Japan-USA Harmonized Assessment by Randomized, Multi-Center Study of OrbusNEich's Combo StEnt (Japan-USA HARMONEE): Assessment of a Novel DES Platform For Percutaneous Coronary Revascularization in Patients With Ischemic Coronary Disease and NSTEMI Acute Coronary Syndrome
Phase: NA
Conditions: Coronary Arteriosclerosis, Non ST Segment Elevation Acute Coronary Syndrome
Sponsor: OrbusNeich

OrbusNeich Medical 
 
Protocol 
HARMONEE 
 
Protocol Number: VP-0601 
 
Confidential 
Amendment 1.02/March 16, 2015 
 
1
 
 
 
 
 
 
 
 
 
 
 
Study Protocol 
 
Japan-USA Harmonized Assessment by Randomized, Multi-Center 
Study of OrbusNEich’s Combo StEnt (Japan-USA HARMONEE): 
Assessment of a Novel DES Platform For Percutaneous Coronary 
Revascularization in Patients with Ischemic Coronary Disease and 
NSTEMI  Acute Coronary Syndrome  
 
Phase: Japan Pivotal  
U.S. Investigational Device Exemption  
Date: March 16, 2015 
Version: Amendment 1.02 
 
Principal Investigators: 
 
Shigeru Saito, MD 
Director of Cardiology & Catheterization     
Laboratories and Vice President 
Shonan Kamakura General Hospital  
 
1370-1 Okamoto 
Kamakura City 247-8533 Japan 
Phone: +81-467-461717 Ext: 10490 
e-mail: transradial@kamakuraheart.org 
    
 
Mitchell W. Krucoff, MD 
Professor, Medicine/Cardiology 
Duke University Medical Center 
Durham NC 27705 
USA 
Phone: +1-919-668-8422 
e-mail: mitchell.krucoff@duke.edu 
Sponsor: 
OrbusNeich Medical K.K.  
3-6-11 Uehara, Shibuya  
Tokyo 151-0064 
Japan  
Phone: +81-3-5738-5765 
OrbusNeich Medical, Inc. 
5363 NW 35th Avenue 
Fort Lauderdale FL 33309 
USA 
Phone: +1-954-730-0711 
 
Notwithstanding the contents of this protocol, this clinical trial will be conducted in accordance 
with local regulations in each country. This document contains information that is privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable laws and 
regulations. The information in this document is the property of the Duke Clinical Research 
Institute (DCRI) and may not be reproduced, published, or disclosed to others without written 
authorization from DCRI.  
 

OrbusNeich Medical 
 
Protocol 
HARMONEE 
 
Protocol Number: VP-0601 
 
Confidential 
Amendment 1.02/March 16, 2015 
 
3
PROTOCOL VERSION AND AMENDMENT TRACKING 
 
Version/Amendment Number 
Approval Date 
Regulatory 1.0 
 
Regulatory 2.1 
October 23, 2013 
Regulatory 2.5 
December 13, 2013 
Regulatory 2.51 
February 5, 2014 
Regulatory 2.6 
May 5, 2014 
Amendment  1.0 
December 8, 2014 
Amendment 1.02 
March 16, 2015 
 
 
 
 
 

OrbusNeich Medical 
 
Protocol 
HARMONEE 
 
Protocol Number: VP-0601 
 
Confidential 
Amendment 1.02/March 16, 2015 
 
4
PROTOCOL SYNOPSIS 
Name of Company 
OrbusNeich Medical  
Product 
Combo Stent (OMKK02 in Japan) 
Protocol Number 
VP-0601 
Protocol Title 
Japan-USA Harmonized Assessment by Randomized, Multi-
Center Study of OrbusNEich’s Combo StEnt (Japan-USA 
HARMONEE): Assessment of a Novel DES Platform For 
Percutaneous Coronary Revascularization in Patients with 
Ischemic Coronary Disease and NSTEMI Acute Coronary 
Syndrome 
Study Purpose 
Treatment for coronary revascularization in patients with 
functionally significant ischemic heart disease, including 
unstable angina and non-ST-elevation myocardial infarction 
(NSTEMI), due to discrete de novo lesions (length 28 mm or 
less) in 1 or more native coronary arteries with a reference 
vessel diameter of 2.5 mm to 3.5 mm 
Main Criteria for Inclusion 
 
Subject must be at least 20 years of age at the time of 
randomization 
 
Clinical or functional evidence of myocardial ischemia 
(eg, stable or unstable angina, stabilized NSTEMI 
confirmed by serum markers, ischemia by positive 
functional study, abnormal fractional flow reserve [FFR], 
or a reversible change in the electrocardiogram [ECG] 
consistent with ischemia) 
 
 
Acceptable candidate with anatomy for percutaneous 
coronary intervention (PCI) with a drug-eluting stent 
(DES) 
 
Agree to return for all study-related follow-up 
assessments, including invasive optical coherence 
tomography (OCT) follow-up assessment at 6 months 
(Cohort A) and at 1 year postprocedure (Cohorts A, B, and 
C) 
 
Acceptable candidate for coronary artery bypass graft 
surgery  
Angiographic anatomy criteria: 
 
Target lesions must be located in a native coronary artery 
with visually estimated diameter of 2.5 mm to 3.5 mm, 
inclusive, and up to 3 de novo target lesions may be 
treated, with a maximum of 2 de novo target lesions per 
epicardial vessel, with a maximum of 2 target vessels.  
 
Target lesions should be treatable with a single stent and 
must measure 28 mm or less in length by visual 
estimation (2 mm or more of nondiseased tissue on either 
side of the target lesion should be covered by the study 
stent). 

OrbusNeich Medical 
 
Protocol 
HARMONEE 
 
Protocol Number: VP-0601 
 
Confidential 
Amendment 1.02/March 16, 2015 
 
5
Name of Company 
OrbusNeich Medical  
Product 
Combo Stent (OMKK02 in Japan) 
 
If more than 1 target lesion will be treated, the reference 
vessel diameter  and lesion length of each target lesion 
must meet the above criteria.  
 
Target lesions must be in a major artery or branch with a 
visually estimated stenosis of 50% or greater and less 
than 100% with a TIMI flow of 1 or greater. 
 
Previous percutaneous intervention of lesions in a target 
vessel (including side branches) is allowed if done 9 or 
more months before the study procedure and greater than 
10 mm from the current target lesion. 
 
Nonstudy percutaneous interventions for lesions in a 
nontarget vessel are allowed if done 9 or more months 
before the study procedure, in the absence of documented 
ischemia or angiographic restenosis related to the vessel. 
Main Criteria for Exclusion 
 
STEMI at index presentation or within 7 days of study 
screening. 
 
Current unstable arrhythmias or intractable angina with 
ECG changes or shock requiring pressors or mechanical 
circulatory assistance (eg, intraaortic balloon pump, left 
ventricular assist device, Impella). 
 
Known left ventricular ejection fraction less than 30%. 
 
Prior heart transplant or any other organ transplant or is on 
a waiting list for any organ transplant. 
 
Receiving or scheduled to receive anticancer therapy for 
malignancy within 30 days before or after the procedure. 
 
Receiving immunosuppression therapy, has known serious 
immunosuppressive disease (eg, human 
immunodeficiency virus), or has severe autoimmune 
disease that requires chronic immunosuppressive therapy 
(eg, systemic lupus erythematosus). 
 
Known hypersensitivity or contraindication to aspirin; 
both heparin and bivalirudin; all available P2Y12 
inhibitors (clopidogrel, prasugrel, ticlopidine, and 
ticagrelor); or any everolimus, sirolimus, cobalt, 
chromium, nickel, tungsten, acrylic, or fluoro polymers; or 
hypersensitivity to contrast media that cannot be 
adequately premedicated. 
 
Has previously received murine therapeutic antibodies and 
exhibited sensitization through the production of human 
antimurine antibodies (HAMAs). 
 
Elective surgery planned within the first 12 months after 
the procedure that will require interruption or 
discontinuation of planned dual antiplatelet therapy. 
 
Known platelet count less than 100,000 cells/mm3 or 
greater than 700,000 cells/mm3, a white blood cell count 
of less than 3000 cells/mm3, or documented or suspected 
liver disease (including laboratory evidence of hepatitis). 

OrbusNeich Medical 
 
Protocol 
HARMONEE 
 
Protocol Number: VP-0601 
 
Confidential 
Amendment 1.02/March 16, 2015 
 
6
Name of Company 
OrbusNeich Medical  
Product 
Combo Stent (OMKK02 in Japan) 
 
Known renal insufficiency (eg, serum creatinine level of 
greater than 2.5 mg/dL or subject is on dialysis). 
 
History of bleeding diathesis or coagulopathy or will 
refuse blood transfusions. 
 
Has had a cerebrovascular accident or transient ischemic 
neurological attack within the past 6 months. 
 
Has had a significant gastrointestinal or urinary bleed 
within the past 6 months. 
 
Known extensive peripheral vascular disease that 
precludes safe 6 French sheath insertion. 
 
Known other medical illness (eg, cancer, chronic 
infectious disease, severe vascular disease, or congestive 
heart failure) or known history of substance abuse 
(alcohol, cocaine, heroin, etc.) that may cause 
noncompliance with the protocol, confound the data 
interpretation, or is associated with a life expectancy of 
less than 1 year. 
 
Currently participating in another clinical study that has 
not yet reached its primary endpoint. 
 
Currently pregnant or breast-feeding or is planning 
pregnancy in the period up to 1 year following index 
procedure. Female subjects of childbearing potential must 
have a negative pregnancy test within 7 days before the 
index procedure. 
Angiographic exclusion criteria: 
 
Unprotected left main coronary artery location. 
 
Unprotected ostial (located within 2 mm of the origin) left 
anterior descending artery or left circumflex. 
 
Located within an arterial or saphenous vein graft or graft 
anastomosis, distal to a diseased arterial or saphenous vein 
graft (visually estimated graft diameter stenosis greater 
than 40%). 
 
Involves a bifurcation in which the side branch is 2 mm or 
greater in diameter AND would be covered by the planned 
stent. 
 
Involves a side branch requiring predilation.  
 
Total occlusion (TIMI flow 0) before wire crossing. 
 
Extreme tortuosity proximal to or within the lesion. 
 
Extreme angulation (90º or greater) proximal to or within 
the lesion. 
 
Heavy calcification, defined as multiple persisting 
opacifications of the coronary wall visible in more than 
one projection surrounding the complete lumen of the 
coronary artery at the site of the lesion. 
 
Restenotic vessel from previous intervention. 
 
Received brachytherapy in any epicardial vessel 
(including side branches). 
 
Target vessel contains angiographically visible thrombus. 

OrbusNeich Medical 
 
Protocol 
HARMONEE 
 
Protocol Number: VP-0601 
 
Confidential 
Amendment 1.02/March 16, 2015 
 
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Name of Company 
OrbusNeich Medical  
Product 
Combo Stent (OMKK02 in Japan) 
 
Serial lesions or diffuse disease with high probability of 
bailout requiring 3 or more stents in a single vessel, more 
than 5 stents per subject, or more than 2 vessels. 
 
Target or nontarget vessel lesion (including all side 
branches) is present with a high probability of requiring 
PCI within 12 months after the index procedure. 
 
Stent overlapping is a planned treatment of the target 
lesion. 
Study Device 
Combo stent, a sirolimus-eluting and anti-CD34 antibody-
coated stent 
Comparator Device 
Everolimus-eluting stent (EES) XIENCE family of stent 
systems: (Xience V, Xience Prime, Xience Xpedition, Xience 
Alpine stents, Abbott Vascular/Abbott Vascular Japan). The 
XIENCE Alpine stent system uses the identical stent and stent 
contacting balloon materials, and the identical drug coating 
formulation and drug dose density as the XIENCE Prime. 
Xience Prime, Xpedition, and Alpine utilized the clinical result 
of XIENCE V and is a product that obtains efficiency 
essentially equal to XIENCE V. 
Study Objectives 
 
Primary 
To demonstrate assurance of the safety and effectiveness of 
Combo—a combination sirolimus-eluting and anti-CD34 
antibody-coated stent—through: 
 
Noninferior clinical effectiveness to state-of-the-art 
second-generation drug-eluting stent (DES), specifically 
o 
Clinically, as comparable target-vessel failure (TVF) at 
1 year 
o Comparable freedom from ischemia assessed in 
primary target vessel by FFR ratio greater than 0.8 at 
1 year 
 
Superior clinical effectiveness to imputed bare metal stent 
TVF at 1 year 
Secondary 
 
To assess the effectiveness of Combo by OCT evaluation 
of healthy level of intimal tissue coverage at 1 year 
(Cohorts A and B combined) 
Prespecified 
 
Evaluation of angiographic late lumen loss at 1 year 
(Cohorts A and B combined) 
 
To assess the safety of Combo by OCT evaluation of 
intracoronary thrombosis and stent malapposition at 1 year 
(Cohorts A and B combined) 
 
Serial observation of both Combo and EES at 6 and 
12 months in the same patients (Cohort A) 

OrbusNeich Medical 
 
Protocol 
HARMONEE 
 
Protocol Number: VP-0601 
 
Confidential 
Amendment 1.02/March 16, 2015 
 
8
Name of Company 
OrbusNeich Medical  
Product 
Combo Stent (OMKK02 in Japan) 
 
To assess the change in HAMA plasma levels at 30-day and 
1-year follow-ups compared with baseline 
 
Comparable rates of death, myocardial infarction (MI), and 
stent thrombosis at 1 year 
 
Study Design 
Subjects will be randomized to receive the Combo stent as the 
investigational treatment arm or an EES as the active-control 
arm, in a multi-center, single-blind, noninferiority study.  
Up to 50 sites are proposed in Japan and the United States. 
Total sample size: 286 subjects (271 evaluable) in each of 2 
arms, for a total sample size of 572 subjects (542 evaluable) 
who are admitted to the hospital for a planned (elective or 
urgent) percutaneous coronary artery intervention procedure. 
Investigators must declare an intended oral antiplatelet 
regimen and intended duration of antiplatelet therapy before 
randomization; postprocedure, subjects will receive aspirin 
indefinitely and P2Y12 inhibition for a minimum of 6 months 
(12 months for acute coronary syndrome diagnosis), according 
to regional standards of care. After stent implantation, subjects 
will be contacted for follow-up at 30 days; 6 months; and 1, 2, 
3, 4, and 5 years. At 12 months a clinical evaluation will be 
completed before cardiac catheterization and angiographic 
assessment in all subjects. 
 The study population will be enrolled as 3 consecutive 
cohorts: 
 
Cohort A: 30 subjects (15 subjects per arm) will undergo 
all clinical follow-up assessments; receive OCT and 
angiographic assessments at 6 months; and receive OCT, 
FFR, and quantitative coronary angiographic (QCA) 
assessment at 12 months after device implantation. Cohort 
A will be the first cohort to enroll.  
 
Cohort B: 110 subjects (55 subjects per arm) will undergo 
all clinical follow-up assessments, with OCT, FFR, and 
QCA assessments at 12 months after device implantation. 
Cohort B will be the second cohort to enroll.  
 
Cohort C: 432 subjects (216 subjects per arm) will 
undergo all clinical follow-up assessments with FFR and 
angiographic assessments at 12 months. Cohort C will be 
the last cohort to enroll.  
In addition, serum will be assessed for HAMA development at 
index, 30 days, and 12 months in Cohort B subjects. Human 
antimurine antibody plasma assessment will be with blood 
draws performed during index procedure, 30-day follow-up 
visit, and 1-year catheterizations.  
Primary endpoint results will be reported after all subjects have 
completed 12 months of clinical and FFR follow-up. A total of 
572 subjects (30+110+432) are enrolled to ensure that 

OrbusNeich Medical 
 
Protocol 
HARMONEE 
 
Protocol Number: VP-0601 
 
Confidential 
Amendment 1.02/March 16, 2015 
 
9
Name of Company 
OrbusNeich Medical  
Product 
Combo Stent (OMKK02 in Japan) 
542 subjects are evaluable for the primary clinical endpoint, 
across all cohorts. 
Duration of Study Participation 
Primary endpoint: 1 year 
Completed follow-up: 5 years 
Number of Subjects 
572 (542 evaluable) 
Number of Sites 
Up to 50, in Japan and the United States 
Primary Endpoint 
TVF, defined as cardiac death, target-vessel MI, or ischemia-
driven target-vessel revascularization (TVR) by percutaneous 
or surgical methods, at 1 year. 
Secondary Endpoint 
Mechanistic OCT healthy level of intimal tissue coverage, by 
OCT core laboratory at 1 year (Cohorts A and B, total N=140 
subjects) 
Additional Prespecified Endpoints 
Efficacy: 
 
Angiographic late loss by quantitative coronary angiogram 
core laboratory at 1 year (Cohorts A and B combined). 
 
In-stent and in-segment angiographic binary restenosis at 
1 year (Cohorts A and B combined). In-segment restenosis 
is defined as restenosis within a region including 5 mm 
proximal and 5 mm distal to the target lesion. 
 
In-stent and in-segment proximal and distal QCA 
measurement of late lumen loss at 1 year (Cohorts A and 
B combined). 
 
Clinically and functionally (FFR) ischemia-driven target-
lesion revascularization (TLR) at 1 year. 
 
Device success, defined as attainment of less than 50% 
residual stenosis of the target lesion.  
 
Lesion success, defined as attainment of less than 50% 
residual stenosis using any percutaneous method. 
 
Procedure success, defined as lesion success without the 
occurrence of in-hospital death, nonfatal MI, stroke, or 
emergency revascularization. 
 
TVF, defined as cardiac death, target vessel MI, or 
ischemic-driven TVR by percutaneous or surgical 
methods at 30 days; 6 months; and 2, 3, 4, and 5 years. 
 
Death (all causes) at 30 days; 6 months; and 1, 2, 3, 4, and 
5 years. 
 
Cardiac death at 30 days; 6 months; and 1, 2, 3, 4, and 
5 years. 
 
Nonfatal MI at 30 days; 6 months; and 1, 2, 3, 4, and 
5 years. 
 
Target-vessel MI at 30 days; 6 months; and 1, 2, 3, 4, and 
5 years. 
 
TLR (ischemia driven) at 30 days; 6 months; and 1, 2, 3, 
4, and 5 years. 

OrbusNeich Medical 
 
Protocol 
HARMONEE 
 
Protocol Number: VP-0601 
 
Confidential 
Amendment 1.02/March 16, 2015 
 
10
Name of Company 
OrbusNeich Medical  
Product 
Combo Stent (OMKK02 in Japan) 
 
TVR (ischemia driven) at 30 days; 6 months; and 1, 2, 3, 
4, and 5 years. 
 
Target-lesion failure, defined as death, MI, and ischemia-
driven TLR. 
 
Safety: 
 
All-cause mortality at postprocedure; 30 days; 6 months; 
and 1, 2, 3, 4, and 5 years 
 
Cardiac mortality at postprocedure; 30 days; 6 months; 
and 1, 2, 3, 4, and 5 years 
 
ARC definite/probable stent thrombosis at postprocedure; 
30 days; 6 months; and 1, 2, 3, 4, and 5 years  
 
ARC definite stent thrombosis at postprocedure; 30 days; 
6 months; and 1, 2, 3, 4, and 5 years 
 
MI (using modified ARC definition1) at postprocedure; 
30 days; 6 months; and 1, 2, 3, 4, and 5 years 
 
Stroke and TIA at postprocedure; 30 days; 6 months; and 
1, 2, 3, 4, and 5 years 
 
OCT safety assessments for late malapposition and 
intracoronary thrombus by OCT core laboratory at 1 year 
(Cohorts A and B combined, N=140 subjects) 
 
Change in HAMA plasma levels at 30 days and 1-year 
follow-up compared with baseline (N=110, all subjects in 
Cohort B) 
 
 

OrbusNeich Medical 
 
Protocol 
HARMONEE 
 
Protocol Number: VP-0601 
 
Confidential 
Amendment 1.02/March 16, 2015 
 
11
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and the investigator brochure, and I agree that 
it contains all necessary details for me and my staff to conduct this study as described. I will 
personally oversee the conduct of this study as outlined herein and will make a reasonable effort 
to complete the study within the time designated. 
 
I will provide all study personnel under my supervision with copies of the protocol and access to 
all information provided by OrbusNeich Medical. I will discuss this material with them to ensure 
that they are fully informed about the efficacy and safety parameters and the conduct of the study 
in general. I am aware that, before beginning this study, the institutional review board responsible 
for such matters must approve this protocol in the clinical facility where it will be conducted. I 
agree to make all reasonable efforts to adhere to the attached protocol. 
 
I agree to provide all subjects with informed consent forms, as required by government regulations 
and International Conference on Harmonisation guidelines. I further agree to report to the sponsor 
any adverse device effects in accordance with the terms of this protocol, the Ministerial Ordinance 
on Good Clinical Practice for Medical Devices, Ordinance of the Ministry of Health and Welfare 
No. 36 (J-GCP) (for Japan), and U.S. Food and Drug Administration regulation 21 Code of Federal 
Regulations 812.150(a)(1) (for the United States). 
 
 
________________________________ 
 
 
 
 
 
Site Principal Investigator Name (print) 
 
 
 
________________________________ 
Signature 
 
 
________________________________ 
 
Date 

OrbusNeich Medical 
 
Protocol 
HARMONEE 
 
Protocol Number: VP-0601 
 
Confidential 
Amendment 1.02/March 16, 2015 
 
12
TABLE OF CONTENTS 
 
Administrative Structure ........................................................................................21 
 
Introduction ............................................................................................................23 
 
Background ................................................................................................23 
 
Preclinical Findings ...................................................................................27 
 
Clinical Experience with Study Device .....................................................28 
 
Rationale ....................................................................................................28 
 
Objectives ..............................................................................................................30 
 
Primary Objective ......................................................................................30 
 
Secondary Objective ..................................................................................30 
 
Prespecified Objectives ..............................................................................30 
 
Subject Selection ....................................................................................................31 
 
Inclusion Criteria .......................................................................................31 
 
Exclusion Criteria ......................................................................................32 
 
Study Design ..........................................................................................................34 
 
Overview of Study .....................................................................................34 
 
Study Procedures .......................................................................................35 
 
Screening and Prerandomization Procedures .............................................38 
 
Enrollment and Randomization/Implantation ............................................39 
 
Enrollment ..................................................................................39 
 
Randomization/Implantation ......................................................39 
 
Postimplantation Procedures ......................................................................40 
 
Postprocedure..............................................................................40 
 
30 (± 7) Days ..............................................................................40 
 
180 (± 30) Days ..........................................................................41 
 
1 Year (± 30 Days) ......................................................................41 
 
Annual (± 60 Days) for 5 Years Postprocedure ..........................42 
 
Unscheduled Visits/Early Termination .......................................43 
 
Study Device ..........................................................................................................44 
 
Description of Study Device ......................................................................44 
 
Sirolimus .....................................................................................45 
 
Bio-Engineered Drug-Eluting Coating .......................................46 
 
SynBiosys™ Multi-Block Copolymer ........................................47 
 
Polymer In Vitro Degradation ..................................47 
 
6.1.3.2  Polymer Biocompatibility ............................48 
 
Anti-CD34 Antibody ..................................................................48 
 
Antihuman CD34 Antibody Component ..................48 
 
Genome Mechanism of Capture ...............................49 
 
Pharmacokinetics of the Combo Stent ........................................50 
 
Delivery System Description .....................................................................51 
 
Implantation of Study Device ....................................................................51 

OrbusNeich Medical 
 
Protocol 
HARMONEE 
 
Protocol Number: VP-0601 
 
Confidential 
Amendment 1.02/March 16, 2015 
 
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Baseline Angiography.................................................................52 
 
Left Ventriculography.................................................................52 
 
Predilation of Target Lesion .......................................................52 
 
Bailout Procedures ......................................................................53 
 
Postdeployment Angiography.....................................................53 
 
Risks............................................................................................53 
 
Postprocedure Subject Management ...........................................57 
 
Follow-up Assessment Procedures ............................................................58 
 
Recommendations for Evaluation of Fractional Flow Reserve Results and 
Revascularization Procedures ....................................................................58 
 
Potential Benefits of Combo Stent .............................................................59 
 
Concomitant Medications/Therapies .........................................................60 
 
Prepercutaneous Coronary Intervention Medications.................60 
 
Aspirin ......................................................................60 
 
Platelet Adenosine Diphosphate Receptor Antagonists60 
 
Other Medications.....................................................60 
 
Medications During Percutaneous Coronary Intervention .........60 
 
Postpercutaneous Coronary Intervention Medications ...............61 
 
Aspirin ......................................................................61 
 
Platelet Adenosine Diphosphate Receptor Antagonists61 
 
Packaging ...................................................................................................61 
 
Product Stability and Shelf-Life ................................................................62 
 
Blinding of Study .......................................................................................62 
 
Receiving, Storage, Dispensing, and Return .............................................63 
 
Receipt of Study Device .............................................................63 
 
Return of Study Device...............................................................63 
 
Subject Safety and Adverse Events .......................................................................64 
 
Institutional Review Boards/Ethics Committees .......................................64 
 
Definitions..................................................................................................64 
 
Adverse Event .............................................................................64 
 
Serious Adverse Event ................................................................64 
 
Anticipated Adverse Device Effects ...........................................65 
 
Unanticipated Adverse Device Effects .......................................65 
 
Device Failure and Device Malfunction .....................................66 
 
User Error ...................................................................................66 
 
Assessment .................................................................................................66 
 
Causality Rating ..........................................................................66 
 
Severity of Adverse Events.........................................................67 
 
Reporting....................................................................................................67 
 
Time Frame .................................................................................67 
 
Adverse Events .........................................................67 
 
Serious Adverse Events ............................................68 
 
Unanticipated Adverse Device Effects, Device Failures, Device 
Malfunctions, and User Error .....................................................68 
 
