The CREST-2 Registry

Objectives:

1. Promote the rapid initiation and completion of enrollment in CREST-2

2. CAS will be performed by experienced operators

3. Clinical outcomes will be closely monitored

4. Prevent inappropriate use of CAS outside of the registry

Registry Data Collection:

The registry will leverage the existing data-collection infrastructure of the Society for
Vascular Surgery's (SVS) Vascular Quality Initiative (VQI) and the American College of
Cardiology's (ACC) National Cardiovascular Data Registry (NCDR). Both organizations have
agreed to participate in this effort. The specific logistics of data-collection and transfer
are:

- The interventionist must pick a registry, SVS VQI or ACC NCDR to enter data.

- The interventionist instructs their registry to transfer de-identified information about
their cases to C2R.

- The cases are reviewed by the C2R Management Committee.

- Reports of the cases, including whether or not they are CREST-2 eligible, will be
maintained. These reports will allow close monitoring of C2R interventionists.

- C2R Management Committee, and other parties (NINDS, CMS) will be informed of the
progress periodically.

The registry will collect information on key co-morbidities and limit the outcome measures to
essential, easily used standardized measures that are commonly part of carotid trials,
including the NIH Stroke Scale and the Modified Rankin Scale (mRS). The 30-day visit will be
conducted face-to-face with a history, examination and testing.

- DEMOGRAPHICS AND MEDICAL HISTORY: Gender, symptomatic status, carotid artery to be
treated, hypertension, diabetes, coronary artery disease, congestive heart failure, and
renal failure.

- MONITORING ENROLLMENT: The Registry will also collect information on features that
represent inclusion/exclusion criteria for the CREST-2 randomized trial. The purpose is
to facilitate monitoring of the type of patients being enrolled in C2R, and ensuring
that CREST-2-eligible patients are not being enrolled excessively into C2R in preference
to CREST-2. Data- collection, transfer and review will occur rapidly enough that sites
not complying with enrollment limitations will be identified rapidly and appropriate
action taken.

- PROCEDURAL DETAILS: The C2R focuses on procedural details that will facilitate an
assessment for credentialing interventionists into the CREST-2 trial. The interventional
management committee will review this data to make decisions regarding whether or not to
approve a particular operator for randomizing patients into the trial. Some of the
factors to be considered will include:

- Total number of cases performed per year, total number of cases performed in career

- Selection of devices, case selection, stroke rate, hemorrhagic complications.

- Techniques for access, sheath placement, wire access, embolic protection, angioplasty,
stent deployment, use of post-stent angioplasty, selection of closure devices, use of
medications (antiplatelets, anticoagulation, atropine, nitroglycerine).

- PATIENT ASSESSMENT AND OUTCOMES: NIH Stroke Scale, modified Rankin Score, access site
hemorrhage, recurrent hospitalization or need for second carotid procedure, new onset of
renal failure, stroke, and death.

Eligibility to participate in the C2R

Centers

- Any center currently certified by CMS to provide CAS will be eligible to apply for
participation in the C2R.

Operators

- Individual operators must have done at least 50 total procedures to be eligible for the
registry. If they have done less than 50 procedures, then they must have done at least 8
procedures over the last 2 years.

- Individual operators must have been reviewed and approved by the interventional
management committee.

- The final decision regarding eligibility will also depend on an assessment of technique,
outcomes and anticipated carotid disease volume at a particular site.

Procedures to ensure enrollment into the randomized trial

- The maximal enrollment number for C2R for a given site prior to randomization into
CREST-2 will be a total of 75 cases or 30 CREST-2 eligible patients, whichever comes
first.

- Operators that have been credentialed by the IMC to enroll patients in CREST-2 must
begin to enroll eligible patients in the trial, while other operators at the same site
continue to work toward credentialed status.

- Sites that have reached the maximum thresholds above and are not initiated as CREST-2
sites will have registry status denied at the discretion of the C2R Management committee
depending on bona fide, good faith efforts to meet CREST-2 site initiation requirements.

