ILUMIEN IV: OPTIMAL PCI

This is a prospective, single-blind clinical investigation randomizing subjects to OCT-guided
coronary stent implantation vs. angiography-guided coronary stent implantation in a 1:1
ratio. The clinical investigation will be conducted at approximately 125 centers in North
America (US and Canada), Europe, Middle East and Asia-Pacific.

All patients will undergo baseline and post PCI imaging with their randomized modality. In
addition, the Angiography group will undergo a blinded post-PCI OCT run to allow comparison
of OCT derived minimum stent area (MSA) in both groups.

After hospital discharge, all patients will have clinical follow-up at 30 days, 1 year, and 2
years.

Inclusion Criteria (all must be present)

1. Subject must be at least 18 years of age.

2. Subject must have evidence of myocardial ischemia (e.g., stable angina, silent
ischemia, unstable angina, or acute myocardial infarction) suitable for elective PCI.

3. Patients undergoing planned Xience stent implantation during a clinically indicated
PCI procedure meeting one or more of the following criteria:

- High clinical-risk, defined as

1. Medication-treated diabetes mellitus, AND/OR

- High angiographic-risk lesion(s), with at least one target lesion in each target
vessel planned for randomization meeting at least one of the following criteria;

1. Target lesion is the culprit lesion responsible for either:

- NSTEMI, defined as a clinical syndrome consistent with an acute
coronary syndrome and a minimum troponin of 1 ng/dL (may or may not
have returned to normal), and >1 mm ST-segment deviation and/or dynamic
T wave changes at rest within 7 days, OR

- STEMI >24 hours from the onset of ischemic symptoms

2. long or multiple lesions (defined as intended total stent length in any
single target vessel ≥28 mm),

3. bifurcation intended to be treated with 2 planned stents (i.e. in both the
main branch and side branch), and where the planned side branch stent is ≥
2.5 mm in diameter.

4. angiographic severe calcification (defined as angiographically visible
calcification on both sides of the vessel wall in the absence of cardiac
motion),

5. chronic total occlusion (CTO) (enrolment and randomization in this case
performed only after successful antegrade wire escalation crossing and
pre-dilatation)

6. in-stent restenosis (all patterns, as long as the lesion is at or within the
stent margin(s) and has an angiographically visually-assessed diameter
stenosis (DS) ≥70% or DS ≥50% with non-invasive or invasive evidence of
ischemia)

4. All target lesions (those lesions to be randomized) must have a visually estimated or
quantitatively assessed %DS of either ≥70%, or ≥50% plus one or more of the following:
an abnormal functional test (e.g. fractional flow reserve, stress test) signifying
ischemia in the distribution of the target lesion(s) or biomarker positive acute
coronary syndrome (ACS) with plaque disruption or thrombus.

5. All target lesions must be planned for treatment with only ≥2.5 mm and ≤3.5 mm stents
and post-dilatation balloons based on pre-PCI angiographic visual estimation. The only
exception is for long target lesions (visually estimated as >20 mm), in which after
implantation of a ≤3.5 mm stent up to half of the stented segment may be post-dilated
with balloons >3.5 mm as needed per operator judgment.

For example, if there is a 34 mm long Left Anterior Descending (LAD) lesion spanning
the proximal and mid segments, a 38 mm long 3.0 mm diameter Xience stent may be
implanted, and the proximal half of the stent may be post-dilated with a 3.75 mm
balloon.

6. No more than 2 target lesions requiring PCI are present in any single vessel., and no
more than 2 target vessels are allowed. Thus, up to 4 randomized target lesions per
patient in a maximum of 2 target vessels are allowed, including branches. The intended
target lesions will be declared just prior to randomization.

Note: A lesion is defined as any segment(s) of the coronary tree, no matter how long,
which is planned to be covered with one contiguous length of stent, whether single or
overlapped. A bifurcation counts as a single lesion even if the side branch is planned
to be treated.