Regulatory Reporting of Unanticipated Adverse Device Effects ..............69 

OrbusNeich Medical 
 
Protocol 
HARMONEE 
 
Protocol Number: VP-0601 
 
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Amendment 1.02/March 16, 2015 
 
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Protocol-Specific Endpoint Events ............................................................69 
 
Criteria for Withdrawal of Subjects from Study ........................................70 
 
Efficacy Assessments.............................................................................................71 
 
Safety Assessments ................................................................................................72 
 
Adverse Events ..........................................................................................72 
 
Laboratory Testing .....................................................................................72 
 
Statistical Analysis Plan and Determination of Sample Size .................................73 
 
Statistical Design .......................................................................................73 
 
Primary Analysis ........................................................................................73 
 
Primary Endpoint ........................................................................73 
 
Primary Endpoint Analysis .........................................................74 
 
Major Secondary Analyses ........................................................................74 
 
Secondary Efficacy Endpoint .....................................................74 
 
Additional Prespecified Endpoints .............................................74 
 
Efficacy .....................................................................74 
 
Safety ........................................................................75 
 
Optical Coherence Tomography Substudy Analyses ................................75 
 
Introduction .................................................................................75 
 
Objective .....................................................................................76 
 
Sample Size.................................................................................77 
 
Optical Coherence Tomography Image Acquisition ..................77 
 
Primary Neointimal Thickness Quantification by Optical Coherence 
Tomography ................................................................................78 
 
Secondary Optical Coherence Tomography Assessment ...........78 
 
Stent Morphometric Parameters .................................................78 
 
Surrogate Safety Parameters .......................................................79 
 
Tissue Characterization...............................................................79 
 
Angiographic Late Loss Analysis ..............................................................79 
 
Introduction .................................................................................79 
 
Performance Goal Justification ...................................................79 
 
Human Anti-Murine Antibody Analysis ...................................................81 
 
Introduction .................................................................................81 
 
Objective .....................................................................................82 
 
Sampling Procedure ....................................................................82 
 
HAMA Data Analysis Plan.........................................................82 
 
Other Planned Analyses .............................................................................82 
 
Analysis of Baseline Characteristics...........................................82 
 
Additional Consistency Analyses ...............................................82 
 
Statistical Methods .....................................................................................83 
 
General Statistical Methods ........................................................83 
 
Power and Sample Size...............................................................83 
 
Event-Rate Estimates ................................................83 

OrbusNeich Medical 
 
Protocol 
HARMONEE 
 
Protocol Number: VP-0601 
 
Confidential 
Amendment 1.02/March 16, 2015 
 
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Identification of a Clinically Acceptable Margin (Delta)
 ..................................................................................84 
 
Bayesian Network Meta-Analysis ............................85 
 
Comparison to an Imputed Bare Metal Stent Control89 
 
Power to Detect Noninferiority Based on Assay 
Sensitivity Boundary Conditions ..............................93 
 
Data and Safety Monitoring ...................................................................................94 
 
Safety Monitoring ......................................................................................94 
 
Data Management to Maintain Blinding....................................................94 
 
Data Monitoring and Quality Control ....................................................................95 
 
Required Data ............................................................................................95 
 
Data Collection and Tracking ....................................................................95 
 
Study Responsibilities ............................................................................................96 
 
Investigator Responsibility/Performance ...................................................96 
 
Study Data Reporting and Processing........................................................96 
 
Training ......................................................................................................96 
 
Monitoring the Investigational Sites ..........................................................96 
 
Study Documentation.................................................................................97 
 
Source Documentation ...............................................................................97 
 
Protocol Deviations ....................................................................................98 
 
Study Supply Accountability .....................................................................99 
 
Data Transmittal and Record Retention .....................................................99 
 Study Closeout .........................................................................................100 
 Audit/Inspections .....................................................................................100 
 Publication Policies ..................................................................................100 
 Study Committees ....................................................................................100 
 Principal Investigators and National Coordinators ...................100 
 Steering Committee ..................................................................101 
 Executive Operations Committee .............................................101 
 Data and Safety Monitoring Committee ...................................101 
 Clinical Events Classification Committee ................................101 
 
Ethical Considerations .........................................................................................102 
 
Role of Sponsor........................................................................................102 
 
Informed Consent.....................................................................................102 
 
Confidentiality of Subjects ......................................................................103 
 
Authorization for Use and Disclosure of Protected Health Information 
(HIPAA) ...................................................................................................103 
 
Insurance ..................................................................................................103 
 
Human Subject Protections ......................................................................103 
 
Institutional Review Board/Ethics Committee Review ...........................104 
 
Financial Disclosure.................................................................................104 
 
References ............................................................................................................105 

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Appendix 1: Optical Coherence Tomography Image Analysis Parameters ........112 
17.  
Appendix 2: Instructions for use /Investigator Brochure……………………….116 

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LIST OF TABLES 
Table 1. 
REMEDEE 9-Month Binary Angiographic Restenosis ...................................26 
Table 2. 
REMEDEE 9-Month Secondary Effectiveness and Safety Endpoints ............27 
Table 3. 
Schedule of Procedures ....................................................................................36 
Table 4. 
Pharmacokinetic Analysis for the Combo Stent ..............................................50 
Table 5. 
Combo Stent Delivery System Size Matrix by Catalogue Numbers ...............51 
Table 6. 
12-Month Event Rates Among All-Comers in Bern-Rotterdam Registry, 
Excluding ST-Elevation Myocardial Infarction Subjects, N=7638 .................83 
Table 7. 
12-Month Event Rates Among Subgroups in Bern-Rotterdam Registry.........84 
Table 8. 
Absolute Delta Values for Clinical Trials of Next-Generation Drug-Eluting Stents, 
Assuming 1-Sided Alpha of 0.05 .....................................................................84 
Table 9. 
Network Meta-Analysis of 21 Studies of Currently Approved Drug-Eluting Stents 
vs Everolimus-Eluting Stents ...........................................................................85 
Table 10. One-Year Target-Vessel Failure Rates in the SPIRIT Trials...........................90 
Table 11. One-Year Target-Failure Rates in the TAXUS Trials .....................................90 
Table 12. Boundary Sample Size and Control Event Rate, Combo vs Everolimus- .......92 
Table 13. Boundary Sample Size and Boundary Relative Risk Delta: Combo vs Everolimus-
Eluting Stent; Combo vs Bare Metal Stent ......................................................93 
Table 14. Power to Exclude Assay Sensitivity Boundaries for Each Event Rate ............93 
 
LIST OF FIGURES 
Figure 1. REMEDEE Study Design ................................................................................26 
Figure 2. Schematic of Study Design ..............................................................................35 
Figure 3.  Combo Stent....................................................................................................45 
Figure 4. Structural Formula of Sirolimus ......................................................................45 
Figure 5. Combo Stent Surface Modification .................................................................46 
Figure 6. In Vivo Elution of Combo Stent and Cypher (percentage of total drug eluted over 
time) .................................................................................................................47 
Figure 7. Structure of Murine Antihuman CD34 Monoclonal Antibody ........................49 
Figure 8. Endothelial Progenitor Cell Capture ................................................................50 
Figure 9. Illustration of the Balance Between Achieving Adequate Neointimal Coverage to 
Protect Against Stent Thrombosis While Maintaining Adequate Blood Flow to 
Prevent Ischemia ..............................................................................................77 
Figure 10.  Strut Level Analysis of the Neointimal Thickness  .........................................78 
Figure 11. In-Stent Late Loss Performance Goal vs Everolimus-Eluting Stent ...............80 
Figure 12. In-Segment Late Loss Performance Goal Relative to Everolimus-Eluting Stent80 
Figure 13.  Relative Risk (95% credible interval) of Currently Approved Drug-Eluting Stents 
vs Everolimus-Eluting Stents ...........................................................................88 
Figure 14. Absolute Delta for Various Sample Sizes ........................................................89 
Figure 15. Presence of Neoatherosclerosis ......................................................................114 
Figure 16. Presence of Fibrin ..........................................................................................115 
 
 
 

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ABBREVIATIONS 
AAR 
anti-antibody response 
ACC 
American College of Cardiology 
ACS 
acute coronary syndrome 
ADE 
adverse device effect 
ADP 
adenosine diphosphate  
AE 
adverse event 
AHA 
American Hospital Association 
ARC 
Academic Research Consortium 
BDI 
butane diisocyanate  
BDO 
butanediol  
BMS 
bare metal stent 
CABG 
coronary artery bypass graft 
CCS 
Canadian Cardiovascular Society 
CD34Ab 
anti-CD34 antibody 
CEC 
Clinical Events Classification Committee 
CFR 
Code of Federal Regulations (U.S.) 
CK-MB 
creatine kinase-myocardial band 
CL 
caprolactone 
CRA 
clinical research associate 
CRC 
clinical research coordinator 
DAPT 
dual antiplatelet therapy 
DCRI 
Duke Clinical Research Institute 
DES 
drug-eluting stent 
DSMC 
Data and Safety Monitoring Committee 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture  
EES 
everolimus-eluting stent 
EPC 
endothelial progenitor cell 

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FAME 
Fractional Flow Reserve (FFR) vs. Angiography in Multivessel Evaluation 
FDA 
Food and Drug Administration (U.S.) 
FFR 
fractional flow reserve 
FKBP 
FK-binding protein 
GA 
glycolide 
GMP 
Good Manufacturing Practice 
HAMA 
human antimurine antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
investigator brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ID 
identification 
IDE 
Investigational Device Exemption 
IFU 
instructions for use 
IRB 
institutional review board 
IXRS 
interactive web response system 
J-GCP 
Ministerial Ordinance on Good Clinical Practice for Medical Devices. 
Ordinance of the Ministry of Health and Welfare No. 36 (Japan) 
LA 
lactide 
LAR 
legally authorized representative 
LMWH 
low-molecular-weight heparin 
LVEF 
left ventricular ejection fraction 
mAbs 
monoclonal antibodies 
MACE 
major adverse cardiac events  
MI 
myocardial infarction 
MTC 
mixed treatment comparison 
mTOR 
mammalian target of rapamycin  
NSTEMI 
non–ST-elevation myocardial infarction 
OCT 
optical coherence tomography 
OD 
optical density 
OR 
odds ratio 

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PCI 
percutaneous coronary intervention 
PEG 
polyethylene glycol 
PHI 
protected health information 
PK 
pharmacokinetics 
PMDA 
Pharmaceuticals and Medical Devices Agency (Japan) 
PTCA 
percutaneous transluminal coronary angioplasty 
PVC 
premature ventricular contraction 
QCA 
quantitative coronary angiography 
RR 
risk ratio 
SAE 
serious adverse event 
SOP 
standard operating procedure 
STEMI 
ST-elevation myocardial infarction 
TIA 
transient ischemic attack 
TIMI 
thrombolysis in myocardial infarction 
TLF 
target-lesion failure 
TLR 
target-lesion revascularization 
TVF 
target-vessel failure 
TVR 
target-vessel revascularization 
UADE 
unanticipated adverse device effect 
 

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ADMINISTRATIVE STRUCTURE 
Principal Investigators 
Shigeru Saito, MD 
Director of Cardiology & Catheterization 
Laboratories and Vice President  
Shonan Kamakura General Hospital 
1370-1 Okamoto 
Kamakura City 247-8533 Japan 
Mitchell W. Krucoff, MD 
Professor, Medicine/Cardiology 
Duke University Medical Center 
Durham NC 27705 
USA 
 
 
Data Coordinating Center 
David F. Kong, MD 
Duke Clinical Research Institute 
Duke University 
2400 Pratt Street 
Durham NC 27705 
USA 
 
 
OrbusNeich Medical Study Managers 
Akira Sano 
Debbie Morrell 
Manager, Clinical Development 
Manager, Clinical Development 
OrbusNeich Medical K.K. 
OrbusNeich Medical, Inc. 
Oakhouse 201 
5363 NW 35th Avenue 
3-6-6 Uehara, Shibuya 
Fort Lauderdale FL 33309 
Tokyo, Japan 
USA 
 
 
Data and Safety Monitoring Committee (DSMC) 
Duke Clinical Research Institute 
Duke University 
2400 Pratt Street 
Durham NC 27705 
USA 
 
 
Clinical Events Classification Committee 
Duke Clinical Research Institute 
Duke University 
2400 Pratt Street 
Durham NC 27705 
USA 
 

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Site Management 
Japan 
CMIC 
7-10-4 Nishi-Gotanda  
Shinagawa-ku  
Tokyo, Japan 
United States 
Duke Clinical Research Institute 
Duke University 
2400 Pratt Street 
Durham NC 27705 
USA 
 
Human Antimurine Antibody Core Laboratory 
Celerion Switzerland AG 
Allmendstrasse 32 
8320 Fehraltorf, Switzerland 
 
Quantitative Coronary Angiographic Core Laboratory 
Optical Coherence Tomography Laboratory 
Cardiovascular Research Foundation 
111 East 59th Street, 12th Floor 
New York NY 10022 
USA 
 
Fractional Flow Reserve Core Laboratory 
 
University Hospitals of Cleveland 
11100 Euclid Avenue 
Cleveland OH 44194 
USA 
 
Clinical Helpline  
ALMAC Clinical Technologies 
25 Fretz Road 
Souderton PA 18964  
USA 
 
 
 

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INTRODUCTION 
 
Background 
One of the original limitations of percutaneous transluminal coronary angioplasty (PTCA) was 
restenosis, which occurred in 20% to 40% of patients.2,3 The loss of luminal diameter resulting in 
restenosis is primarily due to 2 mechanisms: elastic recoil of the vessel and neointimal hyperplasia. 
Coronary stenting reduced restenosis compared to balloon angioplasty alone by preventing acute 
elastic recoil.4,5 However, stents still provoke increased neointimal hyperplasia with a consequent 
incidence of late luminal loss.6,7 New bare-metal stent (BMS) designs with thinner struts are 
associated with restenosis rates around 12% to 15% in patients undergoing single-vessel 
revascularization and higher rates of restenosis in longer lesions, smaller vessels, multivessel 
percutaneous coronary intervention (PCI) procedures, and in patients with a diagnosis of diabetes. 
Adjunct therapies (eg, pharmacological therapy, coronary radiation, and coronary debulking) do 
not reduce restenosis more than stent placement alone. 
Localized drug elution, in particular of -limus drug analogues, from stents coated with polymer 
loaded with inhibitory drugs has further reduced restenosis rates compared to bare metal platforms. 
A substantial body of evidence has emerged demonstrating that local delivery of cell cycle 
inhibitors from the stent surface dramatically reduces neointimal hyperplasia and subsequent 
restenosis. The longest historical data available are with stents using the drug sirolimus. More than 
a decade ago, Sousa, et al.8,9 reported the safety and feasibility of a sirolimus-eluting stent; in this 
cohort of 30 consecutive patients who received active treatment, no patient exhibited restenosis at 
a 4-month angiographic follow-up. Evaluation of 2-year clinical outcomes revealed no deaths, 1 
Q-wave myocardial infarction (MI) (unrelated to the target lesion), 1 coronary artery bypass graft 
(CABG) for an ostial left circumflex coronary artery progression, and 1 target-vessel 
revascularization (TVR) for lesion progression. Follow-up extended up to 39 months demonstrated 
that no new events had occurred. Event-free (death, MI, CABG, repeat PTCA) survival at 
36 months for first-in-man patients was 90.1%. 
In the SIRolImUS-Eluting Stent in De Novo Native Coronary Lesions (SIRIUS) trial, 556 patients 
were randomized to receive the sirolimus-eluting Cypher® stent and 545 to receive a bare metal 
Bx Velocity stent. Mean follow-up minimal luminal diameter on angiography was significantly 
different at 2.50 mm in the sirolimus group and 1.68 mm in the control. This led to a 10.5% mean 
diameter stenosis at follow-up vs 40.1% for the control group and a late loss reduction from 1.00 
mm in the control to 0.17 mm in the sirolimus group. In-segment restenosis occurred in 8.9% of 
the sirolimus group and in 36.3% of the control group (p < 0.001). Stent thrombosis occurred in 
2 patients (0.4%) in the sirolimus arm and in 4 patients (0.8%) in the control arm. The primary 
endpoint, target-vessel failure (TVF), was reduced by 59%, from 21.0% in the control group to 
8.6% in the sirolimus group.10,11 
While drug-eluting stents (DESs) have decreased the rates of in-stent restenosis compared with 
BMSs,12,13 concerns about nonhealing of DES sites resulting in stent thrombosis, ST-elevation 
myocardial infarction (STEMI), and death were widely reported in 200614,15 and have led to 
extended use of dual antiplatelet therapy (DAPT) despite the risk of bleeding and costs associated 
with such extended therapy. Mechanisms associated with stent thrombosis, in addition to early 
interruption of DAPT, include strut malapposition or fracture, inhibition of endothelial cell 
recovery by mammalian target of rapamycin (mTor) inhibitors or paclitaxel, and persistent 

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inflammatory reactions to durable stent polymer. The end common pathway of all of these 
mechanisms is a thrombotic nidus consisting of incomplete reendothelialization within the stented 
segment, ie, the failed recovery of healthy neointima within the stented site.14,16–18  
Thus, while effectiveness of DES platforms has reduced restenosis to less than 10%, concerns with 
late and very late stent thrombosis with these permanent coronary implants has led to a focus on 
long-term safety of these permanent implants in more than 10 million patients worldwide, with 
more than 1 million additional patients worldwide per year undergoing stenting. To address these 
rare but catastrophic safety concerns, many manufacturers of new DES platforms have focused on 
design features intended to augment safety without negating current high levels of effectiveness. 
A number of engineering modifications emerged in second-generation DES platforms, including 
the selection of more inert, biocompatible durable polymers (Endeavor, Endeavor Resolute, 
Xience V) and bioabsorbable polymers applied only to the abluminal stent surface (Nobori, 
Biomatrix, Combo).19 Data comparing first- and second-generation DES platforms have been 
encouraging that these modifications have, indeed, improved safety at least in the setting of 
prolonged use of DAPT.20,21 Endeavor platforms randomized against both Cypher and TAXUS 
first-generation DES platforms showed inferior late loss but noninferior clinical outcomes and 
superior safety (stent thrombosis) over 3-year follow up.22–24 EES V platforms randomized against 
TAXUS first-generation DESs in multiple independent cohorts showed superior clinical outcomes 
and superior safety 3 to 5 years after PCI.25–27 
Even with such improved outcomes, stent thrombosis rates of 0.3% to 0.6% per year over a 
patient's lifetime and the use of prolonged DAPT following more than 1 million stent procedures 
performed per year remains significant unmet clinical challenges. Dual antiplatelet therapy for 
12 months or longer results in bleeding complications as well as elevated costs of care associated 
with PCI. Finally, the histopathological trauma associated with stent implantation continues to 
generate early stent thrombosis events at a rate of about 0.9% to 1.3% in the first 30 days, an event 
rate that is identical for both BMS and DES platforms. Thus DES platform engineering continues 
to direct itself toward better, safer medical device designs without compromising the very high 
level of effectiveness that generation 2 DESs have demonstrated. 
New design features include DES platforms that do not use polymer at all; DES platforms that are 
completely made of bioabsorbable polymer; new metal alloys that support thinner struts but are 
resistant to strut fracture; and technologies designed to enhance the speed, completeness, and 
quality of reendothelialization following PCI. Of all currently advancing, safety-oriented designs, 
the OrbusNeich Medical Combo stent (Identification Mark: OMKK02 in Japan), combining 
abluminal only, bioabsorbable polymer with CD34 endothelial progenitor cells (EPCs)-capture 
technologies represents a unique potential to advance both short- and long-term safety with PCI.  
Bone marrow-derived EPCs circulate in the peripheral blood and migrate to areas of vascular 
injury. It is hypothesized that the EPCs differentiate into mature endothelial cells, contributing to 
the vascular repair and formation of a functional endothelium.28,29 
The ability to capture circulating EPCs was demonstrated by the Genous™ Endothelial Progenitor 
Cell Capturing Stent (OrbusNeich Medical Technologies, FL), a bare-metal stainless-steel stent 
coated with antihuman CD34+ antibodies that bind circulating EPCs. In animal studies, a rapid 
enhancement of EPCs binding to the stent struts was observed, and a confluent monolayer of 
adherent CD34+ cells was approached after 60 minutes of incubation.30 In humans, the safety and 
efficacy of the bare-metal EPC-capturing stent was demonstrated in the nonrandomized Healthy 

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Endothelial Accelerated Lining Inhibits Neointimal Growth-First in Man (HEALING-FIM) 
study,31 and the HEALING II study evaluating patients with noncomplex coronary lesions.32 The 
HEALING-First-in-Man study included 16 patients. At the 9-month clinical follow-up, the 
composite of cardiac death, stroke, MI, and TVR was 6.3%, and no cases of stent thrombosis were 
reported. In the nonrandomized HEALING II study, 63 patients with noncomplex lesions were 
enrolled. At the 18-month clinical follow-up, no stent thrombosis was observed, and the composite 
of cardiac death, MI, and target-lesion revascularization (TLR) was 7.9%, mainly attributed to a 
relatively low (for a BMS platform) clinically driven TLR rate of 6.3%. In a subsequent single-
center registry of 405 unselected patients treated percutaneously with the Genous bare-metal/EPC-
capturing stent,33 the primary endpoint, defined as the composite of cardiac death, MI, and TLR at 
1 year, was 13.3%, mainly attributable to TLR, which was 10.9%—again, relatively encouraging 
for a BMS platform. The occurrence of definite and probable stent thrombosis was low, 0.5% and 
0.7%, respectively. The data available today suggest that the use of the EPC-capturing stent 
technology is safe and that the results from nonrandomized trials can be replicated in patients with 
a variety of clinical and angiographic characteristics. 
The OrbusNeich Combo platform advances this experience with CD34Ab on a bare-metal 
platform to the use of this technology in a safety-oriented (abluminal, bioabsorbable polymer) DES 
using sirolimus, the -limus analogue with the longest-standing experience in coronary stenting 
worldwide. In the REMEDEE study, Combo randomized 2:1 against TAXUS in 183 patients 
showed noninferior late loss, restenosis, and clinical outcomes (see Figure 1, Table 1, and Table 
2).  

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Figure 1. 
REMEDEE Study Design 
 
Table 1. 
REMEDEE 9-Month Binary Angiographic Restenosis  
and In-Segment Late Loss 
 
Combo 
(N=124) 
TAXUS 
(N=59) 
P-value 
Restenosis 
 
 
 
    In-stent 
5.5% 
9.6% 
0.34 
    In-segment 
8.3% 
13.5% 
0.30 
Minimum lumen diameter (mm) 
 
 
 
    In-stent, mean ± SD 
2.31 ± 0.58 
2.30 ± 0.56 
0.86 
    In-segment, mean ± SD 
2.09 ± 0.56 
1.97 ± 0.57 
0.19 
In-stent late lumen loss (mm) mean ± SD 
0.39 ± 0.45 
0.44 ± 0.56 
0.55 

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Combo 
(N=124) 
TAXUS 
(N=59) 
P-value 
In-segment late lumen loss (mm) 
0.27 ± 0.46 
0.41 ± 0.54 
0.08 
Proximal in-segment, mean ± SD 
0.19 ± 0.44 
0.29 ± 0.53 
0.24 
Distal in-segment, ± SD 
0.09 ± 0.30 
0.13 ± 0.30 
0.45 
N, number; SD, standard deviation 
 
Table 2. 
REMEDEE 9-Month Secondary Effectiveness and Safety Endpoints 
 
 
(to 9 months + 30 days: protocol clinical assessment 270 + 30 days) 
 
Combo 
(N=124) 
TAXUS 
(N=59) 
P-value 
Measures at 9 Months 
 
 
 
     Death 
1.0% 
0.0% 
0.49 
     Cardiac death 
0.0% 
0.0% 
N/A 
     Myocardial infarction (protocol definition) 
2.4% 
1.7% 
0.75 
     Q-wave 
0.0% 
0.0% 
N/A 
     Non–Q-wave 
2.4% 
1.7% 
0.75 
    Clinically driven target-lesion revascularization 
5.2% 
9.5% 
0.35 
Major adverse cardiac events (protocol definition) 
8.7% 
11.0% 
0.69 
Stent thrombosis 
0.0% 
0.0% 
N/A 
Clinically driven target-vessel revascularization 
7.0% 
9.5% 
0.65 
Clinically driven target-vessel failure (protocol definition) 
10.4% 
11.0% 
0.97 
Clinically driven target-lesion failure (protocol definition) 
8.7% 
11.0% 
0.69 
 
 
Preclinical Findings 
The Combo stent has been shown to be biocompatible and safe through numerous laboratory and 
preclinical implant studies. The degradable polymer-based drug-elution technology, the 
immobilized anti-CD34 antibody cell-capture technology, and the combination thereof have been 
found to be nontoxic, nonirritating, nonimmunogenic, and blood compatible. The Combo stent, 
along with the constituent components of polymer-matrix and immobilized antibodies applied to 
stents, has been found to be well tolerated in preclinical implant studies. Further, the Combo stent 
has been shown in preclinical implant studies to be efficacious in sustained drug delivery to the 
local implant site tissue through PK studies, in controlling neointimal proliferation, and in 
enhancing reendothelialization of implanted stents. 
In the preclinical studies, the Combo stent demonstrated significantly lower neointimal 
hyperplasia, while also showing improved endothelial coverage relative to other commercially 
available DESs. There was also a noticeably lower presence of inflammation and foreign-body 
reaction. Thus, the Combo stent appeared effective at inhibition of neointimal growth while 
enhancing endothelial coverage. These features might potentially result in low rates of in-stent 

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restenosis comparable to those of commercially available DESs and in reduced rates of late stent 
thrombosis. 
 
