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

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.

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