Excellence In Peripheral Artery Disease Thrombin Receptor Antagonist Intervention In Claudication Evaluation (XLPAD-TRACE Trial)

Study Overview
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Brief Summary
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This is a Phase 4, randomized clinical trial to evaluate whether addition of Vorapaxar 2.08 mg daily vs. placebo daily on background antiplatelet therapy, prescribed for 6 months to patients with established peripheral artery disease (PAD) and Intermittent Claudication (IC) treated with standard medical therapy (SMT) would lead to an improvement in the peak walking time (PWT).

Detailed Description
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Primary trial objective: To evaluate whether addition of Vorapaxar 2.08 mg daily vs. placebo daily on background antiplatelet therapy, prescribed for 6 months to patients with established PAD and IC treated with standard medical therapy (SMT) would lead to an improvement in the peak walking time (PWT) Study endpoints Primary endpoint: Change from baseline to 6 months in the PWT on a graded treadmill test (GTT per Gardner protocol) between participants enrolled in the test and control arms of the study Secondary endpoints Change from baseline to 6 months in the claudication onset time (COT) on GTT between participants enrolled in the test and control arms of the study. Change from baseline to 6 months in the walking impairment questionnaire distance scores (WIQ) between participants enrolled in the test and control arms of the study. Change from baseline to 6 months in self-reported quality of life score using the Medical Outcomes Study 12-Item Short form survey (SF-12) between participants enrolled in the test and control arms of the study Tertiary endpoints The first occurrence of clinically indicated lower extremity endovascular or surgical revascularization procedure during the entire study duration post-randomization in participants enrolled in the test or control arms of the study. The first occurrence of all-cause death, MI, ischemic stroke during the entire study duration post-randomization in participants enrolled in the test or control arms of the study. The first occurrence of severe bleeding defined according to the Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries (GUSTO) classification during the entire study duration post-randomization in participants enrolled in the test or control arms of the study.

Official Title
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Excellence In Peripheral Artery Disease Thrombin Receptor Antagonist Intervention In Claudication Evaluation (XLPAD-TRACE Trial)

Conditions
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Peripheral Arterial Disease

Intervention / Treatment
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* Drug: Placebo + background APT + SMT
* Drug: Vorapaxar 2.08 mg/d + background APT + SMT.


Participation Criteria
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Eligibility Criteria
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Pre-screening criteria Laboratory values available ≤ 1 year of the date of screening: hemoglobin ≥9g, platelet count >50,000 mm3 or <600,000 mm3 No history of stroke or transient ischemic attack (TIA) No allergy to aspirin ≥40 years of age Presence of documented PAD by ABI <0.80 at rest or ≥20% drop in claudication limited exercise ABI in any limb and one of the following criteria in the corresponding limb: i.Prior surgical and/or endovascular lower extremity intervention (infra-renal aorta to pedal arteries) ii. Known presence of flow-limiting stenosis (≥70%) by clinically indicated angiography, computed tomographic (CT) or magnetic resonance imaging (MRI) tests or by Duplex ultrasonography (DUS) defined standard clinical criteria in lower extremity arteries Documented IC Rutherford/Becker (RC) category ≥2 Presence of any one of the listed classes of agents [angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), lipid lowering therapy, aspirin and beta-blocker drugs]-No MI or percutaneous coronary intervention (PCI) with DES within the past 11 months No planned surgical or endovascular procedures other than for the treatment of IC for the expected duration of the study No warfarin or other chronic oral anticoagulant use within the last 14 days No use of ticagrelor, clopidogrel, prasugrel or ticlopidine within last 7 days No contraindication(s) to the use of antithrombin or antiplatelet agents (history of intra-cerebral hemorrhage or ICH, presence of intracerebral mass, recent or <12 weeks gastrointestinal bleed requiring blood transfusion, any blood transfusion within the last 6 weeks, any trauma requiring surgery within the last 4 weeks or any surgical or endovascular procedure within the last 4 weeks No use of cilostazol and/or pentoxyphilline within last 7 days Severe psychiatric or behavioral illness that in the judgement of the investigator precludes study participation No history of major or minor amputation Severe heart, vascular and lung disease in the discretion of the investigator that precludes study participation. Ability to walk for at least 15 min/day, at least 3 days/week, at ≥20 steps/min Inclusion criteria Treadmill PWT= 2-10 min on Gardner protocol Estimated survival ≥1 year in the judgment of the site investigator Use of at least one aspirin dose within at least 5 days prior to randomization at 325 mg dose in aspirin naïve patients (0-5 days of prior aspirin use) or at least one aspirin dose prior to randomization at 81 mg dose in patients on chronic (>5 days) aspirin therapy (at clinically indicated doses). Presence of any one of the listed classes of agents [angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), lipid lowering therapy, aspirin and beta-blocker drugs] Exclusion Criteria: MI or percutaneous coronary intervention (PCI) with DES within the past 11 months Positive pregnancy test Planned surgical or endovascular procedures other than for the treatment of IC Warfarin or other chronic oral anticoagulant use within 14 days Use of Ticagrelor, Clopidogrel, Prasugrel or Ticlopidine within 7 days Contraindication(s) to the use of antithrombin or antiplatelet agents (history of intra-cerebral hemorrhage or ICH, presence of intracerebral mass, recent or <12 weeks gastrointestinal bleed requiring blood transfusion, any blood transfusion within the last 6 weeks, any trauma requiring surgery within the last 4 weeks or any surgical or endovascular procedure within the last 4 weeks Use of cilostazol and/or pentoxyphilline within 7 days