Clinical Experience with Study Device 
The study device has been previously evaluated in a Prospective, Randomized Study to Evaluate 
the Safety and Effectiveness of an AbluMinal Sirolimus CoatED Bio-Engineered StEnt (Combo 
Bio-Engineered Sirolimus Eluting Stent) Compared with a TAXUS® Liberté® Stent Control Arm 
for Treatment of Stenotic Lesions in Native Coronary Arteries (REMEDEE) trial. This study 
randomized 183 patients in a 2:1 fashion to Combo or TAXUS Liberté stents. 
In the 12-month follow-up data set, the clinically driven target-lesion failure (TLF) rate was 8.9% 
for patients treated with the Combo stent, compared with 10.2% for those treated with the TAXUS 
stent. Clinically driven TLF was defined as a composite of death, MI, and clinically driven TLR. 
In addition, the rate of clinically driven TLR was 4.9% for patients treated with the Combo stent, 
compared with 8.5% for those treated with the TAXUS stent. There was no stent thrombosis in 
either of the groups. 
 
Rationale 
This study is intended to demonstrate that the Combo stent platform shows superiority to an 
imputed BMS performance goal, noninferior effectiveness and safety vs best-in-class second-
generation everolimus-eluting stent (EES) (Xience V, Xience Prime, Xience Xpedition, Xience 
Alpine stents; [Abbott Vascular/Abbott Vascular Japan]), and evidence of mechanistic activity of 
the anti-CD34-Ab EPC capture technology with healthy level of intimal tissue coverage superior 
to that of the best-in-class EES.  
To ensure the robustness and interpretability of results, the current proposal includes a number of 
unique design features: 
 Largest randomized DES study ever performed in Japan 
 Enriched population, including stabilized non-STEMI (NSTEMI) subjects with greater 
likelihood of plaque rupture associated with their clinical syndromes 
 Collaboration between with Japan and the United States as a “Proof of Concept” program 
under the auspices of the Harmonization by Doing Initiative, WG 1, including concomitant 
enrollment in U.S.A. sites as an FDA-approved IDE study 
 Head-to-head randomization against state-of-the-art EES platform control, analyzed for 
clinical noninferiority 
 Statistical analysis vs imputed BMS analyzed for clinical superiority 
 Fractional flow reserve (FFR) follow-up of 100% of subjects enrolled, providing clinically 
relevant physiologic assessment of all subjects for 1-year ischemia-driven TVR analysis 
 Mechanistic OCT imaging observations in 140 subjects using 6 French catheters as 
follows: 
o Cohort A (30 subjects, 1:1 Combo and EES): Mechanistic imaging observations to 
provide serial 6-month and 1-year OCT evaluation of healthy intimal tissue 
coverage, intracoronary thrombosis, and stent malapposition and quantitative 
coronary angiographic (QCA) analysis to assess 1-year late loss. 

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o Cohort B (110 subjects, 1:1 Combo and EES): Mechanistic imaging observations 
to assess 1-year OCT evaluation of healthy intimal tissue coverage, intracoronary 
thrombosis, and stent malapposition, and QCA analysis to assess 1-year late loss. 
Combined with the 12-month imaging of Cohort A, this study will provide OCT 
and QCA observations at 1 year in 140 patients, half with Combo and half with 
EES.  
 In the 110 subjects in Cohort B, baseline, 30-day and 1-year human antimurine antibody 
(HAMA) titers will also be collected. 
 

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OBJECTIVES 
 
Primary Objective 
While EPC capture has intuitively attractive and exciting mechanistic novelty for both short- and 
long-term PCI safety, definitive demonstration of impact on stent thrombosis or the safety of 
shorter DAPT therapy with current stent thrombosis rates under 2% is not feasible for a premarket 
evaluation. Thus the objective for pivotal premarket approval is to demonstrate assurance of the 
safety and effectiveness of Combo—a combination sirolimus-eluting and anti-CD34 antibody-
coated stent—through: 
 Noninferior clinical effectiveness to state-of-the-art second-generation DES, specifically 
o Clinically, as comparable TVF at 1 year 
o Comparable freedom from ischemia assessed in primary target vessel by FFR ratio 
greater than 0.8 at 1 year 
 Superior clinical effectiveness to imputed BMS TVF at 1 year 
 
Secondary Objective 
 Superior OCT evidence of healthy level of intimal tissue coverage at 1 year compared to 
EES considered mechanistically related to the activity of anti-CD34 Ab EPC capture and 
analyzed in an independent, blinded core laboratory (Cohorts A and B combined) 
  
 
Prespecified Objectives 
 Evaluation of angiographic late lumen loss at 1 year (Cohorts A and B combined) 
 To assess the safety of Combo by OCT evaluation of intracoronary thrombosis and stent 
malapposition at 1 year (Cohorts A and B combined) 
 Serial observation of both Combo and EES at 6 and 12 months in the same patients (Cohort 
A) 
 To assess the change in HAMA plasma levels at 30-day and 1-year follow-ups compared 
with baseline 
 Comparable rates of death, MI, and stent thrombosis at 1 year 
 
 
 
 

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SUBJECT SELECTION 
 
Inclusion Criteria 
To be eligible for this trial, subjects must meet all of the following criteria: 
1. Subject is able to verbally confirm understanding of risks, benefits, and treatment 
alternatives of Combo vs EES stent, and the subject or a legally authorized representative 
(LAR) must provide written informed consent before any study-related procedures are 
performed. 
2. Subject must be at least 20 years of age at the time of randomization. 
3. Subject must have clinical or functional evidence of myocardial ischemia (eg, stable or 
unstable angina, stabilized non–ST-elevation MI confirmed by serum markers, ischemia 
by positive functional study, abnormal FFR, or a reversible change in the 
electrocardiogram [ECG] consistent with ischemia). 
4. Subject must be acceptable candidate with anatomy suitable for PCI with a DES. 
5. Subject agrees to return for all study-related follow-up assessments, including invasive 
OCT follow-up assessment at 6 months (Cohort A) and at 1 year postprocedure (Cohorts 
A, B, and C). 
6. Subject is an acceptable candidate for CABG surgery. 
Angiographic Anatomy Criteria— 
7. Target lesions must be located in a native coronary artery with visually estimated diameter 
of 2.5 mm to 3.5 mm, inclusive, and up to 3 de novo target lesions may be treated, with a 
maximum of 2 de novo target lesions per epicardial vessel, with a maximum of 2 target 
vessels. 
8. Target lesions should be treatable with a single stent, and must measure 28 mm or less in 
length by visual estimation (2 mm or more of nondiseased tissue on either side of the target 
lesion should be covered by the study stent). 
9. If more than 1 target lesion will be treated, the reference vessel diameter and lesion length 
of each target lesion must meet the above criteria.  
10. Target lesions must be in a major artery or branch with a visually estimated stenosis of 
50% or greater and less than 100% with a TIMI flow of 1 or greater. 
11. Previous percutaneous intervention of lesions in a target vessel (including side branches) 
is allowed if done 9 or more months before the study procedure and greater than 10 mm 
from the current target lesion. 

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12. Nonstudy percutaneous interventions for lesions in a nontarget vessel are allowed if done 
9 or more months before the study procedure, in the absence of documented ischemia or 
angiographic restenosis related to the vessel. 
 
Exclusion Criteria 
If a subject meets any of the following criteria, he or she may not be enrolled in the study: 
1. STEMI at index presentation or within 7 days of study screening. 
2. Subject has current unstable arrhythmias or intractable angina with ECG changes or shock 
requiring pressors or mechanical assist device (intraaortic balloon pump, left ventricular 
assist device, Impella, etc.). 
3. Subject has known left ventricular ejection fraction (LVEF) less than 30%. 
4. Subject has received a heart transplant or any other organ transplant or is on a waiting list 
for any organ transplant. 
5. Subject is receiving or scheduled to receive anticancer therapy for malignancy within 
30 days before or after the procedure. 
6. Subject is receiving immunosuppression therapy, has known serious immunosuppressive 
disease (eg, human immunodeficiency virus), or has severe autoimmune disease that 
requires chronic immunosuppressive therapy (eg, systemic lupus erythematosus). 
7. Subject has known hypersensitivity or contraindication to aspirin; both heparin and 
bivalirudin; all available P2Y12 inhibitors (clopidogrel, prasugrel, ticlopidine, and 
ticagrelor); any everolimus, sirolimus, cobalt, chromium, nickel, tungsten, acrylic, or 
fluoro polymers; or hypersensitivity to contrast media that cannot be adequately 
premedicated. 
8. Subject has previously received murine therapeutic antibodies and exhibited sensitization 
through the production of HAMAs. 
9. Subject has elective surgery planned within the first 12 months after the procedure that will 
require interruption or discontinuation of planned DAPT. 
10. Subject has known platelet count less than 100,000 cells/mm3 or greater than 
700,000 cells/mm3, a white blood cell count of less than 3000 cells/mm3, or documented 
or suspected liver disease (including laboratory evidence of hepatitis). 
11. Subject has known renal insufficiency (eg, serum creatinine level of greater than 2.5 mg/dL 
or subject is on dialysis). 
12. Subject has history of bleeding diathesis or coagulopathy or will refuse blood transfusions. 
13. Subject has had a cerebrovascular accident or transient ischemic neurological attack within 
the past 6 months. 
14. Subject has had a significant gastrointestinal or urinary bleed within the past 6 months. 
15. Subject has known extensive peripheral vascular disease that precludes safe 6 French 
sheath insertion. 

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16. Known other medical illness (eg, cancer, chronic infectious disease, severe vascular 
disease, or congestive heart failure) or known history of substance abuse (alcohol, cocaine, 
heroin, etc.) that may cause noncompliance with the protocol, confound the data 
interpretation, or is associated with a life expectancy of less than 1 year. 
17. Currently participating in another clinical study that has not yet reached its primary 
endpoint. 
18. Currently pregnant or breast-feeding or is planning pregnancy in the period up to 1 year 
following index procedure. Female subjects of childbearing potential must have a negative 
pregnancy test within 7 days before the index procedure. 
Angiographic Exclusion Criteria— 
If the target lesion meets any of the following criteria, the subject may not be enrolled in the study: 
19. Unprotected left main coronary artery location. 
20. Unprotected ostial (located within 2 mm of the origin) left anterior descending artery or 
left circumflex. 
21. Located within an arterial or saphenous vein graft or graft anastomosis, distal to a diseased 
arterial or saphenous vein graft (visually estimated graft diameter stenosis greater than 
40%). 
22. Involves a bifurcation in which the side branch is 2 mm or greater in diameter AND would 
be covered by the planned stent. 
23. Involves a side branch requiring predilation.  
24. Total occlusion (TIMI flow 0) before wire crossing. 
25. Extreme tortuosity proximal to or within the lesion. 
26. Extreme angulation (90º or greater) proximal to or within the lesion. 
27. Heavy calcification, defined as multiple persisting opacifications of the coronary wall 
visible in more than one projection surrounding the complete lumen of the coronary artery 
at the site of the lesion. 
28. Restenotic vessel from previous intervention. 
29. Received brachytherapy in any epicardial vessel (including side branches). 
30. Target vessel contains angiographically visible thrombus. 
31. Serial lesions or diffuse disease with high probability of bailout requiring 3 or more stents 
in a single vessel, more than 5 stents per subject, or more than 2 vessels. 
32. Target or nontarget vessel lesion (including all side branches) is present with a high 
probability of requiring PCI within 12 months after the index procedure. 
33. Stent overlapping is a planned treatment of the target lesion. 
 

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STUDY DESIGN 
This study will be conducted in accordance with current Ministerial Ordinance on Good Clinical 
Practice for Medical Devices. Ordinance of the Ministry of Health and Welfare No. 36 (J-GCP) 
(Japan) guidelines, U.S. Food and Drug Administration (FDA) regulations and guidelines, 
International Conference on Harmonisation (ICH) guidelines on GCP (ICH E6, the principles of 
which have their origin in the Declaration of Helsinki), and all other applicable national and local 
laws and regulations. 
 
Overview of Study 
This is a multi-center, single-blind, randomized, active-controlled, clinical trial in PCI subjects. 
Subjects will be randomized to receive the Combo stent as the investigational treatment arm or an 
EES as the active-control arm, in a noninferiority study.  
Up to 50 sites are proposed in Japan and the United States to enroll 286 subjects (271 evaluable) 
in each of 2 arms, for a total sample size of 572 subjects (542 evaluable) who are admitted to the 
hospital for a planned (elective and urgent) percutaneous coronary artery intervention procedure. 
Investigators must declare an intended oral antiplatelet regimen and intended duration of anti-
platelet therapy before randomization; postprocedure, subjects will receive aspirin indefinitely and 
P2Y12 inhibition for a minimum of 6 months (12 months for acute coronary syndrome [ACS] 
diagnosis), according to recommended regional standards of care. After stent implantation, 
subjects will be contacted for follow-up at 30 days; 6 months; and 1, 2, 3, 4, and 5 years. At 
12 months a clinical evaluation will be completed before cardiac catheterization and angiographic 
assessment.  
There will be 3 consecutively enrolled cohorts of study subjects: 
1. Cohort A: 30 subjects (15 subjects per arm) will undergo all clinical follow-up assessments; 
receive OCT and angiographic assessments at 6 months; and receive OCT, FFR, and QCA 
assessments at 12 months after device implantation. Cohort A will be the first cohort to 
enroll.  
2. Cohort B: 110 subjects (55 subjects per arm) will undergo all clinical follow-up 
assessments, with OCT, FFR, and QCA assessments at 12 months after device 
implantation. Cohort B will be the second cohort to enroll.   
3. Cohort C: 432 subjects (216 subjects per arm) will undergo all clinical follow-up 
assessments with FFR and angiographic assessments at 12 months. Cohort C will be the 
last cohort to enroll.  
In addition, serum will be assessed for HAMAs development at index, 30 days, and 12 months in 
the in Cohort B subjects. When possible, HAMA plasma assessment will be from blood draws 
performed during catheterizations to minimize the need for additional needle punctures.  
The primary clinical endpoint is TVF, defined as cardiac death, target-vessel MI, or ischemia-
driven TVR by percutaneous or surgical methods, at 1 year. Primary endpoints will be reported 
after all subjects have completed 12 months of follow-up. A total of 572 subjects (30+110+432) 
are enrolled to ensure that 542 subjects are evaluable for the primary clinical endpoint, across all 
cohorts. 

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The secondary efficacy endpoint is mechanistic OCT healthy level of intimal tissue coverage, 
determined by the OCT core laboratory at 1 year for subjects in Cohorts A and B combined (total 
N=140 subjects). 
Additional prespecified endpoints include clinically and functionally ischemia-driven TLR, 
including use of target-vessel FFR, analyzed dichotomously using the Fractional Flow Reserve 
(FFR) vs. Angiography in Multivessel Evaluation (FAME) study criteria of 0.8 during a 2-minute 
infusion of adenosine or adenosine triphosphate.34 Abnormal FFR-driven interventions at 1 year 
will be included in the evaluation of ischemia-driven TLR. 
Other prespecified endpoints are death, MI, composite cardiac death and MI, TLF composite and 
individual components, and stent thrombosis, to be assessed at each follow-up.  
See Figure 2 for a schematic of the study design. 
 
Figure 2. 
Schematic of Study Design 
 
Study Procedures 
Potentially eligible subjects will be identified by clinicians at the participating study sites, by 
review of catheterization laboratory schedules, or other means as locally relevant. Study personnel 
will assess each subject against each inclusion and each exclusion criterion, and the investigator 
will determine the subject’s eligibility for study participation. Interested subjects will be asked to 
give written informed consent and undergo a screening evaluation to include a medical history, 

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physical assessment, laboratory tests, and review of concomitant and protocol-required 
medications. The informed consent form (ICF) for the enrolled subjects will include details of 
Cohorts A, B, and C. The ICFs will also include information regarding HAMA blood collections 
at baseline, 30 days, and the 12-month follow-up.  
Subjects may qualify for enrollment based on prior diagnostic angiographic data obtained within 
the last 3 months. Females of childbearing potential must have a negative pregnancy test result 
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 7 days 
before each angiographic procedure. Subjects who have given written informed consent and meet 
all inclusion and no exclusion criteria will be randomized into 1 of 2 treatment arms in this study. 
The informed consent process and all assessments will be documented in the subject’s medical 
record or comparable source document. Results from all study assessments on randomized subjects 
(as described below) will be entered in the eCRF. 
The schedule of procedures is presented in Table 3. 
Table 3. 
Schedule of Procedures 
 
Screening and 
Prerandomization 
Enrollment and 
Randomization/ 
Implantation 
Postprocedure 
30 (± 7) Days 
180 (± 30) Days 
1 Year (± 30 Days) 
Annual (± 60 Days) 
Follow-ups for  
5 Years
Unscheduled 
Visits/ET 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Physical assessment, including vital 
signs (weight, heart rate, blood pressure) 
Xa 
 
 
X 
 
Xb 
 
 
Angina classc 
Xa 
 
X 
X 
X 
Xb 
X 
X 
12-lead ECG 
Xa 
 
X 
 
Xb.i 
Xb 
 
X 
Concomitant medications 
Xa 
 
 
X 
X 
Xb 
X 
X 
Pregnancy test (serum or urine) 
Xd 
 
 
 
Xb,e,i 
Xb,e 
 
 
Troponin I or T, CK-MB 
X, Xu 
 
X 
 
 
 
 
X 
Chemistry panel and complete blood 
countg 
X 
 
 
 
 
 
 
 
Lipid profile (total cholesterol, HDL, 
LDL, triglycerides) 
X 
 
 
 
 
 
 
 
Protocol-required medications 
Xa 
X 
X 
X 
X 
Xb 
X 
X 
Diagnostic angiogram (digital) 
Xh, r 
 
 
 
 
 
 
 
Pre-implant, target vessel angiogram 
(digital) 
Xh,s 
 
 
 
 
 
 
 

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Screening and 
Prerandomization 
Enrollment and 
Randomization/ 
Implantation 
Postprocedure 
30 (± 7) Days 
180 (± 30) Days 
1 Year (± 30 Days) 
Annual (± 60 Days) 
Follow-ups for  
5 Years
Unscheduled 
Visits/ET 
Post-Implant angiogram (digital)t 
 
 
Xh 
 
 
 
 
 
Follow-up angiogram (digital)t 
 
 
 
 
Xi 
Xh 
 
 
HAMA plasma samplesj 
 
Xk 
 
X 
 
X  
 
 
FFR assessmenth,l  
 
 
 
 
 
X 
 
 
Implant device 
 
X 
 
 
 
 
 
 
 LVEF assessmentm 
 
X 
 
 
 
 
 
 
OCTt  
 
 
 
 
Xi 
Xf,l 
 
 
Core Laboratory QCAf, t   
 
X 
 
 
 
X 
 
 
Collection of all AEs  
 
X 
X 
X 
 
 
 
 
Collection of all SAEsq 
 
X 
X 
X 
X 
X 
 
 
Collection of AEs/SAEs related to study 
device onlyq 
 
Xn 
Xn 
Xn 
Xb,n 
Xb,n 
Xn 
Xn 
Event data collection for instances of 
specified cardiovascular endpoint 
eventsq 
 
 
X 
X 
X 
X 
X 
X 
 
AE, adverse event; CK-MB, creatine kinase-myocardial band; ECG, electrocardiogram; ET, early termination;  
FFR, fractional flow reserve; HAMA, human antimurine antibodies; HDL, high-density lipoprotein;  
LDL, low-density lipoprotein; LVEF, left ventricular ejection fraction; OCT, optical coherence tomography;  
QCA, quantitative coronary angiogram; SAE, serious adverse event  
  
aWithin 24 hours before procedure. 
bComplete before coronary angiogram and catheterization. 
cCurrent Canadian Cardiovascular Society, Braunwald classifications 
dWithin 7 days or immediately before randomization. 
eIf not done within the previous 7 days. 
fOnly Cohorts A and B.  
gChemistry panel (alkaline phosphatase, aspartate amino transferase, alanine amino transferase, total bilirubin, calcium, sodium, 
potassium, glucose, creatinine, blood urea nitrogen); complete blood count (hemoglobin, hematocrit, platelets, white blood cell 
count, red blood cell count); C-reactive protein; N-terminal pro brain natriureticpeptide. 
hAll cohorts. 
iOnly Cohort A. 
jOnly Cohort B. 
kBefore stent implantation and heparin therapy. For subjects already receiving heparin, HAMA collection should occur 4-6 hrs 
post heparin therapy. 
lPrimary target vessel only. 
mWithin 14 days or immediately before randomization via echocardiogarphy, single photon emission-computed tomography, 
computed tomography, magnetic resonance imaging, or left ventriculography. 
nAll AEs and SAEs related to the device, anticipated and unanticipated adverse device effects, (Specified cardiovascular endpoint 
events data collection will be reported on the eCRF endpoint pages only) 
oIncludes death, myocardial infarction, stroke and transient ischemic attack, target lesion revascularization (ischemia driven), 
target vessel revascularization (ischemia driven), and stent thrombosis (Academic Research Consortium definition). 
qSpecified cardiovascular endpoint events collection as noted in o will be reported on the eCRF endpoint pages only 

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rSubjects may qualify for enrollment based on prior angiographic data obtained within the last 3 months.  If a prior diagnostic 
angiogram is not available (within 3 months) a screening diagnostic angiogram is required prior to enrollment/randomization and 
can be completed at the same time as the Pre-implant, target vessel(s) angiogram. Randomized subjects’ angiograms are to be 
provided to central image data center  
SPre-Implant, target vessel(s) (baseline) angiogram (all qualifying subjects, digital) will be used for the final assessment of 
subject eligibility. Randomized subjects angiograms to be provided to the central image data center  
tProvided to central image data center 
u For subjects with non-ST-elevation MI and abnormal serum markers, sufficient measurements should be obtained to show a 
decreasing trend in at least one serum marker consistent with stabilized NSTEMI. 
 
 
Screening and Prerandomization Procedures 
Patients to be admitted for a planned (elective or urgent) percutaneous coronary artery intervention 
procedure should be screened for study eligibility by a member of the study team (physician and/or 
research coordinator) previously trained to the study protocol. Subject selection factors to be 
assessed should include judgment regarding risk of antiplatelet therapy. Subjects who meet general 
eligibility criteria will be asked to sign an ICF.  
After eligible subjects have signed the ICF, the following assessments should be completed as part 
of standard of care, from time of implant procedure:  
 Medical history, including previous MI, previous PCI, previous CABG, peripheral vascular 
disease, stroke, hypertension, congestive heart failure, diabetes mellitus, cigarette smoking, 
chronic renal failure, hypercholesterolemia, angina status, and family history of coronary 
artery disease. If already completed within the past 30 days, those findings may be used. 
 Physical assessment, including vital signs (height, weight, heart rate, blood pressure). 
 Angina class 
 Stable Angina: Current Canadian Cardiovascular Society [CCS], where class 
0=asymptomatic, class I=angina during strenuous physical activity without 
limitation, class II=slight limitation from angina only during vigorous physical 
activity, class III=moderate limitation from symptoms from everyday living 
activities, and class IV=severe limitation with inability to perform any activity 
without angina or angina at rest. 
 Unstable angina: Braunwald Classification where severity is new onset of severe 
angina or accelerated angina; no rest pain, angina at rest within past month but not 
within preceding 48 hours (angina at rest, subacute), angina at rest within 48 hours 
(angina at rest, acute).  Clinical circumstance where develops in presence of 
extracardiac condition that intensifies myocardial ischemia (secondary unstable 
angina); develops in absence of extracardiac condition (primary unstable angina); 
or develops within 2 weeks after acute MI (postinfarction unstable angina).    
 12-lead ECG; if already completed within the past 24 hours, this measurement may be 
used. 
 Concomitant medications. 
 Pregnancy test (serum or urine), performed within 7 days before the angiographic 
procedure.  
 Troponin I or T, creatine kinase-myocardial band (CK-MB); if already completed within 
the past 48 hrs, those measurements may be used.  For subjects with non-ST-elevation MI 
and abnormal serum markers, sufficient measurements should be obtained to show a 
decreasing trend in at least one serum marker consistent with stabilized NSTEMI. 

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 Chemistry panel (alkaline phosphatase, aspartate amino transferase, alanine amino 
transferase, total bilirubin, calcium, sodium, potassium, glucose, creatinine, blood urea 
nitrogen); complete blood count (hemoglobin, hematocrit, platelets, white blood cell count, 
red blood cell count); C-reactive protein; and N-terminal pro brain natriuretic peptide. If 
already completed within the past 30 days, those measurements may be used. 
 Lipid profile (total cholesterol, high-density lipoprotein, low-density lipoprotein, 
triglycerides). If already completed within the past 30 days, those measurements may be 
used. 
 Protocol-required medications. 
 Diagnostic angiogram  (digital, all cohorts). Subjects may qualify for enrollment based on prior 
angiographic data obtained within the last 3 months.  If a prior diagnostic angiogram is not available 
(within 3 months) a screening diagnostic angiogram is required prior to enrollment/randomization 
and can be completed at the same time as the Pre-Implant, target vessel(s) baseline angiogram. 
Randomized subjects’ angiograms are to be provided to the central image data center.  
 Pre-Implant, target vessel(s) (baseline) angiogram (all qualifying subjects, digital) will be 
used for the final assessment of subject eligibility. If a subject does not have a prior 
diagnostic angiogram, the preprocedure and diagnostic angiogram can be completed in one 
angiogram assessment for final eligibility assessment immediately prior to enrollment. 
Randomized subjects angiogram are to be provided to the central image data center.  
Subjects who do not meet angiographic inclusion criteria, including measurements that are 
taken after predilation, will not be randomized in this study but will be documented on a 
screening log. 
 
A screening log will be provided to each study site to maintain a record of all of the subjects 
screened. This screening log must be completed and email (pdf) or faxed to the Data Coordinating 
Center on a weekly basis. 
 
