebosDrug
Also called Placebo
Placebo oral tablet daily
| Study group | Role | What they receive |
|---|---|---|
| Experimental: Vorapaxar | Active comparator | Drug: Vorapaxar 2.08 mg orally daily for a year Other name: Zontivity Receives: Drug: Vorapaxar |
| Placebo Comparator: Placebos | Placebo comparator | Medication: Matching Placebo Daily tablet Receives: Drug: Placebos |
What is being measured
The primary outcome is the main question the study is designed to answer.
Bypass Graft Flow Mediated Vasodilation under Fasted Conditions using B-mode ultrasonography on Day 180 for each treatment condition.
Ultrasonographic evaluation of the graft before and after sphygmomanometric cuff inflation on the calf is performed and the measure of interest is percent increase in vein graft diameter.
Measured: 6 Months
Secondary outcomes (3)
Change From Baseline in Flow Mediated Vasodilation (FMD) Under Fasted Condition on Day 180 [ Time Frame: baseline and day 180 for each treatment arm ]
Ultrasonographic evaluation of the graft before and after sphygmomanometric cuff inflation on the arm is performed and the measure of interest is percent increase in brachial artery diameter.
Measured: 6 Months
Platelet Activation blood testing
The investigators will be measuring levels of platelet dilysyl-MDA cross-links 30 days after treatment initiation. Higher levels indicate more platelet activation.
Measured: 30 days
Change in Six Minute Walk Test from Baseline to 1 year
The distance walked in a 100 foot hallway in 6 minutes.
Measured: One year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Nov 2016 (estimated)
- Study start1 Oct 2017
- Primary completion10 Jan 2018
- Study completion10 Jan 2018
Why it stopped: We could not secure adequate medication
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Peripheral Artery DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vanderbilt University
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Principal investigator, Joshua Beckman, Vanderbilt University
- Investigators
- Joshua A Beckman, Principal investigator, Vanderbilt University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02975583
- Sponsor's protocol ID
- 161925
- Status last verified
- Jan 2018
- First submitted
- 18 Nov 2016
- Last updated
- 25 Jan 2018
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: There is no plan to share IPD at this time.
Study at a glance
From the registry record, last updated by the sponsor on 25 Jan 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Double-blind, Randomized, Parallel Design Two Center Study to Compare the Effect of Vorapaxar vs. Placebo on Lower Extremity Vein Graft Maturation, Remodeling, and Function
- ClinicalTrials.gov ID
- NCT02975583
- Acronym / sponsor ID
- 161925
- Conditions
- Peripheral Artery Disease
- Keywords
- Atherosclerosis
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: We could not secure adequate medication
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Vanderbilt UniversityUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- 1 Oct 2017 (actual)
- Primary completion
- 10 Jan 2018 (actual)
- Study completion
- 10 Jan 2018 (actual)
- First posted
- 29 Nov 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
There are no medical therapies indicated for reduction of limb ischemic events. Studies of dual-antiplatelet therapy with aspirin and clopidogrel versus aspirin alone (CASPAR) as well as studies of systemic anticoagulation (WAVE) have shown no benefit for either strategy in the reduction in limb vascular events. Surgical bypass grafting involves harvesting of the vein, warm ischemia with disruption of vaso vasorum, ischemia-reperfusion, and finally heightened hemodynamic stress in the new arterial environment. Vein grafts rapidly remodel in response to the increase in blood flow and pressure in an attempt to normalize them into physiological range. The investigators have previously identified 3 distinct temporal phases of the remodeling process: During the first 30 days following implantation is a critical period of luminal enlargement which appears to be an endothelium-independent process. The second phase occurs between 1 and 3 months and represents a period of stiffening of the vein graft indicating synthesis of fibrous proteins. The third period is referred to as biochemical remodeling wherein the vein recovers clinically measureable endothelial function. It is likely diabetes mellitus impacts each of these phases. TRA2°P-TIMI 50 demonstrated a reduction in acute limb ischemic (ALI) events (42% reduction) and urgent peripheral arterial revascularizations (35% reduction), a finding unique among medical therapies. While the temporal trend in reduction in ALI events occurred early and late after exposure suggestion an antithrombotic mechanism, the reduction in elective revascularization occurred later suggested beneficial effects beyond platelet inhibition. The purpose of this trial is to study the physiological impact of vorapaxar on lower extremity bypass graft maturation and function.