Note: All lesions in a randomized target vessel that are intended to be treated by PCI
are designated as target lesions, and at least one target lesion in each randomized
target vessel must meet angiographic high-risk inclusion criteria summarized above in
3B). The only exception is for patients who qualify for the trial on the basis of
medication-treated diabetes, in which case no target lesion is required to meet
angiographic high-risk inclusion criteria.

7. All target lesions intended to be treated by PCI in the target vessel are amenable to
OCT-guided PCI (i.e. no lesion-specific angiographic exclusion criteria are present -
see Section 5.4.2 below).

Example: If a qualifying angiographic high-risk lesion is in the proximal LAD, and
there is a second target lesion in the distal LAD which is a focal lesion not
otherwise meeting high-risk criteria, both the proximal LAD and distal LAD lesions
must be amenable to OCT (e.g. no excessive tortuosity or calcification precluding
delivering the OCT catheter), and each lesion must undergo OCT-guided stenting.
Otherwise the vessel should be excluded from randomization.

8. For a female subject of childbearing potential, a pregnancy test must be performed
with negative results known within 7 days prior to the index procedure per site
standard, and pregnancy must not be intended for at least 2 years.

9. For a female subject with a recent birth, subject is not breast-feeding at the time of
the screening visit and will not be breast-feeding for up to 2 years following the
index procedure.

10. Subject or a legally authorized representative must provide written Informed Consent
prior to any study related procedure.

Clinical exclusion criteria:

1. STEMI ≤24 hours from the onset of ischemic symptoms

2. Creatinine clearance ≤30 ml/min/1.73 m2 (as calculated by the Modification of Diet in
Renal Disease (MDRD) formula for estimated GFR) and not on dialysis. Note: chronic
dialysis dependent patients are eligible for enrolment regardless of creatinine
clearance.

3. Hypotension, shock or need for mechanical support or intravenous vasopressors

4. Congestive Heart Failure (CHF) (Killip class ≥2 or New York Heart Association (NYHA)
class ≥3)

5. Left Ventricular Ejection Fraction (LVEF) ≤30% by the most recent imaging test within
30 days prior to procedure (echo, MRI, contrast left ventriculography or other)

6. Unstable ventricular arrhythmias

7. Inability to take dual antiplatelet therapy (DAPT) (both aspirin and a P2Y12
inhibitor) for at least 12 months in the patient presenting with an ACS, or at least 6
months in the patient presenting with stable coronary artery disease (CAD), unless the
patient is also taking chronic oral anticoagulation in which case a shorter duration
of DAPT may be prescribed per local standard of care.

8. Planned cardiac or non-cardiac surgery within 24 months after the index procedure

9. Prior PCI within the target vessel within 12 months (unless the target lesion is the
prior PCI site - i.e. in-stent restenosis)

10. Any planned PCI within the target vessel(s) within 24 months after the study
procedure, other than a planned staged intervention in a second randomized target
vessel.

Note: Planned staged interventions must be noted at the time of randomization, and the
decision to stage may be modified within 24 hours of completion of the index PCI. See
Section 6.5.3.7 for more details of multi lesion and vessel treatment.

Note: PCI in non-target vessels is permitted >48 hours after the index procedure.

11. Any prior PCI in a non-target vessel within 24 hours before the study procedure, or
within previous 30 days if unsuccessful or complicated.

Note: Patients requiring non-target vessel PCI may be enrolled and the non-target
vessel(s) may be treated in the same index procedure as the randomized lesions (in all
cases prior to randomization), as long as treatment of the lesion(s) in the non-target
vessel is successful and uncomplicated.

Successful and uncomplicated definition for non-target vessel treatment during the
index procedure: Angiographic diameter stenosis <10% and TIMI III flow (visually
assessed) for all non-target lesions and vessels, without dissection ≥ NHLBI type C,
perforation, prolonged chest pain (>5 minutes) or prolonged ST-segment elevation or
depression (>5 minutes), or cardiac arrest or need for defibrillation or cardioversion
or hypotension /heart failure requiring mechanical or intravenous hemodynamic support
or intubation.