Enrollment and Randomization/Implantation 
 Enrollment 
Subjects who have given written informed consent and meet all inclusion and no exclusion criteria 
will be eligible to be enrolled in this study. 
 Randomization/Implantation 
After informed consent is obtained and it is confirmed that all clinical and angiographic inclusion 
criteria have been met and that no exclusion criteria are met, an interactive web response system 
(IXRS) will be used to randomize those subjects into 1 of 2 treatment arms. Subjects will be 
considered enrolled into the study when they are randomized into a treatment arm.  
An IXRS system will centrally randomize eligible subjects, assign each subject a unique 
identification (ID) number, and identify the randomization arm for the subject. The study 
coordinator will access the IXRS system to obtain the randomization arm after the angiogram has 
confirmed that the subject meets all angiographic eligibility criteria. Subjects will be randomly 
assigned in a 1:1 ratio to receive either the Combo stent or the EES control. Randomization will 
be stratified based upon NSTEMI vs elective presentation and single-vessel vs multi-vessel 
disease. After randomization, the device will be implanted in the subject. If subjects are 

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randomized into a treatment arm and the study device is not delivered beyond the guiding catheter, 
the subjects will be followed through the 30-day visit and included in the intent-to-treat analysis. 
At the time of randomization, the following assessments and procedures will be performed: 
 Investigator declaration of antiplatelet therapy and duration. 
 Protocol-required medications. 
 HAMA plasma samples (Cohort B only) will be sent to the Central Laboratory.  Samples 
to be collected prior to stent implantation and heparin therapy.  For subjects already 
receiving heparin therapy HAMA collection should occur 4-6 hrs post heparin therapy. 
 Device implantation per IFU/IB and clinical practice. 
 LVEF (within 14 days of or immediately before randomization, via echocardiography, 
single photon emission-computed tomography, computed tomography, magnetic 
resonance imaging, or left ventriculography).  Subjects presenting without documentation 
of prior LVEF assessment as described previously will be required to undergo ejection 
fraction assessment at the time of the pre-implant baseline angiogram to determine 
enrollment eligibility 
 Pre-Implant target-vessel baseline angiogram (digital, all randomized subjects angiograms 
are to be provided to the central image data center).  Cohort A and B subjects’ angiogram 
will be provided to QCA Core Laboratory by central image data center manager. 
 Collection of all AEs and SAEs  
 
Postimplantation Procedures 
 Postprocedure  
Following the implantation procedure, the following assessments and procedures will be 
performed within 24 hours post-PCI or before discharge: 
 Immediate, post-implant target vessel(s) angiogram (all cohorts, digital, angiograms to be 
provided to the central image data center) 
 Angina class (current CCS, Braunwald classifications) 
 12-lead ECG (PI signed and dated) 
 Troponin I or T, CK-MB 
 Protocol-required medications 
 Collection of all AEs and SAEs. (Specified cardiovascular endpoint events collection as 
noted will be reported on the eCRF endpoint pages only)   
 Cardiovascular Endpoint Event data collection for instances of 
o Death 
o MI 
o TLR (ischemia driven) 
o TVR (ischemia driven)  
o Stroke and transient ischemic attack (TIA) 
o Stent thrombosis (Academic Research Consortium [ARC] definition) 
 
 30 (± 7) Days 
At 30 (± 7) days postprocedure, the following assessments and procedures will be performed: 

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 Physical assessment, including vital signs (weight, heart rate, blood pressure) 
 Angina class (current CCS, Braunwald classifications) 
 Concomitant medications 
 Protocol-required medications 
 HAMA plasma samples (only subjects enrolled in Cohort B) will be sent to the Central 
Laboratory  
 Collection of all AEs and SAEs ., (Specified cardiovascular endpoint events collection as 
noted will be reported on the eCRF endpoint pages only) 
 Cardiovascular Endpoint Event data collection for instances of 
o Death 
o MI 
o TLR (ischemia driven) 
o TVR (ischemia driven) 
o Stent thrombosis (ARC definition)  
o Stroke and TIA 
 180 (± 30) Days 
At 180 (± 30) days postprocedure, the following information may be collected by telephone, unless 
noted for cardiac catheterization procedure (Cohort A only): 
 Angina class (current CCS, Braunwald classifications) 
 Concomitant medications 
 Pregnancy test (serum or urine), performed within 7 days before the angiographic 
procedure (Cohort A only, complete before coronary angiogram and catheterization) 
 12-lead ECG (Cohort A only, complete before coronary angiogram and catheterization, PI 
signed and dated) 
 Protocol-required medications 
 Follow-up angiogram, target vessel (s) (only Cohort A, digital, angiogram to be provided 
to the central image data center for transfer to QCA Core Lab) 
 OCT of the PRIMARY vessel (only Cohort A) will be provided to the central image data 
center for transfer to OCT Core Laboratory 
 Collection of AEs/SAEs (Cohort A: complete prior to cardiac catheterization and coronary 
angiogram.  Specified cardiovascular endpoint events data collection as noted will be 
reported on the eCRF endpoint pages only).    
 Cardiovascular Endpoint Event data collection for instances of 
o Death 
o MI 
o TLR (ischemia driven) 
o TVR (ischemia driven) 
o Stent thrombosis (ARC definition)  
o Stroke and TIA 
 1 Year (± 30 Days) 
At 1 year (± 30 days) postprocedure, the following assessments and procedures will be performed: 

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 Physical assessment, including vital signs (weight, heart rate, blood pressure) (complete 
before coronary angiogram and catheterization) 
 Angina class (current CCS, Braunwald classifications) (complete before coronary 
angiogram and catheterization) 
 12-lead ECG (PI signed and dated, complete before coronary angiogram and 
catheterization) 
 Concomitant medications (complete before coronary angiogram and catheterization) 
 Pregnancy test, if not done within the previous 7 days (serum or urine; complete before 
coronary angiogram and catheterization) 
 Protocol-required medications (complete before coronary angiogram and catheterization) 
 Follow-up, target vessel(s) angiogram (all cohorts, digital, angiogram to be provided to the 
central image data center) 
 HAMA plasma samples (before stent implantation; only subjects enrolled in Cohort B) 
sent to the Central Laboratory 
 FFR assessment of PRIMARY target vessel only (all cohorts) will be provided to Core 
Laboratory 
 OCT assessment of PRIMARY target vessel only (only Cohorts A and B) will be 
provided to the central image data center for transfer to the OCT Core Laboratory 
 QCA of all target vessels (Cohort A and B only) will be provided to central image data 
center for transfer to Core Laboratory 
 Collection of AEs/SAEs (complete prior to cardiac catheterization and coronary 
angiogram. Specified cardiovascular endpoint events data collection as noted will be 
reported on the eCRF endpoint pages only) 
  
 Cardiovascular Endpoint Event data collection for instances of 
o Death 
o MI 
o TLR (ischemia driven) 
o TVR (ischemia driven) 
o Stent thrombosis (ARC definition)  
o Stroke and TIA 
 
 Annual (± 60 Days) for 5 Years Postprocedure 
At 2, 3, 4, and 5 years (± 60 days) postprocedure, the following information may be collected by 
telephone: 
 Angina class (current CCS, Braunwald classifications) 
 Concomitant medications 
 Protocol-required medications 
 Collection of AEs/SAEs related to device only.  (Specified cardiovascular endpoint events 
data collection as noted will be reported on the eCRF endpoint pages only)   
 Cardiovascular Endpoint Event data collection for instances of 
o Death 
o MI 
o TLR (ischemia driven) 

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o TVR (ischemia driven) 
o Stent thrombosis (ARC definition) 
o Stroke and TIA 
 Interventional angiogram submission.  It is recommended to submit any angiograms for 
clinical care treatment which were performed since the last patient visit and not 
previously submitted to the data central imaging center 
 Unscheduled Visits/Early Termination 
Unscheduled visits are defined as subject visits outside of routine standard of care practice, outside 
of protocol defined visits, and contacts the study PI and is asked to return to the study PI clinic 
specifically for a study related concern.  Additionally, all in-hospital cardiac events that occur 
outside of scheduled protocol visits should be captured as an unscheduled visit.   At unscheduled 
visits or at early termination postprocedure, the following assessments and procedures will be 
performed: 
 Angina class (current CCS, Braunwald classifications) 
 12-lead ECG (PI signed and dated) 
 Concomitant medications 
 Troponin I or T, CK-MB 
 Protocol-required medications 
 Collection of AEs/SAEs related to device only. (Specified cardiovascular endpoint events 
data collection as noted will be reported on the eCRF endpoint pages only) 
 Cardiovascular Endpoint Event collection for instances of 
o Death 
o Myocardial Infarction 
o TLR (ischemia driven) 
o TVR (ischemia driven)  
o Stroke and TIA 
o Stent thrombosis (ARC definition) 
 Interventional angiogram collection (for clinical standard of care treatment only) to be 
provided to the central image data center 
 
All angiograms performed, including unscheduled angiograms for clinical care, will be sent to the 
Angiographic Core Laboratory for review. 

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STUDY DEVICE 
 
Description of Study Device 
The Combo stent™ (Figure 3) is a coronary balloon expandable vascular prosthesis, consisting of 
a 316L–stainless-steel alloy platform coated with a biocompatible, biodegradable polymer 
containing sirolimus (also known as rapamycin). Covalently attached to this matrix is a layer of 
murine, monoclonal, antihuman CD34 antibody. The immobilized antibody surface specifically 
targets CD34+ cells from the circulating blood, of which EPCs are CD34+. The base platform for 
the Combo stent is the OrbusNeich Medical R stent, which has a proprietary dual-helix stent design 
with a strut thickness of 0.0040”. The 316L stainless-steel base platform (R stent) is coated 
sequentially with the drug/polymer matrix on the abluminal surface, then treated to immobilize 
antibody on the coated stent surface, and then finally treated with a stabilization treatment to 
preserve the antibody activity in the dried immobilized state on the stent. The treated stent is 
machine-crimped onto a low-profile, rapid-exchange PTCA dilation catheter, and then the crimped 
stent is subjected to visual inspection, verification of the outer diameter profile, and leak tested. 
Once found to be within specification, the mounted stent delivery system is placed into a high-
density polyethylene hoop dispenser which in turn is placed into a Tyvek™/Mylar™ pouch. The 
pouch is heat-sealed and then labeled on the outside to maintain stent identity. Units are 
individually serialized to maintain unit identity, and the complete traceability of the manufacturing 
process flow is documented. The product is sterilized via an ethylene oxide sterilization process. 
Poststerile lot release testing includes total drug content, elution profile, antibody activity, 
endotoxin, and functional performance tests. The OrbusNeich Medical full quality assurance 
system is compliant to ISO 13485:2003, Medical Device—Quality Management Systems—
Requirements for Regulatory Purposes and Directive 93/42/EEC for Medical Devices, Annex II 
(3) as verified by Intertek/American Manufacturing Trade Action Coalition Certification Services 
Limited (0473). The Combo stent conforms to the relevant provisions of the International Council 
of Electronic Commerce Consultants Council Directive 93/42/European Economic Community 
for Medical Devices dated 14 June 1993 and is in accordance with Annex II Conformity 
Assessment Procedure. 
 

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Figure 3. 
 Combo Stent 
 Sirolimus 
Sirolimus (rapamycin), the active ingredient in Rapamune® (Wyeth), has been tested extensively. 
The following is a brief summary of the available data; complete drug safety information is 
available through FDA.gov: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21083s017,21110s020lbl.pdf.  
Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus. The chemical name 
of sirolimus is: 
(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)9,10,12,13,14,21,22,23,24,25,
26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2[(1S,3R,4R)-4-hydroxy-3-
methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy6,8,12,14,20,26-hexamethyl-23,27-epoxy-
3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine1,5,11,28,29(4H,6H,31H)-pentone. 
Its molecular formula is C51H79NO13, and its molecular weight is 914.2. The structural formula 
of sirolimus is shown in Figure 4 below. 
 
Figure 4. 
Structural Formula of Sirolimus 
Sirolimus inhibits T-cell activation and smooth muscle and endothelial cell proliferation in 
response to cytokine and growth-factor stimulation. Sirolimus binds to the immunophilin known 
as intracellular FK-binding protein (FKBP)12. The rapamycin-FKBP-12 complex binds to and 
inhibits activation of the mTOR, resulting in cell cycle arrest in the late Gap 1 phase and preventing 
progression to the synthesis phase. 
The safety and efficacy of oral sirolimus (Rapamune, Wyeth), used as a prophylaxis of organ 
rejection in patients receiving renal transplants, were evaluated and established through 
2 randomized, double-blind trials. Extensive studies have been conducted to investigate the 
mechanism of immunosuppressive activity, prevention of acute renal allograft rejection, clinical 
pharmacokinetics (PK), concentration-effect relationships, and therapeutic drug monitoring. 
Sirolimus has also been safely used in clinical studies as an antirestenotic drug component in the 
Cypher sirolimus-eluting coronary stent. Carcinogenicity studies were conducted in mice and rats. 
In an 86-week female mouse study at sirolimus doses 30 to 120 times higher than the 2-mg daily 
clinical dose (adjusted for body surface area), there was a statistically significant increase in 

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malignant lymphoma at all dose levels compared with controls. In a second mouse study at dosages 
that were approximately 3 to 16 times the clinical dose (adjusted for body surface area), 
hepatocellular adenoma and carcinoma in males were considered sirolimus related. In the 
104-week rat study, at dosages equal to or lower than the clinical dose of 2 mg daily (adjusted for 
body surface area), there were no significant findings. Sirolimus was not genotoxic in the in vitro 
bacterial reverse mutation assay, the Chinese hamster ovary cell chromosomal aberration assay, 
the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay. 
Fertility was diminished slightly in both male and female rats following oral administration of 
sirolimus at doses approximately 10 times or 2 times, respectively, the clinical dose of 2 mg daily 
(adjusted for body surface area). In male rats, atrophy of testes, epididymides, prostate, 
seminiferous tubules, and/or reduction in sperm counts were observed. Reduction of sperm count 
in male rats was reversible upon cessation of dosing in one study. Testicular tubular degeneration 
was also seen in a 4 week intravenous study of sirolimus in monkeys at doses that were 
approximately equal to the clinical dose (adjusted for body surface area). 
 Bio-Engineered Drug-Eluting Coating 
The Combo stent has a single-layer sirolimus-eluting coating that is applied to the abluminal stent 
surface. An anti-CD34 antibody surface modification is then applied to the entire stent surface 
(Figure 5). 
 
Figure 5. 
Combo Stent Surface Modification 
To prevent restenosis, the drug/polymer coating consists of sirolimus loaded in the biodegradable 
SynBiosys™ polymer. The total drug content is approximately half the dose of the commercially 
available Cypher stent, but with the same release profile. The degradation of the polymer occurs 
in approximately 90 days. To promote healing, the anti-CD34 surface modification is applied to 
the entire stent such that the luminal surface of the deployed stent presents an immuno-affinity 
surface to promote the capture of circulating EPCs for the contacting blood. 
Figure 6 (below) shows the in vivo elution profile of the final sterile Combo stent product 
compared with the commercially available Cypher stent. 

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Figure 6. 
In Vivo Elution of Combo Stent and Cypher (percentage of total drug eluted 
over time) 
 SynBiosys™ Multi-Block Copolymer 
The polymer coating of the Combo stent consists of a blend of the antiproliferative drug sirolimus 
with 2 bioabsorbable polymers, GLL01 and GPCGL01 (SynBiosysTM Polymer, Technology 
Transfer Specification, SurModics, December 2008). These copolymers, also referred to as 
SynBiosys copolymers, belong to a new class of proprietary bioabsorbable urethane-linked multi-
block copolymers provided to OrbusNeich Medical by SurModics, Inc. Both copolymers are 
composed of prepolymers based on glycolide (GA), lactide (LA), and ε-caprolactone (CL), 
combined in various ratios and initiated with butanediol (BDO) or polyethylene glycol (PEG). The 
prepolymers are linked together by 1,4-butane diisocyanate (BDI) to create the multi-block 
architecture characteristic of these materials. 
 Polymer In Vitro Degradation 
The SynBiosys GLL01 and GPCGL01 are synthetic bioabsorbable urethane-linked multi-block 
copolymers, which degrade mainly by the hydrolysis of the ester and urethane bonds present in 
the polymer backbones. The hydrolytic degradation proceeds via a bulk erosion mechanism. First, 
the water diffuses into the material, which may induce a slight swelling of the polymer coating. 
Second, the ester and urethane bonds are randomly cleaved without producing soluble 
components. Third, the progressive chain scission leads to the formation of oligomers and 
monomers that are released from the coating layer, resulting in the actual mass loss of the material. 
The degradation products of SynBiosys copolymers are mainly lactic acid, which is a naturally 
occurring compound in the human body, and glycolic acid. Both compounds degrade into pyruvic 
acid, which in turn is metabolized into carbon dioxide and water via the Krebs cycle. Caprolactone 
degrades into ω-hydroxyhexanoic acid, which is then eliminated via the urinary pathway. 
Polyethylene glycol and BDO are both excreted as such through the urinary pathway. Finally, the 
urethane moieties engendered by BDI during the polymerization process hydrolyze to form 1,4-
butanediamine, also known as putrescine, which is also a naturally occurring compound in the 
human body. Putrescine is eliminated via the urinary pathway. 
0
20
40
60
80
100
0
0.25
1
3
7
14
28
35
Amount of drug (%)
Time (days)
% Elution over time
Combo
Cypher

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 6.1.3.2  Polymer Biocompatibility 
Both the SynBiosys copolymers GLL01 and GPCGL01 are solely composed of biologically safe 
monomers and polymers already employed in numerous regulatory-approved and marketed 
biomedical implants and drug-delivery systems. These polymers are also widely used in fully 
bioabsorbable coronary stents and stent coatings.35 The coating material of the BioMatrix® DES 
system (Biosensors International Group)36 and the fully bioabsorbable Igaki-Tamai® stent (Kyoto 
Medical Planning) are based on poly(LA). The Igaki-Tamai stent and BioMatrix DES system were 
given their CE mark approvals in 2007 and 2008, respectively.37 
Various studies have reported the biocompatibility of the substances released during the 
degradation of SynBiosys-like polymers. For instance, Guan et al. demonstrated that degradation 
products of polymers based on BDI, CL, PEG, and putrescine, which were collected over periods 
of 4 weeks, did not affect the endothelial cell viability.38,39 Similarly, Asplund et al. showed that 
polymers based on BDI and CL did not release toxic products. The in vivo (subcutaneous) study 
of the materials revealed a typical foreign-body response such as the formation of macrophages 
and collagen after the first week and confirmed their biocompatibility over at least 6 weeks.40 Van 
Minnen et al. showed that polymer foams based on D, L-LA, CL, BDO, and BDI that were 
implanted subcutaneously also induced a temporary increase in macrophages and giant cells upon 
implantation, but overall the foams remained biocompatible during a degradation period of 
3 years.41 The cytotoxicity, irritation, sensitization, and hemocompatibility of GLL01 and 
GPCGL01 were evaluated in vitro and in vivo upon implantation of polymer-coated stents. 
 Anti-CD34 Antibody 
The Genous Bio-engineered Surface Technology is a surface treatment comprising a composite 
layer of covalently bound base matrix and a top layer of monoclonal antihuman CD34 antibody. 
The surface modification produces a cell binding immuno-affinity surface for capture of 
circulating CD34+ cells, including EPCs. Endothelial progenitor cells are a class of circulating, 
bone marrow-derived blood cells. The capture of circulating EPCs is the prohealing approach to 
reendothelialization.  
The antibody used for the Genous Technology is a murine, monoclonal antibody directed towards 
the epitope class III of human CD34. The human CD34 is a monomeric cell surface antigen with 
a molecular mass of approximately 110 kDa that is selectively expressed on human hematopoietic 
progenitor cells. The anti-CD34 antibody is produced and purified under Good Manufacturing 
Practice (GMP) guidelines for production of therapeutic monoclonal antibodies. 
 Antihuman CD34 Antibody Component 
The antibody is a highly purified 1324-amino acid antibody that has an approximate molecular 
mass of 145 kDa. The antibody is a fully intact IgG2a immunoglobulin containing light and heavy 
chain variable and constant regions (Figure 7). The anti-CD34 antibody is current GMP produced 
in a hollow-fiber bioreactor perfusion system using a murine hybridoma in a nutrient medium 
containing 10% fetal bovine serum. The hybridoma was produced by the fusion of CD34 
immunized BALB/c mouse sarcoma virus spleen cells with NS-0 myeloma cells. The antibody 
production purification process removed process and product impurities using protein A affinity 
chromatography, pH treatment, cation and anion exchange chromatography, filtration, and 
diafiltration. 

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Figure 7. 
Structure of Murine Antihuman CD34 Monoclonal Antibody 
 Genome Mechanism of Capture 
The Genous Bio-engineered Surface Technology serves as a surface modification for antibody 
capture of EPCs from circulating blood onto the surface of the stent, thus promoting 
reendothelialization. CD34 is a cell surface protein found on the EPCs that are captured via 
immobilized anti-CD34 antibodies on the Genous-treated stent surfaces. The mechanism of EPC 
capture for the immune-affinity approach on an intravascular stent coated with immobilized 
antibody toward EPC cell surface antigens is shown in Figure 8. 
 
 

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Figure 8. 
Endothelial Progenitor Cell Capture 
By antibody recruitment of the patient’s own EPCs to the site of vascular injury (eg, the site of a 
coronary stent implant), an acceleration and enhancement of the normal endothelialization process 
occurs. Functional endothelium is known to reduce inflammation; prevent thrombosis; and inhibit 
smooth muscle cell migration, proliferation, and the expression of extracellular matrix, along with 
functioning to maintain blood flow through vasodilation of the vessel. Rapid establishment of a 
functioning endothelial layer should help to promote the transformation of the injured site to a 
healthy state and reestablish vascular homeostasis. 
 Pharmacokinetics of the Combo Stent 
The PK of sirolimus when released from the Combo stent were studied in a porcine model. Each 
animal had 5 stents implanted per time point. Whole-blood sirolimus PK parameters for this study 
are outlined in Table 4. Preclinical studies show that an equivalent amount of drug is delivered to 
blood vessels compared to commercially available sirolimus-eluting stents. However, the Combo 
stent releases less drug into the blood and downstream organs. 
Table 4. 
Pharmacokinetic Analysis for the Combo Stent 
Pharmacokinetics Parameter 
Value 
Correlation coefficient of fit of the concentrations during the elimination phase based 
on a semi-log plot 
0.994 
Elimination constant (L/h)  
0.0028 
Terminal half-life (h) 
247.0 

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Pharmacokinetics Parameter 
Value 
Time to maximum concentration (h) 
1.00 
Maximum concentration (ng/mL) 
3.98 
Time to last quantifiable sirolimus concentration (< 10 pg/mL) (h) 
672 
Last quantifiable sirolimus concentration (ng/mL) 
0.39 
Observed area-under-the-time-concentration curve (mg/mL*h) 
827.4 
Mean residence time (h) 
220.1 
h, hour; L, liter; mg, milligram; mL, milliliter; ng, nanogram; pg, picogram 
 
Delivery System Description 
The Combo stent is mounted on a low-profile rapid-exchange percutaneous transluminal coronary 
stent delivery catheter with a working length of 138 cm. The balloon is inflated, and the stent is 
deployed by injecting diluted contrast medium solution through the trailing hub of the catheter. 
The guide wire lumen is accessed through the side port, which is located nominally 25 cm proximal 
to the leading tip of the catheter. A guide wire with a maximum diameter of 0.014” may be inserted 
through the side port. The delivery catheter has 2 shaft markers (90 and 100 cm from the distal tip) 
that indicate the relative position of the delivery catheter to the guiding catheter. The delivery 
system has 2 radiopaque marker bands; the inside edges delimit the working length of the balloon. 
The stent is mounted on the balloon between the marker bands. The stent and delivery system are 
available in the nominal lengths and diameters in Table 5. Although there is a 4.0 delivery system, 
it will not be included in this clinical trial. 
Table 5. 
Combo Stent Delivery System Size Matrix by Catalogue Numbers 
Delivery 
Balloon 
Diameter 
(mm) 
Nominal Stent Length (mm) 
9 
13 
15 
18 
23 
28 
33 
2.5 
225-092-8 
225-132-8 
225-152-8 
225-182-8 
225-232-8 
  
  
2.75 
227-092-8 
227-132-8 
227-152-8 
227-182-8 
227-232-8 
  
  
3.0 
230-092-8 
230-132-8 
230-152-8 
230-182-8 
230-232-8 
230-282-8 
230-332-8 
3.5 
235-092-8 
235-132-8 
235-152-8 
235-182-8 
235-232-8 
235-282-8 
235-332-8 
mm, millimeter 
 
 
Implantation of Study Device  
Use of a coronary stent and delivery system requires advanced angioplasty skills. Please refer to 
the Combo stent instructions for use (IFU)/investigator brochure (IB) for detailed technical 
guidance and instructions (Section 17.0). The following information provides general guidance 
but does not obviate the need for the physician to have undergone formal training as well as follow 
the IFU/IB for the treatment or control stent in the use of coronary stents and delivery systems.  
Predilation with a balloon shorter than stent is required to avoid “geographical miss” (ie, balloon 
injury to any segment of the vessel that will not be entirely covered by the stent) during the 

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procedure. Postdilation is recommended based on investigator judgment. If postdilation is 
performed, it must be done with a balloon shorter than and within the boundaries of the stent to 
ensure complete apposition while avoiding injury to the unstented area. 
 Baseline Angiography 
Baseline angiography of the target vessel will be completed per the Angiographic Core Laboratory 
Guidelines. Assessment of angiographic eligibility is based on a visual assessment of the 
immediate preprocedure angiogram obtained by the investigator. For accurate baseline QCA 
measurements, a 5 French or larger guide catheter must be used. Following intracoronary injection 
of nitroglycerin (dose per standard hospital practice), baseline angiography of the involved vessel 
will be performed for at least 2 orthogonal views showing the target lesion free of foreshortening 
or vessel overlap according to the Angiographic Core Laboratory Guidelines. Angiographic 
images of the target lesion must be sent to the Angiographic Core Laboratory per specified delivery 
method. 
If there is more than 1 target vessel, operators will be asked to declare 1 target vessel as a primary 
target vessel before randomization. The primary target vessel will be analyzed with FFR at the 1-
year follow-up visit for all subjects. 
Angiography of nontarget vessels (if required) may be performed per site standard. 
 Left Ventriculography 
Subjects presenting without documentation of prior LVEF assessment (echocardiography, single 
photon emission-computed tomography, computed tomography, magnetic resonance imaging, or 
left ventriculography) within the previous 14 days that meets enrollment inclusion criteria (30% 
or greater) will be required to undergo ejection fraction assessment at the time of the angiogram 
to determine enrollment eligibility. Documented left ventriculography should be performed with 
a pigtail catheter (even with radial access), ensuring that the left ventricle is fully opacified. At 
least 2 consecutive nonpremature ventricular contraction (PVC) or post-PVC beats must be 
present; otherwise, the ventriculogram should be repeated. 
 Predilation of Target Lesion 
Predilation is to be performed per study stent IFU/IB, as follows:  
 Predilation can be performed with an angioplasty balloon only (no cutting balloons, 
AngioSculpt balloons, or atherectomy). 
 Predilation balloon must be shorter than the planned stent length to limit predilation injury 
within the area to be stented. 
 It is recommended that a predilation balloon that is 0.5 mm smaller in diameter than the       
reference vessel be used. 
 