Detailed description
Peripheral artery disease (PAD) is characterized by atherosclerotic occlusive disease of the lower extremities. More than 8 million Americans and 200 million people globally have PAD. Recent data reveal a prevalence of 15% in the MEDICARE population. In populations at risk, patients with a history of diabetes or cigarette smoking, the risk may rise as high as 30%. In addition to the heightened risk of myocardial infarction and stroke, PAD increases the risk of lower extremity claudication and critical limb ischemia. Lower extremity bypass grafting is an important method of restoring blood flow to the distal limb, reducing symptoms of claudication, and preventing amputation in patients with severe PAD.
Vorapaxar is a protease activated receptor (PAR)-1 antagonist that inhibits thrombin activation of the PAR-1 receptor. Vorapaxar has been FDA approved for patients with PAD to reduce the rate of cardiovascular death, MI, stroke, and urgent coronary revascularization. It is prohibited in patients with a previous stroke. In addition, patients treated with vorapaxar were noted to have a significant reduction in the rates of acute limb ischemia. This study will be a randomized, double blind, placebo-controlled randomized study of vorapaxar vs. placebo in 80 patients undergoing femoral-popliteal bypass grafting for Rutherford 3 - 5 disease.
Baseline visit: Informed consent will be signed. Vital signs will be taken and blood drawn fasting for baseline values.
First visit, pre-surgery: Blood will be drawn for platelet activation testing. A 6 minute walk test will be performed. Brachial artery reactivity testing will be performed. An ankle-brachial index will be performed.
30 days: Platelet testing will be performed. 90 days: Limited history and physical exam. 180 days: Limited history and exam, blood draw for biomarkers, brachial artery reactivity testing. Vein bypass graft reactivity testing.
360 days: 6 minute walk test and ankle brachial index will be performed.
Randomization: The Investigational Pharmacy will create a block randomization. Patients in the active treatment group will receive vorapaxar 2.08 mg daily or matching placebo. Treatment will continue for 1 year.
In addition, 20 healthy subjects to serve as a control population to define normal parameters during a single visit day. The healthy subjects will not be administered vorapaxar or placebo.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Experimental: Vorapaxar | Active comparator | Drug: VorapaxarDrug: Vorapaxar 2.08 mg orally daily for a year Other name: Zontivity |
| Placebo Comparator: Placebos | Placebo comparator | Drug: PlacebosMedication: Matching Placebo Daily tablet |
Who may qualify
- Ages
- 35 to 75 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Male or female, age 35 years or older
- Atherosclerotic, infrainguinal PAD
- Rutherford classes 3-5 planned for lower extremity bypass grafting
- Adequate inflow into the index femoral artery
- Adequate popliteal, tibial, or pedal revascularization target
Key exclusion criteria (14 listed)
- Complete occlusion of the iliac artery
- Aortoiliac occlusive disease or severe common femoral artery disease
- Presence of a femoral, popliteal or tibial aneurysm of the index limb
- Life expectancy less than 2 years
- A vascular disease prognosis that includes an anticipated above ankle amputation on index limb within 4 weeks of index procedure
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| VorapaxarAlso: Zontivity2.08 mg oral tablet daily | Drug | Experimental: Vorapaxar |
| PlacebosAlso: PlaceboPlacebo oral tablet daily | Drug | Placebo Comparator: Placebos |
Primary outcome
Bypass Graft Flow Mediated Vasodilation under Fasted Conditions using B-mode ultrasonography on Day 180 for each treatment condition.
Time frame: 6 Months
Ultrasonographic evaluation of the graft before and after sphygmomanometric cuff inflation on the calf is performed and the measure of interest is percent increase in vein graft diameter.
3 secondary outcomes
Change From Baseline in Flow Mediated Vasodilation (FMD) Under Fasted Condition on Day 180 [ Time Frame: baseline and day 180 for each treatment arm ]
Time frame: 6 Months
Platelet Activation blood testing
Time frame: 30 days
Change in Six Minute Walk Test from Baseline to 1 year
Time frame: One year
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Jan 2018.
- Individual participant dataSharing planned: No. There is no plan to share IPD at this time.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Joshua A Beckman principal investigator
Vanderbilt University Medical Center
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Vorapaxar in people with Peripheral Artery Disease, run by Vanderbilt University.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 25 Jan 2018. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Bypass Graft Flow Mediated Vasodilation under Fasted Conditions using B-mode ultrasonography on Day 180 for each treatment condition. (time frame: 6 Months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jan 2018.