12. Subject has known hypersensitivity or contraindication to any of the study drugs
(including heparin and all P2Y12 inhibitors, one or more components of the study
devices, including everolimus, cobalt, chromium, nickel, platinum, tungsten, acrylic
and fluoropolymers, or radiocontrast dye that cannot be adequately pre-medicated.

13. Subject has received any solid organ transplants or is on a waiting list for any solid
organ transplants.

14. Subject is receiving immunosuppressant therapy or has known immunosuppressive or
severe autoimmune disease that requires chronic immunosuppressive therapy (e.g., human
immunodeficiency virus, systemic lupus erythematosus, etc.). Note: corticosteroids are
not included as immunosuppressant therapy.

15. Subject has previously received or is scheduled to receive radiotherapy to a coronary
artery (vascular brachytherapy), or the chest/mediastinum.

16. Subject has a platelet count <100,000 cells/mm3 or >700,000 cells/mm3.

17. Subject has a documented or suspected hepatic disorder as defined as cirrhosis or
Child-Pugh ≥ Class B.

18. Subject has a history of bleeding diathesis or coagulopathy, or has had a significant
gastro-intestinal or significant urinary bleed within the past six months.

19. Subject has had a cerebrovascular accident or transient ischemic neurological attack
(TIA) within the past six months, or any prior intracranial bleed, or any permanent
neurologic defect, or any known intracranial pathology (e.g., aneurysm, arteriovenous
malformation, etc.).

20. Subject has extensive peripheral vascular disease that precludes safe 6 French sheath
insertion. Note: femoral arterial disease does not exclude the patient if radial
access may be used.

21. Subject has life expectancy <2 years for any non-cardiac cause.

22. Subject is in the opinion of the Investigator or designee unable to comply with the
requirements of the study protocol or is unsuitable for the study for any reason.

23. Subject is currently participating in another investigational drug or device clinical
study that has not yet completed its primary endpoint.

24. Subject is part of a vulnerable population who, in the judgment of the investigator,
is unable to give Informed Consent for reasons of incapacity, immaturity, adverse
personal circumstances or lack of autonomy. This may include: Individuals with mental
disability, persons in nursing homes, children, impoverished persons, persons in
emergency situations, homeless persons, nomads, refugees, and those incapable of
giving informed consent. Vulnerable populations also may include members of a group
with a hierarchical structure such as university students, subordinate hospital and
laboratory personnel, employees of the Sponsor, members of the armed forces, and
persons kept in detention.

Angiographic exclusion criteria

1. Syntax score ≥33, unless a formal meeting of the Heart Team, including a cardiac
surgeon, concludes that PCI is appropriate.

2. Planned use of any stent <2.5 mm in a target vessel based on visual estimation (note:
a smaller stent may be used in a bail-out scenario - e.g. to treat a distal dissection
- but its use cannot be planned prior to enrolment)

3. Planned use of a stent or post-dilatation balloon ≥3.75 mm for the target lesion (see
inclusion criteria #2 for the one exception to this exclusion criterion)

4. Severe vessel tortuosity or calcification in a target vessel such that it is unlikely
that the OCT catheter can be delivered (note: severe vessel calcification is allowed
if it is expected that the OCT catheter can be delivered at baseline or after vessel
preparation with balloon pre-dilatation or atherectomy)

5. The target lesion is in the left main coronary artery

6. The target lesion is in a bypass graft conduit. Note: A native coronary artery may be
randomized if a prior bypass graft conduit to the vessel is totally occluded, but not
if it is patent.

7. The target lesion is an ostial right coronary artery (RCA) stenosis

8. The target lesion is a stent thrombosis

9. Planned use of any stent other than Xience in a target lesion