Carefully inspect the sterile package before opening. Do not use the product after the “Use By” 
date. Do not use if any defects are noted. 

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 Bailout Procedures 
Bailout procedures may be performed if the subject experiences a major dissection requiring 
intervention or when an unplanned additional device is required to cover the target lesion. Bailout 
procedures may also be performed for an occlusive complication manifest as decreased target 
vessel flow, chest pain, or ischemic ECG changes that do not respond to repeat balloon inflations 
or intracoronary vasodilators (such as nitroglycerin, adenosine, verapamil, diltiazem, nicardipine, 
nitroprusside). Although a bailout procedure is not considered an endpoint event (unless the 
subject experiences death, MI, or CABG), bailout procedures should be avoided unless required 
for safe subject management. Use of bailout procedures should be uncommon. Ordinarily, each 
target lesion should be covered by a single stent, with a maximum of 2 target lesions per vessel 
and 3 target lesions per subject. Patients at high risk for bailout procedures (especially procedures 
exceeding 3 stents per vessel, 5 stents per subject, or more than 2 vessels) should be excluded from 
the protocol.  
If a bailout stent is required for a target lesion (as in the case of edge dissection), a device from the 
assigned treatment group (Combo or EES) should be used. The bailout device should be a Combo 
stent if the target lesion has been treated with a Combo stent. Similarly, the bailout device should 
be an EES if the target lesion has been treated with an EES. The bailout device should overlap the 
previous device by 1 to 2 mm. If a stent of appropriate length and diameter of the same treatment 
assignment is not available, a commercially approved stent should be selected. Mixing different 
kinds of stents should be avoided unless there is no alternative. Other approved devices or therapies 
may be implemented in the treatment of occlusive complications at the investigator’s discretion. 
 Postdeployment Angiography 
In all subjects, the postprocedure target lesion angiography will be performed according to the 
Angiographic Core Laboratory Guidelines and must be captured in the similar manner used for the 
preprocedure images. These angiographic images should be performed after guide wire removal 
and intracoronary nitroglycerin if spasm is suspected. Two orthogonal views should be obtained 
using the same methods as the preprocedure angiogram. The procedure is considered complete 
after final angiographic recording of the treatment area and the guide catheter has been removed 
from the subject. Angiographic images of all target vessels for Cohorts A and B must be sent to 
the core laboratory per specified delivery method. 
 Risks 
Risks associated with using the Combo stent are believed to be the same as those associated with 
percutaneous treatment procedures for a stenosed coronary artery using any other DES. There are 
potential additional risks of using this investigational device compared with a currently approved 
DES in that the frequency of AEs associated with stenting could possibly be increased with the 
Combo stent, although no such safety concerns have surfaced in the studies to date. 
Use of this type of device is known to be associated with the following risks: 
 Coronary or stent thrombosis 
 Increased vascular and/or bleeding complications (due to anticoagulation) 

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 Increased length of hospital stay relative to length of stay for coronary balloon angioplasty 
alone. Judicious selection of subjects to receive this device rather than balloon angioplasty 
alone is strongly advised 
 Infection secondary to contamination of the stent, which may lead to thrombosis, 
pseudoaneurysm, or vessel rupture 
 Spasm, thrombosis, and/or distal embolization caused by implantation of the stent; stent 
could migrate from the site of implantation down the arterial lumen 
 Rupture and life-threatening bleeding caused by excessive stretching of the artery 
 Partial deployment of stents in particularly resistant lesions 
 Stent dislodgment from the balloon surface during deployment and/or migration from the 
target site postdeployment 
 Allergic reaction to this implant in subjects with an unknown hypersensitivity to stainless-
steel alloy 
 Sensitization towards murine antibodies 
 Unknown long-term clinical outcome for this permanent implant 
 
It is known from studies of oral sirolimus administration that the following drugs and foods may 
interact with sirolimus: 
 Bromocriptine 
 Carbamazepine 
 Cimetidine 
 Cisapride 
 Clarithromycin 
 Clotrimazole 
 Cyclosporine 
 Danazol 
 Diltiazem 
 Erythromycin 
 Fluconazole 
 Grapefruit juice 
 HIV-protease inhibitors (eg, 
ritonavir, indinavir) 
 Inducers of CYP3A4 and P-gp 
 Inhibitors CYP3A4 and P-gp 
 Itraconazole 
 Ketoconazole 
 Metoclopramide 
 Nicardipine 
 Phenobarbital 
 Phenytoin 
 Rifabutin 
 Rifampin 
 Rifapentine 
 
 St. John’s wort (hypericum 
perforatum) 
 Strong inducers of CYP3A4 and 
P-gp 
 Strong inhibitors of CYP3A4 and 
P-gp 
 Telithromycin 

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 Troleandomycin 
 Verapamil 
 Voriconazole 
 
Pregnancy, Category C: There are no adequate sirolimus or Combo stent-related studies in 
pregnant women.  
Lactation, Category C: It is unknown whether sirolimus is excreted in human milk. A decision 
should be made whether to continue nursing or implant the Combo stent. 
Potential complications and adverse effects (in alphabetical order) which may be associated with 
percutaneous coronary treatment procedures, including use of this product, include, but are not 
limited to, the following:  
 Acute or subacute closure of the 
coronary artery 
 Allergic reactions to stainless-steel 
alloy or contrast medium 
 Aneurysm/pseudoaneurysm 
 Arrhythmias, including ventricular 
fibrillation 
 Arteriovenous fistula 
 Cardiac tamponade 
 Coronary artery spasm 
 Coronary or stent thrombosis 
 Coronary vessel dissection, 
perforation, rupture, or injury 
 Death 
 Distal embolization of stent 
 Drug reactions, including to 
antiplatelet agents, anticoagulation 
agents, or contrast media 
 Emergent coronary artery bypass 
surgery 
 Failure to deliver the stent 
 Fever  
 Hemorrhage or bleeding 
complications that may require 
transfusion 
 Hypotension/hypertension 
 Immunologic reaction to murine 
antibodies 
 Infection 
 Myocardial ischemia/infarction 
 Peripheral ischemia 
 Renal failure 
 Restenosis of stented segment 
 Shock/pulmonary edema 
 Stable or unstable angina 
 Stent migration 
 Stroke/cerebrovascular accident 
 Target vessel and/or lesion 
revascularization 
 Total occlusion of the coronary 
artery 
 Vascular complications, including 
hematoma, pseudoaneurysm, or 
hemorrhage at the insertion site, 
which may require vessel repair 
 

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The occurrence of the above complications may lead to a repeat catheterization and/or PCI, MI, 
emergency bypass surgery, or death. Since the Combo stent is an investigational device, risks are 
not entirely known, but are believed to be similar to those that are associated with the standard, 
customary stenting of a stenosed coronary artery. 
All efforts will be made to minimize these risks by selecting investigators who are experienced 
and skilled in using interventional devices and who are trained in the protocol and the Combo and 
EES IFUs/IBs. 
The Cypher sirolimus stent is approved for use, and the risks associated with sirolimus are well 
documented. It is believed that the side effects with sirolimus on the Combo stent will be similar 
to those associated with sirolimus on the Cypher stent, but they may be slightly different (higher 
or lower) than those with the Cypher stent. The EES comparator stent contains everolimus, which 
is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an 
inhibitor of mTOR. Everolimus is approved in the United States under the name of Zortress by 
Novartis Pharmaceuticals for the prophylaxis of organ rejection in adult kidney-transplant 
recipients at low-moderate immunologic risk, at the dose of 1.5 mg/day when taken by mouth. 
Outside the United States, Zortress is sold under the brand name Certican in more than 
70 countries. Everolimus is also approved in the United States under the name of Afinitor for the 
treatment of patients with advanced renal cell carcinoma (cancer) after failure of treatment with 
sunitinib or sorafenib, at doses of 5 to 20 mg/day when taken by mouth. The amount of drug that 
circulates in the bloodstream following implantation of a XIENCE PRIME stent is several-fold 
lower than that obtained with oral doses (1.5 mg–20 mg/day). The following list includes the 
known risks of everolimus at the oral doses listed above: 
 Abdominal pain 
 Acne 
 Anemia 
 Anorexia 
 Asthenia 
 Coagulopathy 
 Cough 
 Diarrhea 
 Dry skin 
 Dysgeusia 
 Dyspnea 
 Edema, peripheral 
 Epistaxis 
 Fatigue 
 Headache 

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 Hemolysis 
 Hypercholesterolemia 
 Hyperglycemia 
 Hyperlipidemia 
 Hypertension 
 Hypertriglyceridemia 
 Hypogonadism, male 
 Increased serum creatinine 
 Infections: wound infection; urinary tract infection; pneumonia; pyelonephritis; sepsis; and 
other viral, bacterial, and fungal infections 
 Leukopenia or lymphopenia 
 Liver function abnormality  
 Lung and breathing problems 
 Lymphocele 
 Mucosal inflammation 
 Myalgia 
 Nausea 
 Noninfectious pneumonitis 
 Pain in extremity 
 Pruritus 
 Pyrexia 
 Rash 
 Renal tubular necrosis 
 Stomatitis 
 Surgical wound complication 
 Thrombocytopenia 
 Venous thromboembolism 
 Vomiting 
There may be other potential AEs that are unforeseen at this time. 
 Postprocedure Subject Management 
It is recommended that immediately following the procedure: 

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1. Heparin or bivalirudin should be discontinued if an optimal procedural result is obtained. 
2. Activated clotting time should be monitored in accordance with hospital protocol if femoral 
arteriotomy is performed. 
3. Vascular sheaths should be removed according to standard hospital practice. 
4.  Additionally, management should be conducted in accordance with the processes of the 
respective medical institution. 
Approved vascular closure devices may be used after femoral arteriotomies at the discretion of the 
investigator in accordance with the manufacturer’s directions. 
 
Follow-up Assessment Procedures 
There are 3 overlapping mechanistic imaging cohorts.  
1. Cohort A: 30 subjects will receive all clinical assessments, serial angiography assessments 
of all study vessels, QCA assessment of all study vessels at baseline. At 6 months Cohort 
A subjects will receive all clinical assessments and OCT assessment of primary target 
vessel only. At 12 months Cohort A subjects will receive all clinical assessments, 
angiographic and QCA assessment of all study vessels, OCT assessment of primary target 
vessel, and FFR assessment of primary target vessel only. Operators should follow the 
appropriate IFU/IB for the OCT system.  
2. Cohort B: 110 subjects will receive all clinical assessments, angiographic and QCA 
assessment of all study vessels only at baseline. At 12 months Cohort B subjects will 
receive all clinical assessments, angiographic and QCA assessment of all study vessels, 
OCT assessment of primary target vessel, and FFR assessment of primary target vessel. 
Use of a 6 French guide catheter is recommended for these assessments. Operators should 
follow the appropriate IFU/IB for the OCT and FFR systems.  
3. Cohort C: 432 subjects will receive all clinical assessments, angiographic assessments of 
all study vessels, and FFR assessment of the primary target vessel only at 12 months. 
Fractional flow reserve assessments may be obtained using a 4 French catheter. Operators 
should follow the appropriate IFU/IB for the FFR systems. 
 
Recommendations for Evaluation of Fractional Flow Reserve Results and 
Revascularization Procedures 
The recommendations for revascularization are based on the results of the Fractional Flow 
Reserve-Guided Percutaneous Coronary Intervention Plus Optimal Medical Treatment Versus 
Optimal Medical Treatment Alone in Patients With Stable Coronary Artery Disease (FAME) 2 
trial,42 the 2011 American College of Cardiology (ACC) Foundation/American Hospital 
Association (AHA) PCI guidelines,43 and the 2009 ACC/AHA Appropriateness Criteria for 
Coronary Revascularization.44 Note that a positive FFR without subsequent PCI or CABG will not 
be considered revascularization. 
For protocol-mandated angiograms at 12 months, FFR evaluation of the primary target vessel is 
required for all patients. Please also reference the FFR Core Laboratory Guidelines.   In patients 
with more than one target vessel, FFR evaluation of the nonprimary target vessel is strongly 
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 If angiographic stenosis is < 50% diameter reduction, revascularization should not be 
performed.  
 If an angiographic stenosis is ≥ 50% diameter reduction, revascularization should not be 
performed if the FFR is > 0.80. This rule applies even in patients with typical angina 
symptoms, patients with atypical angina symptoms, or subjects without chest pain but 
documented ischemia on noninvasive testing, based on the FAME 2 results that show that 
FFR-directed PCI is appropriate in this setting.  
 If the angiographic stenosis is ≤ 60% diameter reduction, the patient is asymptomatic, and 
there is either no noninvasive testing or the noninvasive testing has equivocal results, 
revascularization should not be performed regardless of the results of the FFR.44 
For catheterizations performed at times other than the scheduled angiographic study visits 
(12 months for subjects in Cohorts A, B, C; 6 months for subjects in Cohort A): 
 If angiographic stenosis is < 50% diameter reduction, revascularization should not be 
performed.  
 If an angiographic stenosis is ≥ 50% diameter reduction, FFR assessment of the lesion is 
strongly recommended. Revascularization should not be performed if the FFR is > 0.80. 
This rule applies even in patients with typical angina symptoms, patients with atypical 
angina symptoms, or patients without chest pain but documented ischemia on noninvasive 
testing, based upon the FAME 2 results that show that FFR-directed PCI is appropriate in 
this setting.  
 If the angiographic stenosis is ≤ 60% diameter reduction or the patient is asymptomatic 
and there is either no noninvasive testing or the noninvasive testing has equivocal results, 
revascularization should not be performed regardless of the results of the FFR.44 
 If FFR measurement is not possible, revascularization may be considered in the setting of 
MI (abnormal biomarkers or ST-elevation), unstable angina with ST-segment depression 
on ECG, or unstable angina accompanied by ischemia documented by noninvasive testing. 
 
Potential Benefits of Combo Stent 
Percutaneous transluminal coronary angioplasty has been widely used as an alternative to medical 
or surgical treatment in selected subjects with symptomatic coronary artery disease. The major 
limitations of PTCA (abrupt closure, intimal dissection, and restenosis from elastic recoil) are 
overcome to a significant extent with coronary stents. 
The Combo stent can be expected to provide the same radial support as other coronary stents to 
minimize closure of a stenosed artery as is commonly indicated for coronary stenting. 
Additionally, the potential benefit of the Combo stent is its effectiveness in inhibition of neointima 
while enhancing endothelial coverage that may reduce rates of stent thrombosis or support shorter 
routine use of DAPT without increasing rates of restenosis compared with other commercially 
available DESs. Well-known components supporting these features include the elution of 
sirolimus and the use of abluminal, bioabsorbable polymer. The most novel feature of the Combo 
platform is the use of CD34 antibody coating, providing a unique endothelial progenitor cell-
capture technology mechanistically targeted to promote faster, more complete healing of the stent 
site and struts. 

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Concomitant Medications/Therapies 
 Prepercutaneous Coronary Intervention Medications 
 Aspirin 
Preloading with aspirin at least 81 to 325 mg, according to regional standard of care therapy, at 
least 2 hours before the PCI is mandatory. For subjects already receiving chronic aspirin therapy, 
the loading dose of at least 81 to 325 mg of aspirin, according to regional standard of care therapy, 
should still be given. Either chewable or intravenous aspirin is mandatory for the loading dose in 
subjects not on chronic aspirin who will receive only 1 dose of aspirin before the PCI. Aspirin 
therapy will be at least 81 to 325 mg, according to regional standard of care therapy, for 1 month 
following the index PCI, then reduced to 81 to 325 mg daily, at the discretion of the investigator. 
 Platelet Adenosine Diphosphate Receptor Antagonists 
Platelet adenosine diphosphate (ADP) receptor antagonist preloading therapy is mandatory, using 
only approved agents at the time of enrollment. In subjects undergoing PCI, the platelet ADP 
receptor antagonist must be given before the start of the interventional procedure. The following 
schedule is recommended: 
 Clopidogrel at least 75mg—600 mg more than 6 hours before PCI or 300 mg more than 
12 hours before PCI (even if the subject is on chronic clopidogrel therapy), according to 
regional standards of care therapy; or 
 Prasugrel at least 20 mg  more than 1 hour before PCI, according to regional standards of 
care therapy; or 
 Other approved adenosine diphosphate (ADP) receptor antagonists, designated before 
randomization. In the US, this includes ticagrelor, 180 mg more than 1 hour before PCI. 
 
For subjects already receiving chronic platelet ADP receptor antagonist therapy, preloading is still 
mandatory. The choice of either clopidogrel, prasugrel, ticagrelor, or other approved 
thienopyridines is left to the discretion of the investigator. The intended duration of dual 
antiplatelet therapy is also left to the discretion of the investigator but must be recorded before 
randomized stent assignment. 
 Other Medications 
The use of other medications (eg, beta-blockers, angiotensin-converting enzyme inhibitors) before 
PCI is left to the discretion of the treating physicians. Best medical practice is recommended.  
As additionally noted in the AC C/AHA PCI guidelines,43 lipid management is strongly 
recommended. All concomitant cardiac medications must be recorded on the electronic case report 
form (eCRF). 
 Medications During Percutaneous Coronary Intervention 
During the procedure, subjects will receive appropriate anticoagulation medications according to 
standard hospital practice. The use of any approved anticoagulant agent at the discretion of the 
investigator is acceptable.  

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The use of glycoprotein IIb/IIIa receptor inhibitors is allowed per the discretion of the investigator 
as long as the agents are approved for use in the participating country. 
 Postpercutaneous Coronary Intervention Medications 
It is very important that the subject is compliant with the postprocedure antiplatelet 
recommendations. Premature discontinuation of prescribed antiplatelet medications could result 
in a higher risk of thrombosis, MI, or death. Before PCI, if a surgical or dental procedure is 
anticipated that requires early discontinuation of antiplatelet therapy, the interventionalist and 
subject should carefully consider whether a DES and its associated recommended antiplatelet 
therapy is the appropriate PCI choice. If a DES is not appropriate, the subject should not be 
enrolled in the trial. Following PCI, should a surgical or dental procedure be recommended, the 
risks and benefits of the procedure should be weighed against the possible risk associated with 
premature discontinuation of antiplatelet therapy. Subjects who require premature discontinuation 
of antiplatelet therapy secondary to significant active bleeding should be monitored carefully for 
cardiac events and, once stabilized, have their antiplatelet therapy restarted as soon as possible per 
the discretion of their treating physician. 
 Aspirin 
Mandatory dosing with aspirin will be at least 81 mg or more post-PCI per day in the hospital and 
then at least 81 mg or more for 30 days, according to regional standard of care therapy. Dosing 
will then continue as at least 81 mg per day indefinitely. Daily aspirin must be given for the 
duration of the trial. Aspirin should not be discontinued for CABG or other reasons unless 
absolutely necessary. 
 Platelet Adenosine Diphosphate Receptor Antagonists 
Chronic daily platelet ADP receptor antagonist therapy using an approved agent requires that all 
subjects receive chronic daily DAPT therapy according to regional standard of care therapy, with 
the choice of agent left to the discretion of the investigator, either: 
 Clopidogrel at least 50 mg per day; or 
 Ticlopidine 250 mg every 12 hours; or 
 Prasugrel at least 3.75 mg per day; or 
 Ticagrelor 90 mg twice daily (if this drug is approved by national regulatory authorities) 
  
Adenosine diphosphate antagonists should not be discontinued within the first 6 months after DES 
implantation, according to recommended standard of care, unless absolutely necessary due to 
major bleeding, major trauma, or major surgery (eg, intracranial surgery) necessitating 
discontinuation of antiplatelet therapy. Many surgeries can safely be performed while the subject 
is on DAPT. If a subject on DAPT requires surgery, strong consideration should be given to 
performing the surgery without antiplatelet agent discontinuation. 
 
Packaging 
The study device will be packed and shipped to sites and resupplied on an as-needed basis. EES 
comparator stents will be selected from the local clinical supply. The label of the study device 
includes the following information: 
 Device is used for the clinical trial 

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 Lot number 
 Storage condition 
 Expiration date 
 Name and address of sponsor  
 
The study device will be stored at room temperature in the boxed state as supplied by the sponsor 
and will be used before the labeled expiration date. Study devices are to be stored separately from 
clinical supplies and accessible only to those who have appropriate authorization. 
 
 
Product Stability and Shelf-Life 
A stability study was conducted on the Combo stent, where total drug content and antibody activity 
were evaluated out to 12 months real-time aging. The total drug content and antibody activity for 
the Combo stent were found to remain stable and within the acceptance criteria for up to 12 months 
stored at 25°C/60% relative humidity. The Combo stent clinical product will have a product shelf-
life of 12 months. 
 
Blinding of Study 
Single blinding practices for the study will include the following: 
 Subjects: Subjects will be informed of the 1:1 randomization between the 2 stent systems 
(Combo:EES) but will remain blinded as to which stents they actually receive until after 
the 12-month follow-up. 
 Implanting physician: It is not possible to blind the implanting physician due to the 
differences in the implant procedure for the treatment and the control stents. 
 Follow-up physician: There will be no requirement that follow-up be performed by a 
physician other than the implanting physician. In follow-up reports, the follow-up 
physician will refer to either stent as a study stent so that these reports will not unblind 
anyone reviewing the report. 
 Clinical research coordinators: Clinical research coordinators (CRCs) will not be blinded. 
In follow-up notes, the CRC will refer to either stent merely as a “study stent” so that these 
notes will not unblind anyone reviewing them. Clinical research coordinators will be 
instructed not to unblind subjects until after the 12-month follow-up visit. 
 Monitors: Monitors will not be blinded. Monitoring reports will refer to either stent as the 
study stent to preclude inadvertent unblinding of those reading the reports. 
 Data Management and Operations: Clinical trial operations at the Duke Clinical Research 
Institute (DCRI) currently utilize standard operating procedures (SOPs) for confidential 
data management that prohibit investigators, sponsor staff, subjects, families, or others 
from access to descriptor or outcomes data and/or its relationship to treatment assignment. 
 Angiographic Core Laboratory: The angiographic core laboratory reviewers will be 
blinded to the treatment and the control stents.  
 Clinical Events Classification Committee: The Clinical Events Classification Committee 
(CEC) may receive core laboratory reports regarding angiographic findings or blinded 

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angiographic films to adjudicate an event. To ensure that CEC members remain blinded to 
treatment assignment, information that will reveal how a subject was randomized will be 
redacted from medical record source documentation and event descriptions.  
 Data and Safety Monitoring Committee: The DSMC will be blinded to treatment arm 
assignment. If it is determined by the DSMC that knowledge of treatment arm assignment 
is necessary to render opinion on the safety of trial design or conduct, this information will 
be disclosed to the DSMC. Material contained in each DSMC review is confidential, and 
all documentation is controlled in accordance with DCRI SOPs. The only exception to this 
policy is in the event that the DSMC recommends alteration to the trial and it is deemed 
essential that the Executive Operations Committee receive information that would 
implicitly result in their knowledge of treatment assignment. 
 
Receiving, Storage, Dispensing, and Return 
 Receipt of Study Device 
Upon receipt of the study device supplies, an inventory must be performed and a device receipt 
log filled out and signed by the person accepting the shipment. It is important that the designated 
study staff counts and verifies that the shipment contains all the items noted in the shipment 
inventory. Any damaged or unusable study devices in a given shipment will be documented in the 
study files. The investigator must notify the study sponsor of any damaged or unusable study 
devices that were supplied to the investigator’s site. 
 Return of Study Device 
At the completion of the study, there will be a final reconciliation of study devices shipped, devices 
used, and devices remaining. This reconciliation will be logged on the device reconciliation form, 
signed, and dated. Any discrepancies noted will be investigated, resolved, and documented before 
the return of unused study devices. Any unused study devices are to be returned to the sponsor. 

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SUBJECT SAFETY AND ADVERSE EVENTS 
 
Ethics Committees/Institutional Review Boards 
Each site will submit the study protocol, ICF, and other study documents to their ethics committee 
(EC)/institutional review board (IRB) for approval. A copy of the signed and dated EC/IRB 
approval for each enrolling center will be stored at the Data Coordinating Center, in accordance 
with GCP. Any amendments to the protocol, other than minor administrative changes, must be 
approved by the site’s EC/IRB before the changes are implemented at the site. 
 
