Open Versus Endovascular Repair of Popliteal Artery Aneurysm Trial

Current therapy for patients with asymptomatic PAA, elective repair has been recommended for
PAA > 2 cm and for smaller aneurysms with associated mural thrombus1. Treatment modalities
are similar in that they exclude the aneurysm from the circulation. Current treatment
options include both open surgical bypass (OPAR) with aneurysm exclusion and endovascular
popliteal artery repair (EPAR) in which the PAA is excluded by a stent graft. Open repair of
PAA has been shown to have excellent graft patency and limb salvage rates, however it is
associated with the need for general or regional anesthesia, 10-20% surgical site infection
rate, and other complications such as seroma, hematoma, and neurological injury.
Endovascular popliteal aneurysm repair is a minimally invasive technique that can be
performed under conscious sedation but may be associated with higher risk of graft
thrombosis, stent fracture, and may have a lower long term success rate. A paucity of strong
comparative data further increases this equipoise. An adequately powered, prospective,
comparative study contrasting OPAR approach with EPAR will guide vascular specialists in
their treatment of PAA and is very much needed.

Trial Conduct The trial will be conducted in compliance with the protocol, Good Clinical
Practice (GCP) guidelines, Declaration of Helsinki and applicable federal regulatory
requirements [Title 21 Code of Federal Regulations Parts 50, 54, 56, 812 and 45CFR46]. This
trial will be registered on NIH clinical trial registry.

Description and Importance of the Population to be Studied One hundred and forty eights
subjects aged 35 or older with asymptomatic ≥ 2.0 cm PAA undergoing repair will be
randomized to undergo either OPAR or EPAR. These patients will be recruited at the
participating VSGNE centers who agreed to enroll and randomize patients for this trial. This
trial will be formally approved by respective Institutional Review Boards.

Investigators will focus on a population of subjects who are candidates for both open
surgery and endovascular therapy as determined by the treating investigator. Such
individuals represent patients who fall into the "grey area of treatment equipoise".
Investigators will exclude subjects with associated acute limb ischemia and hyper-coagulable
states. In the OPAR group the choice of conduit will be at the discretion of the surgeon.
Vein or non-autogenous conduits will be allowed. In the EPAR group, a femoral cu-down for
introduction of stent will be permissible. Percutaneous placement of stent-grafts will also
be allowed. Investigators will exclude individuals who are deemed to be at prohibitive risk
for open vascular surgery by standard American Heart Association AHA criteria as noted on
formal preoperative evaluation or who have significant non-dialysis dependent renal
dysfunction (Cr. >3.0). From an anatomic standpoint, investigators will exclude patients who
cannot have their PAA treated by stent-grafts due to short "proximal or distal landing
zones". Subjects without a patent outflow target vessel will, likewise, be excluded, as
treatment options in such patients are usually limited to medical management, amputation or
experimental therapies.

TRIAL OBJECTIVES AND PURPOSE

The OVER-PAR Trial is a multicenter randomized trial of best open surgical (OPAR) or best
endovascular (EPAR) revascularization in a target population of subjects with asymptomatic ≥
2.0 cm popliteal artery aneurysm who are candidates for both open and endovascular
treatment. The trial has a superiority design and has the following specific aims and
hypotheses:

Trial Design The OVER-PAR Trial is a prospective, randomized, open label (two-arm),
multicenter, superiority trial comparing the effectiveness of open surgical bypass (OPAR)
and endovascular popliteal artery stent graft repair (EPAR) in 148 patients (n=74 in each
group) with asymptomatic, clinically significant PAA. Patients with asymptomatic PAA will be
screened. These patients will be enrolled from VSGNE centers who agreed to participate in
this trial. The proposed trial duration is 4 years. The estimated mean follow-up per subject
will be 2.5 years. The trial is powered at 80% to detect a hazard ratio of 1.53, depending
on crossover rates, and assuming 2% loss to follow-up.

The Randomization Scheme The randomization scheme will be set up at Boston Medical Center.
Participating sites will have access to it by telephone. It is important to emphasize that
both procedures to which patients will be randomized are acceptable modalities of care to
treat PAA. Within each cohort, subjects will be randomized in a 1:1 ratio to one of the 2
treatment arms by study coordinator at each center. Randomization will follow the following
scheme. For each center, sealed, opaque envelopes indicating either OPAR or EPAR repair will
be placed in a container in blocks of 6. Each block of 6 envelopes will contain 3
representing OPAR and 3 representing EPAR. When a participating site recruits a patient, a
phone call will be made to the central study coordinator at BMC who will open an envelope
from the container corresponding to the center and relay the result (OPAR or EPAR) to the
coordinator at the requesting center.

Subjects cannot be randomized on the day of surgery since both procedures require some
pre-operative planning. For example, a patient who undergoes open repair will need a
pre-operative vein mapping to access suitability of vein conduit. Similarly, the patient
awaiting EPAR will require procurement of appropriately sized patient-tailored stent -graft
for repair of PAA.

Since randomization will be performed during the pre-operative period, the patient will be
aware of the surgical plan (open vs. endovascular) prior to the date of the surgery. He or
she will then have an option to withdraw from the study and choose any appropriate treatment
modality, if they so choose. Additionally, if the surgeon, based on his judgment, decides to
offer his patient a different treatment modality from that assigned by the randomization
scheme the subject will become a screening failure. Data from subjects categorized as a
screening failure will be recorded in the usual registry arm of the VSGNE and used in
post-hoc analyses after study completion.

Each subject will be followed for a minimum of 24 months following randomization. Follow-up
will continue during the accrual period and therefore the earliest enrolled surviving
subject will have a maximum of 48 months follow-up.