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 90 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: SMT+APT+Placebo<br>Standard Medical Therapy (SMT): Presence of any two of the listed classes of agents [angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), statin therapy and beta-blocker drugs] + ability to perform at least 15 min of home walking a day, at least 3 times/week, at ≥20 steps/min Background Antiplatelet Therapy (APT) :At least one aspirin dose within 5 days prior to randomization at 325 mg dose in aspirin naïve patients (0-5 days of prior aspirin use) or at least one aspirin dose within 5 days prior to randomization at 81 mg dose in patients on chronic (>5 days of prior use) aspirin therapy. | Drug: Placebo + background APT + SMT<br>* Placebo drug therapy combined with standard medical therapy combined with Antiplatelet therapy (Aspirin therapy)<br>Drug: Vorapaxar 2.08 mg/d + background APT + SMT.<br>* Vorapaxar 2.08 mg/d combined with standard medical therapy combined with Antiplatelet therapy (Aspirin therapy)<br>|
| Active Comparator: SMT+APT+Vorapaxar<br>Standard Medical Therapy (SMT): Presence of any two of the listed classes of agents [angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), statin therapy and beta-blocker drugs] + ability to perform at least 15 min of home walking a day, at least 3 times/week, at ≥20 steps/min Background Antiplatelet Therapy (APT) :At least one aspirin dose within 5 days prior to randomization at 325 mg dose in aspirin naïve patients (0-5 days of prior aspirin use) or at least one aspirin dose within 5 days prior to randomization at 81 mg dose in patients on chronic (>5 days of prior use) aspirin therapy. Vorapaxar: Vorapaxar 2.08mg/day | Drug: Placebo + background APT + SMT<br>* Placebo drug therapy combined with standard medical therapy combined with Antiplatelet therapy (Aspirin therapy)<br>Drug: Vorapaxar 2.08 mg/d + background APT + SMT.<br>* Vorapaxar 2.08 mg/d combined with standard medical therapy combined with Antiplatelet therapy (Aspirin therapy)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to 6 months in the PWT on a graded treadmill test (GTT per Gardner protocol) between participants enrolled in the test and control arms of the study |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to 6 months in the claudication onset time (COT) on GTT between participants enrolled in the test and control arms of the study. | Change from baseline to 6 months in the walking impairment questionnaire distance scores (WIQ) between participants enrolled in the test and control arms of the study. Change from baseline to 6 months in self-reported quality of life score using the Medical Outcomes Study 12-Item Short form survey (SF-12) between participants enrolled in the test and control arms of the study. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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intermittent claudication, randomized controlled trial