Definitions 
 Adverse Event 
The reporting and recording of adverse events (AEs) is crucial to the evaluation of an 
investigational device and to the development of labeling information that appears in the IFU/IB. 
During a clinical trial, the reporting of adverse experience information can lead to important design 
changes in the new device, as well as provide integral safety data. The investigator will monitor 
each subject for clinical and laboratory evidence of AEs throughout the trial.  
An AE is defined as any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users, or other persons, whether 
or not related to the investigational medical device.  
Any pre-existing condition known to the investigator will not, in general, be reportable as an AE, 
unless the investigator believes that the participation of the subject in this study contributed to the 
progression of that condition. 
When an AE has, by its nature, a prolonged course, the event will be considered a single event and 
not multiple events; for example, if a subject develops end-stage renal failure requiring regular 
dialysis, the event is considered end-stage renal failure, not multiple single renal events. 
 Serious Adverse Event 
Any AE that:  
 Led to death 
 Led to a serious deterioration in the health of the subject that resulted in 
o Life-threatening illness or injury or 
o Permanent impairment of a body structure or a body function or 
o In-patient hospitalization or prolongation of existing hospitalization.  
o Medical or surgical intervention to prevent permanent impairment of a body 
structure or a body function 
o Led to fetal distress, fetal death, or a congenital abnormality or birth defect  
o The following hospitalizations are not considered AEs/SAEs: 
 Visit to the emergency room or other hospital department for less than 
24 hours that does not result in admission (unless considered "important 
medical event" or “event life threatening”). 

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 Elective surgery, planned before signing consent. 
 Admissions per protocol for a planned medical/surgical procedure. 
 Routine health assessment requiring admission for baseline/trending of 
health status (eg, routine colonoscopy). 
 Medical/surgical admission for purpose other than remedying ill health state 
and planned before entry into the study. Appropriate documentation is 
required in these cases. 
 Admission encountered for another life circumstance that carries no bearing 
on health status and requires no medical/surgical intervention (eg, lack of 
housing, economic inadequacy, caregiver respite, family circumstances, 
administrative). 
 Anticipated Adverse Device Effects 
A serious adverse device effect (ADE) that by its nature, incidence, severity or outcome has been 
previously identified as noted in the protocol risks section (6.3.6) or IFU/IB.  
 Unanticipated Adverse Device Effects 
Per United States Code of Federal Regulations (CFR) Title 21, Part 812.3, an unanticipated ADE 
(UADE) is any serious adverse effect on health or safety or any life-threatening problem or death 
caused by or associated with a device, if that effect, problem, or death was not previously identified 
in nature, severity, or degree of incidence in the investigational plan or application (including a 
supplementary plan or application) or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects. 
Unanticipated ADEs will include events meeting either A or B as stated below: 
A. Events meeting ALL of the following criteria: 
 Not included in the list of anticipated events (see IFU/IB) 
 Possibly, probably, or definitely related to the investigational device per the site 
investigator 
 Serious (meets any of the following criteria): 
o Life-threatening illness or injury 
o Results in permanent impairment of a body structure or a body structure 
o Necessitates medical or surgical intervention to prevent permanent 
impairment of a body function or a body structure 
o Led to fetal distress, fetal death, or a congenital abnormality or birth defect 
o Led to death 
 
(Permanent means irreversible impairment or damage to a body structure or 
function, excluding trivial impairment or damage.) 

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B. Any other unanticipated serious problem associated with the investigational device that 
relates to the rights, safety, or welfare of subjects. 
 Device Failure and Device Malfunction 
A device has failed or malfunctioned if it is used in accordance with the IFU/IB but does not 
perform according to the IFU/IB and negatively impacts the treatment. Device failures include: 
 Inability to position at desired location 
 Incorrect deployment of device 
 User Error 
A device is used by the investigator in a manner that is an act or omission of an act that results in 
a different medical device response than intended by the manufacturer or expected by the user. 
The term "user error" refers to an error made by the person using the device, for example an error 
of use of the device outside of the IFU/IB. 
 
 
Assessment  
 Causality Rating 
 
RELATIONSHIP  
CAUSALITY 
DEFINITION 
REPORTING 
Not related to 
investigational 
device  
Unrelated 
An event for which an alternative 
explanation (eg, concomitant 
drug or concomitant disease) is 
conclusively identified and/or the 
relationship in time suggests that 
a causal relationship is highly 
unlikely 
All AEs/SAEs, regardless of 
relationship to the study 
device, occurring from 
randomization through the 
first 30 (± 7) days will be 
reported in the eCRF as soon 
as possible.  Specified 
cardiovascular endpoint 
events collection will be 
reported on the eCRF 
endpoint pages only 
 
 
 
 
Not related to 
investigational device  
 
 
 
 
Unrelated 
An event for which an alternative 
explanation (eg, concomitant 
drug or concomitant disease) is 
conclusively identified and/or the 
relationship in time suggests that 
a causal relationship is highly 
unlikely 
All SAEs, regardless of 
relationship to the study 
device, occurring from 
randomization through the 1 
year follow-up visit (+/- 30 
days) will be reported in the 
eCRF as soon as possible.  
Specified cardiovascular 
endpoint events collection will 
be reported on the eCRF 
endpoint pages only 
Related to 
investigational 
device  
Possible 
An event that might be due to the 
use of the study device. An 
alternative explanation (eg, 
concomitant drug or concomitant 
disease) is inconclusive. The 
All AEs/SAEs related 
(possible, probable or 
definite) to the device, 
except events listed as 
protocol-specific endpoints, 

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relationship in time is reasonable; 
therefore the causal relationship 
cannot be excluded. 
(section 7.6) occurring from 
randomization through the 
5-year study period will be 
reported in the eCRF as soon 
as possible.  Specified 
cardiovascular endpoint 
events collection will be 
reported on the eCRF 
endpoint pages only.  
 
Probable 
An event that might be due to the 
use of the study device. An 
alternative explanation (eg, 
concomitant drug or concomitant 
disease) is less likely. The 
relationship in time is suggestive 
of causality. 
Definite 
An event that is due to the use of 
the study device. The event 
cannot be reasonably explained 
by an alternative explanation (eg, 
concomitant drug or concomitant 
disease). 
 
 Severity of Adverse Events 
The severity of an AE will be rated as follows: 
 Mild: AE that is easily tolerated by the subject, causes minimal discomfort, and does not 
interfere with everyday activities. 
 Moderate: AE that is sufficiently discomforting to interfere with normal everyday 
activities; intervention may be needed. 
 Severe: AE that prevents normal everyday activities; treatment or other intervention 
usually needed. 
 
Reporting 
It is understood that complete information about an event may not be known at the time the initial 
report is submitted. The investigator must assess the relationship of the event to the investigational 
device (including the rationale for the assessment) and should make every attempt to obtain as 
much information as possible concerning the event. Additional information pertaining to an event 
should be reported in the eCRF as it becomes available. Specified cardiovascular endpoint events 
will be reported on the eCRF endpoint pages only. 
 Time Frame 
 Adverse Events 
All AEs, except events listed as protocol-specific endpoints (Section 7.6), regardless of 
relationship to the study device, occurring from randomization through the first 30 (± 7) days will 
be reported in the eCRF as soon as possible. 
All AEs related to the device, except events listed as protocol-specific endpoints, (Section 7.6) 
occurring from randomization through the 5-year study period will be reported in the eCRF as 
soon as possible. 

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 Serious Adverse Events 
All SAEs, except events listed as protocol-specific endpoints (Section 7.6), occurring from 
randomization through the 1 year follow-up visit will be reported in the eCRF within 24 hours of 
knowledge of the event.  
All events that lead to or result in death, device-related SAEs and UADEs occurring after 
randomization through the 5-year follow-up will be reported in the eCRF within 24 hours of 
knowledge of the event. If required, the site investigator or their delegate is responsible for 
notifying the site director of a reported SAE within the expected time frame. The investigator or 
qualified designee will enter the required information about the SAE into the AE/SAE page of the 
eCRF, which will be distributed to the appropriate sponsor contact. If only limited information is 
initially available, follow-up reports are required. As follow-up information becomes available, it 
should be entered into the eCRF within 24 hours.  
If the eCRF reporting capability is not available, the SAE should be reported on the paper back-
up SAE form and faxed or e-mailed to DCRI Safety Surveillance. If eCRF, e-mail, and FAX are 
not available, the event should be reported by telephone (see contact information below). If the 
report is initially given by e-mail, FAX, or telephone, then the required information about the SAE 
will be entered into the appropriate module of the eCRF immediately after the eCRF system is 
available by the site. 
 
SAE FACSIMILE TRANSMISSION: 
Duke Clinical Research Institute (DCRI) Safety Surveillance 
Fax: +1-919-668-7138; toll-free within the U.S.: 1-866-668-7138 
SAE e-mail: DCRISafetySurveillance@dm.duke.edu  
SAE telephone: +1-919-668-8624 or toll-free within U.S.: 1-866-668-7799 
 
All SAEs will be followed to resolution or stabilization. Resolution means that the subject has 
returned to a baseline state of health. Stabilization means that the investigator does not expect any 
further improvement or worsening of the AE. 
Safety data will be periodically reviewed to monitor subjects safety through the study period, Study 
leadership will be notified if any events are occurring at an unexpected rate for this study 
population. Risks will be continually assessed to determine if a protocol or ICF revision is 
warranted. 
  Unanticipated Adverse Device Effects, Device Failures, Device Malfunctions, and 
User Error 
In the case of a device failure or malfunction related to the investigational device, the Combo stent 
device must be returned to the manufacturing company, if possible. Device failure, device 
malfunctions, and user error will be reported on the device deficiency eCRF form within 24 hours 
of knowledge of the event. If the eCRF reporting capability is not available, the paper back-up 
device deficiency from should be emailed or faxed to DCRI Safety Surveillance as noted in section 
7.4.1.2 within 24 hours of knowledge of the event.   

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Regulatory Reporting of Unanticipated Adverse Device Effects 
There are situations that may necessitate rapid communication of the occurrence of AEs to the 
regulatory authorities. The DCRI Safety Surveillance medical monitor will determine if a device-
related event meets “unanticipated” criteria (ie, is not identified in the IFU/IB or literature), 
reporting all findings to OrbusNeich Medical for the duration of the trial. All device-related AEs 
will be reported to OrbusNeich for the duration of the trial. Unanticipated ADEs will be reported 
by OrbusNeich Medical to the Pharmaceuticals and Medical Devices Agency (PMDA) (Japan), 
FDA, all reviewing ECs/IRBs, and all participating investigators within 10 working days of when 
DCRI Safety Surveillance was initially notified of the event or within accordance of country 
regulations.  
In accordance with local regulations, OrbusNeich Medical will notify investigators of all SAEs 
that are suspected (related to the investigational product) and unexpected (ie, not previously 
described in the IFU/IB). OrbusNeich Medical will immediately conduct an evaluation of any 
UADEs. If OrbusNeich Medical determines that a UADE presents an unreasonable risk to subjects, 
all investigations or parts of investigations presenting that risk shall be terminated as soon as 
possible. Termination shall occur no later than 5 working days after OrbusNeich Medical makes 
this determination and no later than 15 working days after they first received notice of the effect 
or within accordance of country regulations. 
OrbusNeich Medical retains all regulatory reporting responsibility to the PMDA and the FDA.  
Investigators are responsible for reporting UADEs to their reviewing EC/IRB within 10 working 
days of notification from sponsor.  
 
Protocol-Specific Endpoint Events 
The CEC will adjudicate the following protocol-specific endpoint events as defined in the CEC 
Charter: 
 Death 
 Cardiac death 
 MI 
 Target vessel MI 
 TLR (ischemia driven) 
 TVR (ischemia driven)  
 Stroke and TIA 
 Stent thrombosis (ARC definition) 
These protocol-specific endpoint events will be reported on the appropriate pages in the eCRF 
within 24 hours of knowledge of the event. These events (with the exception of all events that lead 
to or result in death) will not be captured as SAEs and will not be reported to the regulatory 
authorities in an expedited manner. 

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Criteria for Withdrawal of Subjects from Study 
Each enrolled subject shall remain in the study until completion of the required follow-up period; 
however, a subject’s participation in any clinical study is voluntary, and the subject has the right 
to withdraw at any time without penalty or loss of benefit. Conceivable reasons for discontinuation 
may include, but not be limited to, the following: 
 Subject death 
 Subject voluntary withdrawal  
 Subject withdrawal by physician as clinically indicated 
 Subject lost-to follow-up 
 
The reason for subject discontinuation must be documented on the eCRF and source documents. 
The investigator must also report any subject’s discontinuation to his or her EC/IRB, as defined 
by his or her institution’s procedure. When a subject discontinues or is withdrawn from the study 
before study completion, all applicable activities scheduled for the final study visit should be 
performed at the time of discontinuation. Any adverse experiences that are ongoing at the time of 
discontinuation/withdrawal should be reported and followed up in accordance with the safety 
requirements outlined in Section 7.4. 

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EFFICACY ASSESSMENTS  
The primary clinical endpoint is TVF, defined as cardiac death, target-vessel MI, or ischemia-
driven TVR by percutaneous or surgical methods, at 1 year. The primary endpoint will be reported 
after all subjects have completed 12 months of follow-up.  
The secondary efficacy endpoint is mechanistic OCT healthy level of intimal tissue coverage, 
determined by the OCT core laboratory at 1 year for subjects in Cohorts A and B combined (total 
N=140 subjects). 
Additional prespecified efficacy endpoints are: 
 Angiographic late loss by quantitative coronary angiogram core laboratory at 1 year 
(Cohorts A and B combined) 
 In-stent and in-segment angiographic binary restenosis at 1 year (Cohorts A and B 
combined) 
 In-stent and in-segment proximal and distal QCA measurement of late lumen loss at 1 year 
(Cohorts A and B combined) 
 Clinically and functionally (FFR) ischemia-driven TLR at 1 year 
 Device success, defined as attainment of less than 50% residual stenosis of the target lesion  
 Lesion success, defined as attainment of less than 50% residual stenosis using any 
percutaneous method 
 Procedure success, defined as lesion success without the occurrence of in-hospital death, 
nonfatal MI, stroke, or emergency revascularization.   
 TVF, defined as cardiac death, target vessel MI, or ischemic-driven TVR by percutaneous 
or surgical methods at 30 days; 6 months; and 2, 3, 4, and 5 years 
 The following clinical endpoints will be assessed at 30 days; 6 months; and 1, 2, 3, 4, and 
5 years: 
o Death (all causes) 
o Cardiac death 
o Nonfatal MI 
o Target-vessel MI 
o TLR (ischemia driven) 
o TVR (ischemia driven) 
o TLF, defined as death, MI, and ischemic TLR 
 
 
 

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SAFETY ASSESSMENTS 
Safety and tolerability will be assessed on the basis of reported AEs; changes in vital signs; and 
standard clinical laboratory tests, including routine hematology and blood chemistry. Safety 
endpoints will be assessed at postprocedure; 30 days; 6 months; and 1, 2, 3, 4, and 5 years as 
follows: 
 All-cause mortality  
 Cardiac mortality  
 ARC definite/probable stent thrombosis  
 ARC definite stent thrombosis  
 MI (using modified ARC definition)1: Q-wave and non-Q-wave, cumulative, and 
individual  
 Stroke and TIA 
 OCT safety assessments for late malapposition and intracoronary thrombus by OCT core 
laboratory at 1 year (Cohorts A and B, total N=140 subjects)  
 Change in HAMA serum levels at 30 days and 1 year follow-up compared with baseline 
(N=110, all subjects in Cohort B) 
 
 
Adverse Events 
The definitions of AEs and reporting responsibilities of the sponsor and investigator are described 
in Section 7 of this protocol. 
 
Laboratory Testing 
Clinical laboratory tests, requiring approximately 35 mL of blood, will be performed at specified 
times during the first year that each subject is under study. These times are detailed in the Schedule 
of Events in Section 5. Subjects participating in the HAMA blood collection will have an additional 
12 mL of blood total collected for these assessments. 
 
 
 
 

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STATISTICAL ANALYSIS PLAN AND DETERMINATION OF SAMPLE 
SIZE 
 
Statistical Design 
This is a prospective, multi-center, 2-arm, symmetrically randomized, active-control clinical trial 
designed to assess the safety and effectiveness of the Combo stent in subjects with ischemic 
coronary disease and who are suitable for PCI. To support both the logistics of predominantly 
Japanese subject enrollment and a robust evaluation of both efficacy and safety, the analytic plan 
includes both superiority to imputed BMS control and noninferiority to best-in-class 
second-generation DES (Xience V) in 1-year TVF rates. In addition, FFR assessment to evaluate 
the physiology of target vessels in the entire population will augment the endpoint definition of 
ischemia-driven TVR. Finally, key safety considerations will be augmented with a subpopulation 
in whom imaging with OCT for strut coverage, late strut malapposition, and plaque volume, as 
well as serial HAMA assessments, will be reported. 
For the primary efficacy endpoint, this study will include both an imputed BMS control 
performance goal and a randomized concomitant active-control EES stent cohort as reference 
comparators for superiority and noninferiority, respectively. The population studied will require 
enrollment of 572 subjects to get 542 evaluable (assuming a 5% lost-to-follow-up rate), 
randomized evenly to the 2 study arms, admitted to the hospital for a planned (elective) 
percutaneous coronary artery intervention procedure. Each subject will be followed for 5 years. 
The primary analysis sample will be based on the principle of intention-to-treat. For this study, all 
subjects who meet the study-entry criteria, sign the written informed consent, and are randomized 
to a treatment arm will be counted in the primary analysis. 
A secondary analysis will also be performed on the per-treatment population, defined as subjects 
with a successful procedure and follow-up information. 
All statistical analyses will be performed using Statistical Analysis System (SAS), version 9.2 or 
higher, or other widely accepted statistical or graphical software. Subject data listings and tabular 
and graphical presentations of results will be provided. 
 
Primary Analysis 
 Primary Endpoint 
The primary clinical endpoint is TVF, defined as cardiac death, target-vessel MI, or 
ischemia-driven TVR by percutaneous or surgical methods, at 1 year. The primary endpoint will 
be reported after all subjects have completed 12 months of follow-up. Target-vessel failure 
analysis will show noninferiority to an EES and superiority to an imputed BMS control (see 
Section 10.8.2.4). Clinical endpoints will be assessed before any protocol-mandated angiograms, 
to avoid bias from angiographic-triggered revascularization. Abnormal FFR during the protocol 
1-year catheterization will be included with the clinical assessment for both 1-year TVF and 
ischemia-driven TVR calculations. The secondary efficacy endpoint will be 1-year ischemia-
driven TVR, including use of target-vessel FFR, analyzed dichotomously using the FAME study 
criteria of 0.81 during a 2 minute infusion of adenosine or adenosine triphosphate.  

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 Primary Endpoint Analysis 
The primary endpoint will be evaluated using the relationship 
Odds of TVF for Combo = Odds of TVF for Combo  x  Odds of TVF for EES  
Odds of TVF for BMS       Odds of TVF for EES           Odds of TVF for BMS 
 
to determine the performance of Combo relative to bare metal stenting as a measure of clinical 
effectiveness. 
 
Major Secondary Analyses 
One-year protocol recatheterization will provide 3 genres of surrogate endpoint information to 
complement the safety and efficacy evaluation of both the investigational Combo platform and the 
control EES platform. Specifically these include physiologic flow as target-vessel FFR, 
angiographic assessment of late loss, and, in a cohort of 140 subjects, OCT imaging to quantify 
strut coverage, late stent malapposition, and plaque volume. Angiographic late loss and OCT 
image analyses will be conducted in independent, blinded core laboratories. 
 Secondary Efficacy Endpoint 
 Mechanistic OCT healthy level of intimal tissue coverage by OCT core laboratory at 1 year 
(N=140 subjects) 
 Additional Prespecified Endpoints 
 Efficacy 
The following efficacy endpoints will also be assessed: 
 Angiographic late loss by QCA core laboratory at 1 year (Cohorts A and B combined, 
N=140 subjects) 
 In-stent and in-segment angiographic binary restenosis at 1 year (Cohorts A and B 
combined). In-segment restenosis is defined as restenosis within a region including 5 mm 
proximal and 5 mm distal to the target lesion.  
 In-stent and in-segment proximal and distal QCA measurement of late lumen loss at 1 year 
(Cohorts A and B combined). 
 Clinically and functionally (FFR) ischemia-driven TLR at 1 year. 
 Device success, defined as attainment of less than 50% residual stenosis of the target lesion. 
 Lesion success, defined as attainment of less than 50% residual stenosis using any 
percutaneous method. 
 Procedure success, defined as lesion success without the occurrence of in-hospital death, 
nonfatal MI, stroke, or emergency revascularization. 
 TVF, defined as cardiac death, target vessel MI, or ischemic-driven TVR by percutaneous 
or surgical methods at 30 days; 6 months; and 2, 3, 4, and 5 years. 

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 Death (all causes) at 30 days; 6 months; and 1, 2, 3, 4, and 5 years. 
 Cardiac death at 30 days; 6 months; and 1, 2, 3, 4, and 5 years. 
 Nonfatal MI at 30 days; 6 months; and 1, 2, 3, 4, and 5 years. 
 Target-vessel MI at 30 days; 6 months; and 1, 2, 3, 4, and 5 years. 
 TLR (ischemia driven) at 30 days; 6 months; and 1, 2, 3, 4, and 5 years. 
 TVR (ischemia driven) at 30 days; 6 months; and 1, 2, 3, 4, and 5 years. 
 TLF, defined as death, MI, and ischemia-driven TLR. 
 Safety 
The following safety endpoints will be assessed: 
 All-cause mortality at postprocedure; 30 days; 6 months; and 1, 2, 3, 4, and 5 years 
 Cardiac mortality at postprocedure; 30 days; 6 months; and 1, 2, 3, 4, and 5 years 
 ARC definite/probable stent thrombosis at postprocedure; 30 days; 6 months; and 1, 2, 3, 
4, and 5 years  
 ARC definite stent thrombosis at postprocedure; 30 days; 6 months; and 1, 2, 3, 4, and 
5 years 
 MI (using modified ARC definition1) at postprocedure; 30 days; 6 months; and 1, 2, 3, 4, 
and 5 years 
 Stroke and TIA at postprocedure; 30 days; 6 months; and 1, 2, 3, 4, and 5 years 
 OCT safety assessments for late malapposition and intracoronary thrombus by OCT core 
laboratory at 1 year (Cohorts A and B combined, N=140 subjects) 
 Change in HAMA plasma levels at 30 days and 1-year follow-up compared with baseline 
(N=110, all subjects in Cohort B) 
 
Optical Coherence Tomography Substudy Analyses 
 Introduction 
Pathology studies have shown neointimal thickness to be predictive for completeness of stent strut 
coverage and endothelialization after DES implantation. At the typical observed levels of lumen 
loss after DES, ie, below 0.55 mm, angiographic late loss correlates poorly with stent strut 
coverage by healthy endothelium. Therefore, contemporary studies investigating new generation 
DES technologies have utilized intracoronary imaging to provide a direct measure of the amount 
of neointimal growth. 
Intravascular OCT has emerged as a preferred method to investigate the healing response of 
intracoronary stent implants due to its high resolving power to detect strut tissue coverage and 
vascular healing. OCT can be used to detect morphologic and fine anatomic detail associated with 
stent site healing as well as with the occurrence of restenosis on a tissue level. OCT has also been 
used for the serial assessment of the human coronary response to DES implantation to detail the 
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Some concerns have been expressed with regard to over-interpretation of in vivo OCT imaging for 
ultra-thin tissue layers such as endothelium, in particular with regard to reflectivity artifacts as well 
as fibrin or other noncellular substrates to mimic, and hence undermine, strut coverage 
quantification in vivo. Recently, ex vivo assessment of human coronary artery stent explants have 
compared OCT imaging with histopathology assessment, reporting that a neointimal thickness > 
80 microns covering struts by OCT showed a much-improved correlation with histopathology of 
healthy mature tissue covering DES struts. These observations, grounded in human histopathologic 
correlations, provide the most robust basis for a quantitative approach to the use of OCT imaging 
to assess the recovery of healthy endothelium following DES implantation, especially when 
executed by an independent, blinded, and experienced core laboratory facility. 
A unique aspect of the Combo stent device is the incorporation of an immobilized anti-CD34 
antibody on the stent blood-contacting surface with the intended effect of providing an affinity 
surface for circulating CD34+ cells that are key for neointimal formation and vascular healing.  
Anti-CD34 antibody stents have been shown in acute human ex vivo shunt studies to have rapidly 
adherent cells, which express endothelial markers while showing less thrombus formation. In 
preclinical studies, conventional DESs treated with the immobilized anti-CD34 antibody have 
been shown to have an enhanced endothelial coverage and expression of endothelial functional 
markers over the DES alone. Likewise, the Combo device has also been shown in preclinical 
studies to have an enhanced endothelial coverage and expression of endothelial functional markers 
over conventional DESs while showing similar modulation of the neointimal response expected 
from a DES.45 In the REMEDEE first-in-man randomized trial of the Combo device, the device 
was shown to be noninferior to conventional DESs in the control of neointimal proliferation and 
prevention of restenosis, while intravascular ultrasound and OCT imaging show a more 
homogeneous healing reaction with the Combo stent compared with a contemporary DES, with 
less evidence of inflammation and neoatherosclerosis.46 Therefore, given the unique vascular 
healing behavior of the Combo stent due to the dual nature of sirolimus control of neointima and 
anti-CD34 antibody effect on endothelialization and vessel healing, a subset of patients in both 
cohorts will be assessed with OCT to characterize and compare the neointimal responses, both 
quantitatively and qualitatively, as a surrogate marker of the mechanistic role of the novel biologic 
anti-CD34 antibody component of the device. 
 Objective 
Optical coherence tomography assessment of a subset of patients in the trial will provide important 
mechanistic insight into the healing response of the Combo stent compared with the DES 
comparator. Unlike angiographic late loss studies of DES effectiveness to control restenosis, where 
lower late loss or less tissue is viewed as better, in this OCT assessment a higher neointimal 
thickness without signs of hemodynamic compromise (by FFR) will be viewed as superior, since 
neointimal thickness has been shown to correlate histopathologically with mature 
endothelialization and more mature vessel healing.47 The hypothesis of the imaging-physiology 
substudy is that Combo and the DES comparator have similar low rates of physiologic intrastent 
coronary obstruction at 12-months post-DES implantation, with superior strut level tissue coverage 
thickness observed in the Combo platform. This concept of a “well-healed” stent with healthy 
neointimal coverage while maintaining a good physiological blood flow is illustrated in Figure 9. 