Since randomization will be performed during the pre-operative period, the patient will be
consulted about the surgical plan (open vs. endovascular) prior to the date of the surgery.
He or she will then have an option to withdraw from the study and choose any appropriate
treatment modality, if they so choose.

Additionally, if the surgeon, based on his bias, decides to offer his patient a different
treatment modality from that assigned by the randomization scheme the subject will become a
screening failure.

Subject Withdrawal Criteria

Subjects may be withdrawn from the study for the following reasons:

- Subject declines further study participation.

- In the investigator's judgment, it is in the subject's best interest.

All protocol-specified visits and follow-up procedures should be performed for every subject
enrolled in the trial. If the subject refuses to continue with the study visits, every
attempt should be made to continue contact by telephone, written communication, or record
review to determine if outcome events have occurred, unless the subject specifically refuses
such follow-up. The reason for withdrawal will be documented for all subjects withdrawn from
the study. If the withdrawing subject is unwilling to have his/her medical records reviewed
until the end of the trial period (to document vital status and cause of death), he/she must
submit a written refusal.

TREATMENTS TO BE ADMINISTERED Subjects randomized to OVER-PAR endovascular therapy will
receive treatment according to established standard of care for exclusion of PAA by
commercially available endovascular sten-graft. Subjects receiving endovascular
stent-graft(s) will be treated according to the Instructions for Use for the implanted
device(s).

Medications/Treatments Permitted and Not Permitted during the Trial There are no medications
dispensed specifically for this trial. Investigators should follow standard of care
guidelines as well as adhere to Contraindications, Warnings, and Precautions published in
the instructions for use of each commercially available endovascular stent.

ASSESSMENT OF EFFICACY Specification of the Efficacy Parameters All-cause mortality will be
as reported to occur any time after randomization. Perioperative death is the subset
occurring with 30 days of the index procedure.

Amputation above the ankle in the index (treated) leg is a standard definition, as reported
in surgical notes.

Re-interventions will be reviewed for the primary endpoint only (new bypass graft,
jump/interposition graft revision, thrombectomy/ thrombolysis). All re-interventions
(hospitalizations) will be recorded, with length of stay (LOS) discharge diagnoses and
(coded) procedures performed for the cost-effectiveness analysis.

Functional Status will be assessed using the SF-12 which is widely used in cardiovascular
trials and is available in Spanish, French, for use in North American trials.

Quality of Life will be assessed with using VascuQoL questionnaire7 These are standard,
validated instruments, available in Spanish and Canadian French as well as English, for this
trial

STATISTICS Analysis of the Primary Endpoints The first phase of analysis will include a
description of study variables. This step includes generating summary statistics for study
characteristics. Summary statistics will be generated and assessed for the total sample
size. The quartiles and median time-to-event outcomes (e.g. MALE-free survival, or MALE-POD)
will be estimated using the Kaplan-Meier method and will be reported with two-sided 95%
confidence intervals for each intervention arm.

The primary efficacy analysis will be an estimation of the hazard ratio comparing time to
MALE and all death rates of subjects receiving OPAR to those receiving EPAR treatment using
the nonparametric log-rank test. The hazard ratio and its 95% confidence interval will be
estimated in a Cox regression model in which time to MALE+all deaths is the dependent
variable and intervention is the independent variable.

The primary analysis will be conducted on an intention-to-treat basis (i.e. based on their
randomization status), which includes all subjects randomized, after the last subject has
been followed for 1-year or are off study.

Analysis of Secondary Outcomes Other time-to-event outcomes, such as amputation-free
survival, described in the secondary aim will be analyzed similarly to the primary analysis.

The above analyses will also be run on the per-protocol population (i.e. based on the actual
intervention they received).

Inclusion Criteria:

1. Age > 35 years

2. Popliteal artery aneurysm > 2 cm in diameter with or without presence of mural
thrombus

3. Candidate for either OPAR or EPAR as judged by the treating investigator.

4. Greater than 2 cm length of normal superficial femoral artery distal to the deep
femoral artery takeoff and >2 cm length of normal popliteal artery proximal to the
first patent tibial artery.

5. Willing to comply with protocol, attend follow-up appointments, complete all study
assessments, and provide written informed consent.

Exclusion Criteria:

1. Popliteal artery thrombosis

2. Popliteal artery aneurysm causing symptomatic thromboembolic disease or compressive
symptoms.

3. Superficial femoral artery occlusion or distal tibio-peritoneal occlusion

4. Less than 2 cm length of normal artery to accommodate stent graft seal

5. Life expectancy of less than 2 years.

6. Deemed excessive risk for surgical bypass (defined as prohibitive operative risk by
formal pre-procedural cardiac risk assessment undertaken by a cardiologist or
internist according to established AHA guideline criteria).

7. A documented hypercoagulable state (defined as a known blood disorder associated with
venous or arterial thrombosis).

8. Any infrainguinal revascularization procedure on index leg within 12 weeks prior to
treatment initiation.

9. Current immune-suppressive medication, chemotherapy or radiation therapy.

10. Absolute contraindication to iodinated contrast due to prior near-fatal anaphylactoid
reaction (laryngospasm, bronchospasm, cardiorespiratory collapse, or equivalent) and
which would preclude patient from participation in angiographic procedures.

11. Allergy to stainless steel or nitinol.

12. Pregnancy or lactation.

13. Inability or refusal to provide informed consent.

14. Patients who received an investigational drug for peripheral arterial disease within
4 weeks of screening or who participated in another non-observational clinical trial
in the prior 30 days.

15. Prior leg bypass on the ipsilateral limb