- The C2R will track whether or not each patient enrolled in the registry was CREST-2
eligible. Once any operator at a site has been approved to enroll patients in CREST-2,
the site will be expected to offer enrollment into CREST- 2 to every CREST-2 eligible
patient. It is anticipated that not all such CREST-2 eligible patients will consent to
randomization into CREST-2; such patients, can be enrolled into the registry. However,
only 1 CREST-2-eligible patient can be enrolled into C2R for each patient enrolled into
CREST-2, i.e. in a 1:1 ratio.

- Sites that do not maintain the 1:1 ratio of patients enrolled in CREST-2 to
trial-eligible patients enrolled in C2R will be notified by the C2R Management Committee
that they are on a probationary status to remedy the situation. If not remedied, they
will be notified that their C2R status is being revoked.

- Sites that are not enrolling into CREST-2 at a reasonable rate (to be determined by the
C2R Management Committee and the CREST-2 Executive Committee) will have their
eligibility to enroll in the C2R suspended until they are adequately enrolling in the
trial.

- Once the CAS arm of CREST-2 is fully enrolled, continued enrollment of eligible patients
(see inclusion/exclusion criteria above) in the C2R will be allowed.

- The DSMB will review CREST-2 trial results at the end of enrollment of the CREST-2 trial
to decide at that time if it is ethical to continue C2R.

Registry Oversight / Governance

The C2R will be operated under a multi-specialty Steering Committee. The Steering Committee
will include members from relevant disciplines. Representatives from the CREST-2, NINDS, and
CMS will be members of the Steering Committee. The Steering Committee shall provide strategic
direction to C2R, monitor all activities, and have ultimate authority and responsibility for
the scientific integrity and appropriate use of the C2R data for research and publications.
Operational responsibilities of the Steering Committee will include oversight of the CAS
operator/facility credentialing process as well as developing and improving other key aspects
of registry functions.

The Steering Committee will also have the discretion to modify elements of this protocol if
such changes are determined to be necessary for the successful implementation of C2R.

The Management Committee will carry out day-to-day management and regulatory
responsibilities, reporting to the Steering Committee. Membership will include at least one
leader from the surgical, stenting, and neurological communities. The registry Principal
Investigator (PI) will be Brajesh K. Lal, Co-Principal Investigator of CREST-2.

Inclusion Criteria

Asymptomatic patients:

Age ≥ 18 and ≤ 80 and any one of the following

1. ≥70% stenosis, standard surgical risk for CEA

2. ≥70% stenosis, high anatomic risk for CEA

3. ≥70% stenosis, high physiologic risk for CEA

Symptomatic patients:

Symptomatic patients are defined by the following characteristics: Ipsilateral carotid
Transient Ischemic Attack (TIA), with neurologic symptoms persisting less than 24 hours;
Ipsilateral non-disabling stroke: Modified Rankin Scale (mRS) ≤ 3; and Ipsilateral
transient monocular blindness: amaurosis fugax. [Source: current Medicare NCD for CAS]

Age ≥ 18 and ≤ 80 and any one of the following

1. ≥50% stenosis, standard surgical risk for CEA

2. 50% to 69% stenosis, high anatomic risk for CEA

3. 50% to 69% stenosis, high physiologic risk

4. ≥70% stenosis, high anatomic and/or physiologic risk for CEA - currently covered by
Medicare, but sites are strongly encouraged to voluntarily include these patients in
C2R

5. ≥70% stenosis, post-CEA and -CAS - currently covered by Medicare, but sites are
strongly encouraged to voluntarily include these patients in C2R

6. ≥70% stenosis, post-irradiation - currently covered by Medicare, but sites are
strongly encouraged to voluntarily include these patients in C2R

Exclusion Criteria:

Patients with any one of the following conditions are ineligible for enrollment in C2R

1. NYHA Class IV CHF

2. COPD on chronic continuous oxygen therapy

3. Severe (Class Childs D) liver failure

4. End-stage renal failure requiring dialysis

5. Cancer with metastatic spread and/or undergoing active chemotherapeutic treatment

6. Any dementia considered greater than "mild"