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Figure 9. 
Illustration of the Balance Between Achieving Adequate Neointimal Coverage 
to Protect Against Stent Thrombosis While Maintaining Adequate Blood Flow 
to Prevent Ischemia 
The primary OCT metric will be “strut level tissue coverage thickness” at 1 year in subjects with 
normal FFR, based on automated measurements performed from the center of the luminal surface 
of each strut blooming and its distance to the lumen contour. All visible struts at 0.6-mm intervals 
along the entire stented segments will be measured. Other secondary OCT metrics will include 
percentage of covered struts; percentage of malapposed struts; qualitative and quantitative 
assessment of intraluminal thrombus; and quantitative analysis of lumen, stent and neointimal 
volumes. 
 Sample Size 
To test the difference in mean struts neointimal thickness between the Combo and Xience stent 
types at mean neointimal thickness (subject level), 86 subjects with an allocation ratio 1:1 yield 
> 99% power to detect the difference in neointimal thickness of struts between the 2 stent types. 
The sample size assumes a neointimal thickness of struts difference between 2 stent types equal to 
0.050 mm, a common standard deviation of 0.050 mm, and utilizes a 2-sided, alpha level = 0.05. 
If abnormal positive FFR event rate is estimated as 4% for each stent type, the sample size needed 
for each treatment arm should be adjusted to 43/(1 – 0.04) = 45. Therefore, when accounting for a 
20% dropout rate for follow-up, 57 subjects are required to be randomized in each study arm for 
the OCT substudy.  
 Optical Coherence Tomography Image Acquisition 
The following recommendations are required for proper OCT data acquisition according to the 
study. Please reference the OCT Core Laboratory Guidelines: 
 Select ≥ 6French guiding catheter without side holes.  

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 Give the intracoronary nitroglycerin injection (100–200 mcg) before introduction of the 
OCT device into the coronary. 
 The coronary vessel should be flushed with nondiluted angiographic contrast injected 
through a power injector.  
 Cine should be obtained during the pullback/contrast injection.  
 Primary Neointimal Thickness Quantification by Optical Coherence Tomography 
Strut level analysis of the neointimal thickness will be performed by measuring the distance from 
the center of the stent blooming to the lumen centromere. This measurement will take into 
consideration every strut available in a cross-section image at every 0.6-mm longitudinal interval 
(every third frame). Measurements are illustrated in Figure 10. 
 
 
Figure 10.  Strut Level Analysis of the Neointimal Thickness  
Strut level analysis of the neointimal thickness will be performed by measuring the distance from 
the center of the stent strut blooming to the lumen centromere for each individual strut (red arrows). 
 Secondary Optical Coherence Tomography Assessment 
The OCT image assessment will include the determination of stent morphometric characteristics, 
identification of surrogate endpoints of stent healing and safety, and tissue characterization. These 
secondary assessments are outlined below and endpoints defined in the Appendix: Optical 
Coherence Tomography Image Analysis Parameters. 
 Stent Morphometric Parameters 
Optical coherence tomography images will be assessed for quantification of neointimal tissue 
thickness and lumen area and lumen volume compared with the reference segments.  

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Characterization of stent deployment will include strut coverage and apposition, stent length, stent 
expansion and deformation, and intrastent residual stenosis. 
 Surrogate Safety Parameters 
Optical coherence tomography images will be assessed for evidence of edge dissections, stent 
associated vascular positive remodeling, evidence of stent deformation and stent strut fracture and 
gaps, and the presence of intramural thrombus. 
 Tissue Characterization 
The OCT imaging will be used to characterize the nature of the neointimal tissue through semi-
quantitative assessment of optical density to differentiate fibrin from a mature tissue. A qualitative 
assessment will be performed to differentiate homogeneous predominantly fibrotic tissue 
(neointima) from neoatherosclerosis, defined as tissue with characteristics suggestive of lipid 
and/or calcium. 
 
Angiographic Late Loss Analysis 
 Introduction 
As a surrogate endpoint, late loss has provided useful information on the range of long-term 
luminal dimensions that mechanistically correlate with clinical outcome. Direct comparisons 
between stent platforms, however, may yield statistically significant p-values whose clinical 
relevance is unclear. Logistic regression models have reliably estimated TLR rates for DES and 
BMS based upon angiographic late loss measures.48 However, because of the curvilinearity of the 
logistic model, trials comparing 2 effective DESs can have statistically significant differences in 
angiographic late loss, but small expected differences in TLR risk, especially at the lower ranges 
of late loss.  
Thus an objective performance goal for late loss is highly relevant to interpretation of angiographic 
late loss in new DES platforms. In this study, both the Combo and EES platforms are compared to 
a performance goal to ensure that performance of the Combo is comparable to currently approved 
DES (and superior to BMS). 
 Performance Goal Justification 
To understand the relationships between late loss among approved DESs, (a network meta-analysis 
was performed evaluating DESs, including Cypher, TAXUS, Endeavor, Xience, Nobori, Resolute, 
and Combo to estimate the overall expected differences among each of the stents with regard to 
in-segment and in-stent late loss using a Markov chain Monte Carlo method, treating all BMSs as 
a single therapy (data on file, OrbusNeich Medical). The results are displayed in Figure 11 and 
Figure 12. 
 

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Figure 11. 
In-Stent Late Loss Performance Goal vs Everolimus-Eluting 
Stent 
 
 
 
Figure 12. 
In-Segment Late Loss Performance Goal Relative to 
Everolimus-Eluting Stent 
 

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Consequently, based upon the REMEDEE results alone, the Combo stent is superior to BMS with 
regard to in-stent late loss, in the indirect comparison using the Bayesian network methods to 
account for the indirect relationships in the existing evidence.  
Based upon the lower 95% credible limit observed for BMS in the network meta-analyses, the 
maximum difference (delta) relative to EES that would still preserve superiority to BMS 
is -0.54 mm for in-stent late loss and -0.34 mm for in-segment late loss. This boundary constitutes 
the performance goal for the HARMONEE late loss analysis. 
If we assume the mean late loss is similar to the results observed in SPIRIT III and REMEDEE, 
and a 1-sided alpha of 0.025, then a subsample of 80 subjects (40 per arm) would have 91% power 
to detect noninferiority for in-stent late loss and 62% power to detect noninferiority for in-segment 
late loss and satisfy the performance goal. The primary analysis of late loss will include subjects 
from cohorts A and B evaluated using this performance goal. As a sensitivity analysis, 
angiographic late loss will be assessed including all subjects who have QCA performed as a study 
procedure. 
While late loss measured as a continuous variable may report highly statistically significant 
differences of no clinical relevance, physiologic measurement of lesion severity using FFR 
dichotomously analyzed at the 0.81 threshold has been shown in 2 independent, prospective 
randomized trials to be highly predictive of later clinical events. Thus, for this study, although late 
loss will be reported as a mechanistic observation, abnormal FFR will provide a unique and reliably 
unbiased component of the ischemia-driven TVR secondary endpoint. 
 
Human Anti-Murine Antibody Analysis 
Up to 55 patients assigned to the Combo stent will submit blood samples at baseline, at 30 days, 
and at 12 months for measurement of HAMA levels. All patients will provide written informed 
consent for collection of the plasma samples. A core laboratory will provide binary determination 
of changed HAMA antibody levels indicative of anti-antibody response. 
 Introduction 
Murine monoclonal antibodies (mAbs) have proved tremendously useful. However, when used in 
the treatment of patients with various ailments, their effect is not always sustained. This is often 
due to the development of human anti-mouse antibodies, leading to clearance of the murine mAb 
and adverse events.49 Over the past 2 decades these fears have been somewhat allayed as allergic 
reactions have generally proven to be minor and readily reversed.50,51 Hwang and Foote have 
classified therapies as having negligible immunogenicity when the anti-antibody response was 
reported in less than 2% of patients.52 Immunogenicity this low represents an ideal, with very 
reassuring safety. Immunogenicity is tolerable if detectable in 2% to 15% of patients, with use of 
the antibodies warranted for catastrophic or life-limiting disease. Immunogenicity with anti-
antibody response greater than 15% are usually clinical failures with regulatory concerns likely to 
preclude clinical use.  
HAMA antibody levels have been obtained in at least 120 subjects enrolled in previous evaluations 
of the COMBO stent, and there have been no significant changes in HAMA levels detected in 
previous studies (data on file, OrbusNeich Medical). 

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 Objective 
The HAMA analysis will evaluate the frequency of change in HAMA plasma levels at 30 days 
and at the 12-month follow up compared to baseline. 
 Sampling Procedure 
Patients will have blood drawn through vascular access sheaths or by venipuncture at baseline, at 
30 days, and at the 12-month follow-up. All samples will be submitted to a central core laboratory. 
Blood draws will be performed in all Cohort B patients to preserve blinding to treatment 
assignment. The samples obtained from the 55 patients assigned to the Combo stent in Cohort B 
will assure a minimum of 40 complete sets of samples in case of missed visits, losses to follow-
up, or nonevaluable samples. 
Sampling procedure: 
1. Recommended sampling device: Vacutainer red, without additives. 
For example: Becton Dickinson No. 367812 (4 mL) 
2. Centrifuge clotted samples immediately and separate serum into the PP tubes supplied by 
the core laboratory. Samples should be frozen within one hour after collection. 
3. Storage temperature: < -20°C until delivery. 
4. Hemolyzed and lipemic samples are to be avoided. 
 Human Anti-Murine Antibody Data Analysis Plan 
Analysis of the HAMA prespecified endpoint will include the frequency of increased HAMA 
antibody levels, as determined by the core laboratory. A minimum sample size of 40 patients is 
designed such that assuming alpha = 0.05 and an underlying seroconversion rate of 5 per thousand, 
there will be 86.5% power to exclude an anti-antibody response (AAR) upper bound of 8.0%. 
Further, when a total of 160 device exposures is considered (120 from previous studies and 40 
from the present substudy), the upper 95% binomial confidence limit will exclude an AAR rate 
greater than 2.28% if no anti-antibody response is detected.  
 
Other Planned Analyses 
 Analysis of Baseline Characteristics 
All clinically relevant baseline variables will be tabulated and compared among subjects assigned 
the Combo stent and an EES stent control arm of the study. Categorical variables will be tested 
using appropriate contingency table analyses (exact or chi-square approximations), and continuous 
variables will be tested using unpaired Student’s t-test or Wilcoxon rank-sum test, depending on 
variable distribution. Statistical significance on baseline variables will be declared if the 2-sided 
P-value is less than 0.05. 
 Additional Consistency Analyses 
IF and ONLY IF the overall primary noninferiority endpoints are met, additional consistency 
analyses will be performed: 

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 Superiority testing of primary endpoint of Combo vs EES control 
 Subgroup analyses for consistency of effect: 
o Age 
o Sex 
o Diabetes 
o Renal impairment 
o Clinical presentation 
o Ejection fraction 
o Lesion length 
o Reference vessel diameter 
o Multivessel 
 
Statistical Methods 
 General Statistical Methods 
Noninferiority testing of the primary endpoint with an absolute difference delta of 7.0% will be 
performed (Section 10.8.2.2). Additionally, superiority testing to an imputed BMS control will be 
performed to ensure assay sensitivity (Section 10.8.2.4). 
 Power and Sample Size 
 Event-Rate Estimates 
Event-rate estimates were obtained for an all-comers population based upon the Bern-Rotterdam 
Registry (N=12,339), from which 385 patients were excluded due to loss to follow-up, 
1060 patients were excluded due to LVEF less than 20%, and 210 patients were excluded due to 
cardiogenic shock. Of the remaining 10,684 patients, 3046 were excluded for STEMI, leaving a 
population of 7638 patients who would meet the inclusion and exclusion criteria for the proposed 
study. Clinical-event rates for this population are shown in Table 6 below: 
Table 6. 
12-Month Event Rates Among All-Comers in Bern-Rotterdam Registry, 
Excluding ST-Elevation Myocardial Infarction Subjects, N=7638 
 
Everolimus-Eluting 
Stent (N=1980) 
N (%) 
Sirolimus-Eluting 
Stent (N=2860) 
N (%) 
Paclitaxel-Eluting 
(Stent N=2798) 
N (%) 
Cardiac death/MI/TVR 
(=TVF) 
179 (9.0) 
342 (12.0) 
364 (13.0) 
Cardiac death 
53 (2.7) 
64 (2.2) 
81 (2.9) 
MI 
35 (1.8) 
63 (2.2) 
87 (3.1) 
TVR 
116 (5.9) 
256 (9.0) 
258 (9.2) 
MI, myocardial infarction; N, number; TVF, target-vessel failure; TVR, target-vessel revascularization 

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Notably, the TVF rates for stable coronary artery disease and ACS subgroups within this 
population were similar to the event rates observed for the overall population. This consistency of 
effect across subgroups supports evaluation of a broad subject population in the present clinical 
trial (Table 7). 
Table 7. 
12-Month Event Rates Among Subgroups in Bern-Rotterdam Registry 
Stable Coronary Artery 
Disease (N=4575) 
Everolimus-Eluting 
Stent (N=1148) 
N (%) 
Sirolimus-Eluting Stent 
(N=1749) 
N (%) 
Paclitaxel-Eluting Stent 
(N=1678) 
N (%) 
Cardiac death/MI/TVR 
(=TVF) 
101 (8.8) 
197 (11.3) 
209 (12.5) 
Cardiac death 
23 (2.0) 
30 (1.7) 
38 (2.3) 
MI 
12 (1.1) 
38 (2.2) 
50 (3.0) 
TVR 
75 (6.5) 
152 (8.7) 
151 (9.0) 
ACS, excluding STEMI 
(N=3042) 
Everolimus-Eluting 
Stent (N=831) 
N (%) 
Sirolimus-Eluting Stent 
(N=1105) 
N (%) 
Paclitaxel-Eluting Stent 
(N=1106) 
N (%) 
Cardiac death/MI/TVR 
(=TVF) 
78 (9.4) 
143 (12.9) 
154 (13.9) 
Cardiac death 
30 (3.6) 
33 (3.0) 
43 (3.9) 
MI 
23 (2.8) 
25 (2.3) 
37 (3.4) 
TVR 
41 (4.9) 
103 (9.3) 
106 (9.6) 
ACS, acute coronary syndrome; MI, myocardial infarction; N, number; STEMI, ST-segment elevation myocardial infarction; TVF, 
target-vessel failure; TVR, target-vessel revascularization 
 
Based upon these observations, the statistical analysis plan considers potential TVF event rates 
between 7% and 15%. 
 Identification of a Clinically Acceptable Margin (Delta) 
The clinically acceptable margins used in previous trials of next-generation DESs vary widely, as 
shown in Table 8. 
Table 8. 
Absolute Delta Values for Clinical Trials of Next-Generation Drug-Eluting 
Stents, Assuming 1-Sided Alpha of 0.05 
Trial 
Stent Comparison 
Absolute Difference Delta 
PLATINUM 
Promus Element vs Promus/Xience 
3.5% given TLF 5.5% 
Resolute 
Resolute vs Endeavor 
3.3% given TLF 6.5% 
LEADERS 
Biolimus vs Cypher 
4% given TVF 8% 
TWENTE 
Resolute vs Xience 
4.48% given TVF 12.8% 
TLF, target -lesion failure; TVF, target vessel failure 

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The PLATINUM noninferiority trial comparing the Promus Element stent to the Promus/Xience 
stent used an absolute difference delta of 3.5%, assuming a 1-year TLF rate of 5.5% and 1-sided 
alpha of 0.05.53 The Resolute noninferiority trial comparing the Resolute stent to a historical 
control of Endeavor stents used an absolute difference delta of 3.3%, assuming a 1-year TLF rate 
of 6.5% and 1-sided alpha of 0.05.54 The LEADERS trial comparing a biolimus stent to Cypher 
used an absolute difference delta of 4%, assuming a 9-month TVF rate of 8% and a 1-sided alpha 
of 0.05.55 Finally, the TWENTE trial of Resolute vs Xience stent used an absolute difference delta 
of 4.48%, assuming a 1-year TVF rate of 12.8%, as observed in Endeavor III. Again, the 
noninferiority boundary was expressed for the upper limit of a 1-sided 95% CI assuming a 1-sided 
alpha of 0.05. These boundaries have been determined empirically in the above studies. 
To investigate whether Combo is noninferior to EES, the appropriate null hypothesis is that EES 
is better than Combo by at least the noninferiority margin (delta). The alternative hypothesis is that 
Combo is not worse than EES by the noninferiority margin (delta). The quantification of delta 
should be clinically relevant and statistically feasible. Selection of an appropriate delta value, while 
ideally based on prior data and expectations of performance, should be determined by what is 
clinically meaningful. 
In addition to EES, there are several DESs that are approved for clinical use in Japan, including 
Cypher, Nobori, TAXUS, and Endeavor. There are several studies that have compared these DESs 
to each other and to BMS in various combinations. The effect size of each of the currently approved 
DESs in subjects similar to those in the proposed study population can be summarized in a network 
meta-analysis. The 95% upper credible limit (a Bayesian parameter analogous to the upper 95% 
confidence limit) of these estimates relative to EES indicates a maximum reduction in therapeutic 
response that has already been considered acceptable by the clinical community.  
 Bayesian Network Meta-Analysis 
There are 21 studies that evaluated currently approved DESs in subjects similar to the proposed 
study population and measured TVF between 12 and 18 months. The treatment arms in each study, 
TVF events, and sample sizes are provided in Table 9 below: 
Table 9. 
Network Meta-Analysis of 21 Studies of Currently Approved Drug-Eluting 
Stents vs Everolimus-Eluting Stents 
Study 
Treatment 
TVF Events 
N 
Bern-Rotterdam Registry 
Xience  
179 
1980 
 
Cypher  
342 
2860 
 
TAXUS  
364 
2798 
 
 
 
 
COMPARE 
TAXUS  
82 
903 
 
Xience  
56 
897 

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Study 
Treatment 
TVF Events 
N 
 
 
 
 
COMPARE II 
Xience  
41 
912 
Nobori  
87 
1795 
 
 
 
 
 
 
 
 
Endeavor II 
BMS  
100 
591 
 
Endeavor  
58 
592 
 
 
 
 
Endeavor III 
Cypher  
13 
110 
 
Endeavor  
42 
316 
 
 
 
 
Endeavor IV 
TAXUS  
72 
751 
 
Endeavor  
58 
754 
 
 
 
 
REALITY 
TAXUS  
86 
669 
 
Cypher  
82 
684 
 
 
 
 
Resolute AC 
Xience  
108 
1126 
 
Resolute  
101 
1119 
SIRIUS 
Cypher  
52 
533 
 
BMS 
130 
525 
 
 
 
 
SIRTAX-LATE 
TAXUS  
74 
509 
 
Cypher  
46 
503 
SORT-OUT II 
TAXUS  
120 
1033 
 
Cypher  
106 
1065 
 
 
 
 
SORT-OUT III 
Cypher  
53 
1170 
 
Endeavor  
113 
1162 
 
 
 
 
SORT-OUT IV 
Cypher  
105 
1384 
 
Xience  
99 
1390 

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Study 
Treatment 
TVF Events 
N 
 
 
 
 
SORT-OUT V 
Cypher  
68 
1239 
Nobori  
82 
1229 
 
 
 
 
SPIRIT II 
TAXUS  
7 
77 
 
Xience  
10 
220 
 
 
 
 
SPIRIT III 
TAXUS  
37 
319 
 
Xience  
56 
655 
 
 
 
 
SPIRIT IV 
TAXUS  
92 
1195 
 
Xience  
134 
2416 
 
 
 
 
TAXUS IV 
BMS  
127 
652 
 
TAXUS  
66 
662 
 
 
 
 
TAXUS V 
BMS  
115 
567 
 
TAXUS  
82 
560 
 
 
 
 
TWENTE 
Xience  
56 
692 
 
Resolute  
57 
695 
 
 
 
 
ZEST 
TAXUS  
125 
884 
 
Cypher  
73 
878 
 
Endeavor  
90 
883 
BMS, bare metal stent; N, number; TVF, target-vessel failure 
The results of these studies were combined using network meta-analysis to estimate the effect of 
each treatment relative to EES. Network meta-analysis, or mixed treatment comparison (MTC) is 
a technique to meta-analyze networks of trials comparing 2 or more treatments at the same 
time.56,57 Using a Bayesian hierarchical model, all direct and indirect comparisons are taken into 
account to arrive at a single, integrated estimate of the effect of all included treatments based on 
all included studies. A Markov chain Monte Carlo model was created with 10 Markov chains, each 
using 20,000 tuning iterations followed by 50,000 simulation iterations. Satisfactory convergence 
was verified for all model parameters using the Brooks-Gelman-Rubin method.58 
The relative effects and 95% credible intervals are shown for each stent in Figure 13 below: 

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Figure 13.  Relative Risk (95% credible interval) of Currently Approved Drug-Eluting 
Stents vs Everolimus-Eluting Stents 
Each of the DESs has a 95% credible interval consistent with superiority to BMS. Clinical 
acceptance by healthcare providers of the Endeavor, TAXUS, and Nobori stents in this patient 
population on the basis of currently available studies indicates acceptance of an upper 95% credible 
limit greater than 1.80 relative to EES. Relative to EES, an upper bound of 1.77 would be more 
conservative than the upper bounds for 3 of the 5 approved DESs (Endeavor, TAXUS, and 
Nobori). If the TVF rate is 9% for the EES control arm, a relative upper bound of 1.77 corresponds 
to an absolute margin (delta) of 7%. Based on this evidence, this analysis shows a margin (delta) 
of 7% is clinically justified. 
In the Combo study, we are assuming a 2-sided alpha of 0.05. For a trial population of 
542 evaluable subjects (271 per arm), the study has 81% power to detect noninferiority using an 
absolute difference delta of 7%, assuming a 1-year TVF rate of 9% (Figure 14). 

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Figure 14. Absolute Delta for Various Sample Sizes 
To date the largest randomized device trial in Japan succeeded in enrolling fewer than 
400 subjects.59 In this proposal more than 542 subjects are proposed, the largest randomized 
clinical trial ever conducted for medical devices in Japan. Thus, to create a robust and logistically 
feasible study to support this noninferiority analysis, superiority to an imputed BMS will also be 
required to fulfill the primary endpoint and demonstrate assay sensitivity, as is described below. 
 Comparison to an Imputed Bare Metal Stent Control 
An important statistical consideration for the noninferiority evaluation of next-generation DESs is 
“drift”—the risk that a series of active-control trials might push the general therapy in the wrong 
direction by accepting therapies that are worse than previously approved therapy. In order to 
evaluate Combo stent effectiveness and assay sensitivity, the analysis should examine whether the 
effect of Combo on TVF is superior to the effect of a BMS on TVF, had a BMS arm been present. 
The evaluation of Combo as a third-generation product requires 2 indirect comparisons (Xience 
vs TAXUS, TAXUS vs bare metal) in addition to the direct comparison observed in the trial 
(Combo vs EES). In this particular circumstance, the mandate for assay sensitivity is actually more 
stringent (requiring a risk ratio [RR] difference between 1.1 and 1.3) than the requirement for 
noninferiority (estimated as an RR difference between 1.35 and 1.40). 
The techniques for creating indirect comparisons of a new treatment to placebo have been 
described by several investigators, including Eddy et al. (1992),60 Bucher et al. (1997),61 Fisher 
(1998),62 Hauck and Anderson (1999),63 and Hasselblad and Kong (2001).64 Simon (1999)65 gave 
an equivalent Bayesian method.  

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Using these methods it is possible to estimate how Combo would have performed against a BMS 
had a BMS arm been present. The method takes into account the uncertainty in the trial of the 
investigational stent (Combo) as well as the uncertainty about the active-control stent (EES). The 
imputed control calculations for the trial will be based on the results of the TAXUS IV, TAXUS 
V, SPIRIT II, SPIRIT III, and SPIRIT IV trials.  
First consider the SPIRIT II, SPIRIT III, and SPIRIT IV trials, which evaluated Xience V vs 
TAXUS Express stents, with 1-year TVF rates available in the Xience V IFU. The trial results can 
be summarized as a combined estimate using an Empirical Bayes random-effects model as 
described by Hedges and Olkin (1985).66 This estimator has the property that it reduces to a fixed-
effects estimator if no heterogeneity is present. The estimates were computed using FAST*PRO 
Software (Eddy and Hasselblad, 1992).67 The 1-year TVF rates in these trials are summarized in 
Table 10. 
Table 10. 
One-Year Target-Vessel Failure Rates in the SPIRIT Trials 
Trial 
Xience V 
TAXUS 
Odds Ratio, 95% CI 
Relative Risk, 95% CI 
SPIRIT II 
4.5% (10/220) 
9.1% (7/77) 
0.48 ( 0.17, 1.30) 
0.50 (0.20, 1.27) 
SPIRIT III 
8.5% (56/655) 
11.6 (37/319) 
0.71 ( 0.46, 1.11) 
0.74 (0.50, 1.09) 
SPIRIT IV 
5.5% (134/2416) 
7.7% (92/1195) 
0.70 (0.53, 0.93) 
0.72 (0.56, 0.93) 
Combined 
 
 
0.69 (0.55, 0.87) 
0.71 (0.57, 0.88) 
 
Next consider the TAXUS IV, and TAXUS V trials, which compared TAXUS Express to bare 
metal controls in a variety of anatomic settings11 (TAXUS IFU68; personal communication). The 
1-year TVF results can be summarized as a combined estimate using an Empirical Bayes random-
effects model (Table 11). 
Table 11. 
One-Year Target-Failure Rates in the TAXUS Trials 
Trial 
TAXUS 
Control (Bare Metal Stent) 
Odds Ratio, 95% 
CI 
Relative Risk, 95% 
CI 
TAXUS IV 
10.0% (66/662) 
19.4% (127/652) 
0.46 ( 0.34, 0.64) 
0.51 (0.39, 0.68) 
TAXUS V 
18.7% (105/560) 
25.0% (142/567) 
0.69 ( 0.52, 0.92) 
0.75 (0.60, 0.94) 
Combined 
 
 
0.57 ( 0.43, 0.76) 
0.63 (0.49, 0.82) 
 
The following method is taken from Hasselblad and Kong (2001).64 From these estimates, we can 
obtain an imputed comparison of EES to BMS by multiplying the summary odds ratios (ORs): 
Odds of TVF for EES  =  Odds of TVF for EES        x   Odds of TVF for TAXUS 
Odds of TVF for BMS     Odds of TVF for TAXUS      Odds of TVF for BMS 
 
Because these are all independent estimates, the variance of the imputed EES vs BMS estimate is 
the sum of the variances of the EES vs TAXUS estimate variance of the TAXUS vs BMS estimate. 

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Using the meta-analytic estimates above, the OR for EES BMS is 0.395 with 95% CI 0.275, 0.567. 
Next, consider the relationship between Combo and bare metal:  
 
Odds of TVF for Combo =  Odds of TVF for Combo  x   Odds of TVF for EES        x   
 Odds of TVF for BMS      Odds of TVF for EES            Odds of TVF for TAXUS  
Odds of TVF for TAXUS 
 Odds of TVF for BMS 
 
Odds of TVF for Combo  =  Odds of TVF for Combo  x  Odds of TVF for EES  
Odds of TVF for BMS         Odds of TVF for EES           Odds of TVF for BMS 
 
Again, because these are all independent estimates, the variance of the imputed Combo vs BMS 
estimate is the sum of the variances of the Combo vs EES trial and the estimates for EES vs 
TAXUS and TAXUS vs BMS.  
Using these methods, for any particular control event rate and sample size, we can define a delta 
boundary where there is superiority over BMS (and assay sensitivity). For example, if one selects 
an RR delta of 1.2, assay sensitivity is preserved over the following range of sample sizes, 
depending on the control event rate (Table 12).  
 
 

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Table 12. 
Boundary Sample Size and Control Event Rate, Combo vs Everolimus- 
Eluting Stent; Combo vs Bare Metal Stent  
 
EES 
Event 
Rate 
Boundary 
Event 
Rate 
Boundary 
Sample Size 
Trial Result  
(Combo vs EES) 
Imputed Result  
(Combo vs Bare Metal Stent) 
Relative 
Risk 
Ratio 
95% CI 
Relative 
Risk Ratio 
95% CI 
0.07 
0.084 
540 
(270 
per 
arm) 
1.2 
0.71 
2.02 
0.54 
0.29 
1.00 
0.08 
0.096 
482 
(241 
per 
arm) 
1.2 
0.71 
2.02 
0.54 
0.29 
1.00 
0.09 
0.108 
438 
(219 
per 
arm) 
1.2 
0.71 
2.02 
0.54 
0.29 
1.00 
0.10 
0.120 
402 
(201 
per 
arm) 
1.2 
0.71 
2.02 
0.54 
0.29 
1.00 
0.11 
0.132 
374 
(187 
per 
arm) 
1.2 
0.71 
2.02 
0.54 
0.29 
1.00 
0.12 
0.144 
350 
(175 
per 
arm) 
1.2 
0.71 
2.02 
0.54 
0.29 
1.00 
0.15 
0.180 
300 
(150 
per 
arm) 
1.2 
0.71 
2.02 
0.54 
0.29 
1.00 
EES, everolimus-eluting stent 
Consequently, if one selects a sample size of 542 evaluable subjects (which would provide assay 
sensitivity with an RR delta of at least 1.2 at control event rates of 9% and greater), the boundary 
deltas to assure assay sensitivity are as in Table 13. 
 

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Table 13. 
Boundary Sample Size and Boundary Relative Risk Delta: Combo vs 
Everolimus-Eluting Stent; Combo vs Bare Metal Stent 
EES 
Event 
Rate 
Boundary 
Event 
Rate 
Boundary 
Relative 
Risk Delta 
(Combo vs 
EES) 
Trial Result (Combo vs 
EES) 
Imputed Result (Combo vs 
Bare Metal Stent) 
Odds 
Ratio 
95% CI 
Odds 
Ratio 
95% CI 
0.07 
0.084 
1.200 
1.22 
0.65 
2.30 
0.48 
0.23 
1.00 
0.08 
0.099 
1.238 
1.26 
0.70 
2.29 
0.50 
0.25 
1.00 
0.09 
0.114 
1.265 
1.30 
0.74 
2.27 
0.51 
0.26 
1.00 
0.10 
0.129 
1.285 
1.33 
0.78 
2.26 
0.52 
0.28 
1.00 
0.11 
0.143 
1.304 
1.35 
0.81 
2.26 
0.54 
0.29 
1.00 
0.12 
0.158 
1.317 
1.38 
0.84 
2.25 
0.54 
0.30 
1.00 
0.15 
0.205 
1.367 
1.42 
0.91 
2.22 
0.56 
0.32 
1.00 
EES, everolimus-eluting stent 
 Power to Detect Noninferiority Based on Assay Sensitivity Boundary Conditions 
In the proposed trial, if one assumes that the control and experimental event rates are equal, then 
the power to exclude the assay sensitivity boundaries shown in Figure 13 (above) for each event 
rate is equal to the area to the left of the boundary delta value. On that basis, the power by each 
EES event rate is as shown in Table 14 for a sample size of 542 evaluable subjects: 
Table 14. 
Power to Exclude Assay Sensitivity Boundaries for Each Event Rate 
EES Event 
Rate 
Boundary 
Event Rate 
Boundary Relative Risk 
Delta (Combo vs EES) 
Power to Detect Noninferiority Assuming 
Combo Rate = EES Rate 
0.07 
0.084 
1.200 
0.716 
0.08 
0.099 
1.238 
0.764 
0.09 
0.114 
1.265 
0.800 
0.10 
0.129 
1.285 
0.830 
0.11 
0.143 
1.304 
0.856 
0.12 
0.158 
1.317 
0.877 
0.15 
0.205 
1.367 
0.933 
EES, everolimus-eluting stent 

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DATA AND SAFETY MONITORING 
 
Safety Monitoring 
It is the responsibility of the investigator to oversee the safety of the study at his or her site. This 
safety monitoring will include careful assessment and appropriate reporting of AEs/SAEs, and 
UADEs as noted in Section 7, as well as the construction and implementation of a site data and 
safety monitoring plan (Section 13.4). Medical monitoring will include a regular assessment of the 
number and type of adverse device events. 
 
Data Management to Maintain Blinding 
Data that may potentially reveal treatment assignment will be handled with special care, so that 
before unblinding, such data will be available to only data management staff for purposes of data 
cleaning. 

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DATA MONITORING AND QUALITY CONTROL 
 
Required Data 
The full study dataset will be collected for subjects who enter the randomization phase of the study. 
All required data for this study will be entered into the eCRF. 
 
Data Collection and Tracking 
Qualified study staff at each site will perform primary data collection from source document 
reviews. OrbusNeich Medical or their delegate will perform clinical monitoring, including review 
of eCRFs with verification to the source documentation. 
This study will use Web-based e-CRFs developed through a validated platform that enables 
electronic-reporting-electronic-signatures–compliance platform (21 CFR Part 11). Before 
initiation of the trial, each site will be assessed as to computer availability, hardware specifications, 
and Internet connectivity, to evaluate the site’s capability to use this type of data-collection system. 
The investigator's site staff members who will be entering data will receive training on the system, 
after which each person will be issued a unique user ID and password. 
For security reasons, and in compliance with regulatory guidelines, it is imperative that only those 
persons trained in the system use the system, and each must do so using his or her own unique 
access code. Access codes are nontransferable. Site personnel who have not undergone training 
may not use the system and will not be issued user ID and password until appropriate training is 
completed. 
During monitoring visits, the site will ensure that system access is available to the clinical research 
associate (CRA), so that the CRA may verify the data entries against source documentation. At 
the conclusion of the study, each enrolling site will be provided with a copy of its own subjects’ 
data that includes entries and changes made by the site (ie, the audit trail of changes made to the 
database). This will be maintained at the site according to the requirements for records retention. 

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STUDY RESPONSIBILITIES 
This is a global, multi-site trial that will be conducted at up to 50 sites in Japan and the United 
States. This clinical trial is sponsored by OrbusNeich Medical. The Steering Committee for this 
study will have overall responsibility for the oversight and management of the trial. The Steering 
Committee will include Drs. Saito and Krucoff, PIs, and DCRI representatives. Representatives 
from OrbusNeich Medical will be liaisons to the Steering Committee. 
 
Investigator Responsibility/Performance 
By signing this protocol, OrbusNeich Medical and DCRI agree to be responsible for implementing 
and maintaining quality control and quality assurance systems to ensure that all work incidental to 
this protocol is conducted and data are generated, documented, and reported in compliance with 
the protocol; accepted standards of J-GCP; GCP; and all applicable federal, state, and local laws, 
rules, and regulations relating to the conduct of the clinical study. 
The investigator will provide current copies of the study protocol to all subinvestigators or other 
site personnel responsible for study conduct. 
The investigator will provide OrbusNeich Medical with copies of all EC/IRB reports regarding the 
study. 
 
Study Data Reporting and Processing 
Each page of the eCRF will be reviewed by the investigator at the site. The investigator is required 
to sign the eCRF on the appropriate pages to verify that he or she has reviewed the recorded data. 
This review may be delegated to a qualified physician appointed as a subinvestigator by the 
investigator. The transfer of duties to a subinvestigator will be recorded on the delegation list 
(which is kept on file at the site). The investigator shall inspect the eCRFs prepared by the 
subinvestigators and, upon confirming the content thereof, shall sign and seal, or sign the forms. 
The investigator must ensure that all site staff involved in the conduct of the trial are familiar with 
the protocol and all study-specific procedures, and that they have appropriate knowledge of the 
study agents. 
 
Training 
The training of appropriate clinical site personnel will be the responsibility of OrbusNeich Medical 
or their delegate. The investigator is responsible for ensuring that his or her staff conducts the 
study according to the protocol. To ensure proper administration of study agents, uniform data 
collection, and protocol compliance, OrbusNeich Medical or their delegate will present a formal 
training session to study site personnel, to include instructions for study procedures, the 
investigational plan, instructions on in-hospital data collection, methods for soliciting data from 
alternative sources, schedules for follow-up with the study site coordinators, and regulatory 
requirements. Detailed feedback regarding completion of forms will be provided by OrbusNeich 
Medical or their delegate in the course of regular site monitoring. 
 
Monitoring the Investigational Sites 
As part of a concerted effort to follow the study in a detailed and orderly manner in accordance 
with established principles of J-GCP, GCP, and applicable regulations, an OrbusNeich Medical 
study monitor or their delegate will visit the study sites regularly and will maintain frequent 
telephone and written communication. 

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Periodic monitoring visits will be made at all active investigational sites throughout the clinical 
study to assure that the investigator obligations are being fulfilled and all applicable regulations 
and guidelines are being followed. These visits will assure that the facilities are still acceptable, 
the protocol and investigational plan are being followed, the EC/IRB has approved protocol 
changes as required, complete records are being maintained, appropriate and timely reports have 
been made to OrbusNeich Medical or their delegate and the EC/IRB, study device and study device 
inventory are controlled, and the investigator is carrying out all agreed-upon activities. 
During monitoring visits, the monitor will perform a review of inclusion/exclusion criteria, 
informed consent, HIPAA (Health Insurance Portability and Accountability Act) authorization 
(U.S.), events meeting criteria for expedited event reporting, as well as safety and efficacy 
endpoints. Additional review will be performed on a site-by-site basis, as warranted by the findings 
of previous monitoring visits. Any discrepancies will be noted and resolved. 
During monitoring visits, the site will ensure system access is available to the CRAs so that they 
may verify the data entries against the source documentation. 
 
Study Documentation 
Study documentation includes all eCRFs, source documents, monitoring logs, appointment 
schedules, sponsor-investigator correspondence, and regulatory documents (eg, signed protocol 
and amendments, EC/IRB correspondence and approvals, approved and signed subject consent 
forms, Statement of Investigator form, and clinical supplies receipts and distribution records). 
The investigators will prepare and maintain complete and accurate study documentation in 
compliance with U.S. and Japan GCP standards and applicable country, federal, state, and local 
laws, rules, and regulations; and, for each subject participating in the study, promptly complete all 
eCRFs and such other reports as required by this protocol following completion or termination of 
the clinical study or as otherwise required pursuant to any agreement with OrbusNeich Medical or 
their delegate. 
By signing the protocol, the investigator acknowledges that, within legal and regulatory 
restrictions and institutional and ethical considerations, study documentation will be promptly and 
fully disclosed to OrbusNeich Medical or their delegate by the investigator upon request and also 
shall be made available at the investigator’s site upon request for inspection, copying, review, and 
audit at reasonable times by representatives of OrbusNeich Medical or their delegate or responsible 
government agencies as required by law.  
The investigator agrees to promptly take any reasonable steps that are requested by OrbusNeich 
Medical or their delegate as a result of an audit to cure deficiencies in the study documentation 
and eCRFs. 
 
Source Documentation 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical study. 
Accordingly, source documents include, but are not limited to, laboratory reports, ECG tracings, 
x-rays, radiologist reports, subject diaries, biopsy reports, ultrasound photographs, subject 
progress notes, hospital charts, pharmacy records, and any other similar reports or records of any 
procedure performed in accordance with the protocol. 

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Whenever possible, the original recording of an observation should be retained as the source 
document; however, a photocopy is acceptable provided that it is a clear, legible, and exact 
duplication of the original document. 
Regulations require that investigators maintain information in the study subject’s medical records 
that corroborate data collected on the eCRF. In order to comply with these regulatory requirements, 
the following information will be maintained and made available as required by OrbusNeich 
Medical or their delegate’s monitors and/or regulatory inspectors: 
 Medical history/physical condition of the study subject before involvement in the study 
sufficient to verify protocol entry criteria. 
 Medical record documenting that informed consent was obtained for the subject’s 
participation in the study. 
 Dated and signed notes for each subject visit, including results of examinations. 
 Notations on abnormal laboratory results and their resolution. 
 Dated printouts or reports of special assessments (eg, ECG reports). 
 Description of AEs and follow-up of the AEs (minimally, event description, severity, onset 
date, duration, relation to study drug/device, outcome, and treatment for AE). 
 Notes regarding concomitant medications taken during the study (including start and stop 
dates). 
 Subject’s condition upon completion of or withdrawal from the study. 
 
Protocol Deviations 
A protocol deviation is defined as an event where the investigator or site personnel did not conduct 
the study according to the investigational plan or the Investigator Agreement. 
Investigators are required to obtain approval from the OrbusNeich Medical or their delegate’s 
medical monitor before initiating deviations from the investigational plan or protocol, except 
where necessary to protect the life or physical well-being of a subject in an emergency. Significant 
deviations and approval will be documented in writing and maintained in study files. Unless 
OrbusNeich Medical or their delegate has consented to any such deviations in writing, OrbusNeich 
Medical will not assume any resulting responsibility or liability. Preapproval is generally not 
expected in situations where unforeseen circumstances are beyond the investigator’s control, (eg, 
subject did not attend scheduled follow-up visit, blood sample lost by laboratory); however, the 
event is still considered a deviation. 
Deviations will be reported to OrbusNeich Medical or their delegate regardless of whether 
medically justifiable, preapproved by the medical monitor, or taken to protect the subject in an 
emergency. Subject-specific deviations will be reported. Nonsubject-specific deviations will be 
reported to OrbusNeich Medical or their delegate in writing.  
The EC/IRB will be informed of all protocol changes by the sponsor in accordance with applicable 
regulations and the EC/IRB’s established procedures. No deviations from the protocol of any type 
will be made without complying with all the EC/IRB’s established procedures. 

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Investigators will maintain documentation of the dates and reasons for each deviation from the 
protocol, in compliance with J-GCP guidelines and U.S. 21 CFR 812.140. 
 
Study Supply Accountability 
The investigator (and in Japan, the Device Storage Manager) will maintain records of the receipt 
and disposition of all investigational devices. When the enrollment is complete, the investigator 
(and in Japan, the Device Storage Manager) will be notified by the OrbusNeich Medical or their 
delegate and, in a timely manner, will return all study devices as directed by OrbusNeich Medical 
or their delegate. 
 
Data Transmittal and Record Retention 
Required data will be entered in the eCRF at the time of or as soon as possible after the subject 
visit or the availability of test results. Study sites will transcribe subject source data into eCRFs 
using a computerized electronic data capture (EDC) system. The EDC system is compliant with 
all relevant aspects of GCP. Edit checks, electronic queries, and audit trails are built into the system 
to ensure accurate and complete data collection. Data will be transmitted via the Internet from 
investigational sites to a central site, utilizing state-of-the-art encryption mechanisms to ensure 
security and confidentiality. 
Copies of protocol-specified source documents (eg, hospital discharge summaries, 
operative/procedural reports, and other source documents, as applicable) will be provided to the 
Data Coordinating Center as necessary. Copies of study-related documentation will also be 
retained at the site. 
The investigator will maintain the records of device disposition, final eCRFs, worksheets, and all 
other study-specific documentation (eg, study file notebooks or source documentation) until 
notified by the sponsor that records may be destroyed. OrbusNeich Medical or their delegate will 
be contacted if the investigator plans to leave the institution, so that arrangements can be made for 
the transfer of records. If a marketing application is not filed or is withdrawn, the investigator will 
maintain the records for at least 3 years after the formal discontinuation of the clinical development 
program for this product. In Japan, the head of the medical institution shall appoint a record 
keeping manager, who must retain the relevant records for the specified period. 
As this study is being conducted under a U.S. Investigational Device Exemption application, FDA 
regulations require all investigators participating in clinical drug trials to maintain detailed clinical 
data for one of the following periods: 
 At least 2 years following the date on which an Investigational Device Exemption 
Application is approved by the U.S. FDA  
 2 years after OrbusNeich Medical or their delegate notifies the investigator that no further 
application is to be filed with the U.S. FDA 
The investigator will not dispose of any records relevant to this study without either (1) obtaining 
written permission from the sponsor or (2) providing an opportunity for the sponsor to collect such 
records. The investigator takes responsibility for maintaining adequate and accurate hard-copy 
source documents of all observations and data generated during this study. Such documentation is 
subject to inspection by OrbusNeich Medical or their delegate as well as the FDA and other 
regulatory agencies, as provided by law. 

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Study Closeout 
Upon completion of the study (defined as all subjects have completed all follow-up visits, all 
eCRFs are complete, and all queries have been resolved), OrbusNeich Medical or their delegate 
will notify the site of closeout, and a closeout visit will be performed. All unused study materials 
will be collected and returned to the OrbusNeich Medical or their delegate. The monitor will ensure 
that the investigator’s regulatory files are up-to-date and complete and that any outstanding issues 
from previous visits have been resolved. Other issues to be reviewed at the closeout visit include 
discussing retention of study files, possibility of site audits, publication policy, and notifying the 
EC/IRB of study closure. 
 
Audit/Inspections 
OrbusNeich Medical or their delegate’s quality assurance personnel may conduct audits at the 
study sites. Audits will include, but not be limited to, audit trail of data handling and processes, 
SOPs, device supply, presence of required documents, the informed consent process, and 
comparison of eCRFs with source documents. The investigator agrees to accommodate and 
participate in audits conducted at a reasonable time and in a reasonable manner, as needed. 
Regulatory authorities worldwide may also audit the investigator during or after the study. The 
investigator should contact the sponsor immediately if this occurs and must fully cooperate with 
governmental (eg, FDA, PMDA) audits conducted at a reasonable time and in a reasonable 
manner. 
 
Publication Policies 
Members of the steering committee will be primarily responsible for creation, review, and 
submission of publications and presentations relating to the major aspects of the study and 
approved ancillary analyses within a timely fashion after completion of the study. 
The manuscript containing the overall study results will be distributed to OrbusNeich Medical for 
review before submission to a peer-reviewed journal, but the final content will be at the discretion 
of the Steering Committee. Any other manuscripts containing these data, including abstracts, will 
be distributed to OrbusNeich Medical before submission, with a reasonable period for review. 
Submitted publications will conform to international standards for biomedical manuscripts, 
including those regarding authorship. 
 
Study Committees 
  Principal Investigators and National Coordinators 
Dr. Shigeru Saito (Shonan Kamakura General Hospital) and Dr. Mitchell Krucoff (Duke 
University) will provide academic leadership and day-to-day scientific oversight of the study. They 
will report to the Steering Committee. Drs. Saito and Krucoff will also serve in the role of liaison 
between the Steering Committee and site investigators as well as between the DSMC and the 
Steering Committee. The study will be coordinated on a national basis by Dr. Shigeru Nakamura 
(Kyoto Katsura Hospital) in Japan and Dr. Roxana Mehran (Mount Sinai Hospital) in the United 
States. 

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  Steering Committee 
A Steering Committee will be chaired by Dr. David Kong (Duke Clinical Research Institute), 
providing scientific and operational oversight to the study. The study chair will also serve as the 
liaison to the DSMC. The Steering Committee will monitor all aspects of the study, offer 
suggestions to the Executive Committee based on the DSMC recommendations, and oversee the 
presentation of the trial results and any publications.  
  Executive Operations Committee 
The Executive Operations Committee will be responsible for the day-to-day administrative 
management of the study. This committee will meet periodically by teleconference to monitor 
subject enrollment, clinical site progress, and protocol compliance. This committee will be 
responsible for reviewing the final results, determining the methods of presentation and 
publication, and selection of secondary projects and publications. 
  Data and Safety Monitoring Committee  
The study will be conducted under the auspices of an independent DSMC, whose activities will be 
described in a DSMC charter.  
  Clinical Events Classification Committee  
The CEC will adjudicate the following protocol-specific suspected cardiovascular events as 
defined in the CEC Charter: 
 Cardiac death 
 MI 
 TLR (ischemia driven) 
 TVR (ischemia driven)  
 Stroke and TIA 
 Stent thrombosis (ARC definition) 
The CEC will be blinded to subject treatment assignment as well as the primary results of the 
study.  

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ETHICAL CONSIDERATIONS 
By signing this protocol, the investigator agrees to conduct the study in compliance with the 
protocol; OrbusNeich Medical or their delegate’s SOPs and/or guidelines; the FDA regulations; J-
GCP ordinance, based on the ICH guidelines on GCP (ICH E6, the principles of which have their 
origin in the Declaration of Helsinki); and all other applicable national, federal, state, and local 
laws, rules, and regulations relating to the conduct of the clinical study. 
 
Role of Sponsor 
As the study sponsor, OrbusNeich Medical has overall responsibility for the conduct of the study, 
including assurance that the study meets the regulatory requirements of the PMDA, U.S. FDA and 
regulatory requirements of international regulatory agencies appropriate to the conduct of the study 
in centers outside of the United States. In this study, OrbusNeich Medical will have certain direct 
responsibilities and will delegate other responsibilities to DCRI. DCRI will ensure adherence to 
the sponsor’s general responsibilities (21 CFR 812.40) and other responsibilities as agreed between 
DCRI and the sponsor, eg, selection of investigators (21 CFR 812.43), monitoring 
(21 CFR 312.46), and protocol amendments (21 CFR 312.35). OrbusNeich Medical and DCRI 
will ensure compliance with relevant local regulations and guidelines in the conduct of the study 
in centers outside of the United States. 
 
Informed Consent 
The investigator has both ethical and legal responsibility to ensure that each subject being 
considered for inclusion in this study is given a full explanation of the study. Written informed 
consent will be obtained from all subjects (or their LAR) before any study-related procedures 
(including any pretreatment procedures, such as preprocedure sedation) are performed or given.  
Written informed consent will be documented on an ICF approved by the same EC/IRB 
responsible for approval of this protocol. The ICF will conform to J-GCP regulations, FDA 
regulations in 21 CFR Part 50, and to the institutional requirements for informed consent and 
applicable regulations. The investigator agrees to obtain approval from OrbusNeich Medical or 
their delegate of any ICF intended for use in the study, before submission for IRB approval. 
The ICF will be reviewed with the prospective study subject or his or her LAR, and the investigator 
or qualified designee will be available to answer questions regarding procedures, risks, and 
alternatives.  
Once the appropriate essential information has been provided to the subject and fully explained by 
the investigators or qualified designee, and it is felt that the subject understands the implications 
of participating, the subject or his or her LAR will sign and date the EC/IRB-approved written 
ICF. The subject will receive a copy of the signed ICF. The original signed and dated ICF will be 
kept in the site’s regulatory file. Documentation of the subject’s informed consent for and 
participation in this trial will be noted in the subject’s medical record.  
If the subject is illiterate, an impartial witness is required to be present during the entire informed 
consent reading and discussion. Afterward, the subject should be asked to sign and date the ICF, 
if capable. The witness should also sign and date the ICF along with the individual who read and 
discussed the informed consent (ie, study staff personnel). 

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The subject or his or her LAR will be informed in a timely manner if new information becomes 
available that may be relevant to the subject’s willingness to continue participation in the trial. The 
communication of this information to the subject will be documented. 
 
Confidentiality of Subjects 
Subject confidentiality will be maintained throughout the clinical study in a way that ensures the 
information can always be tracked back to the source data. For this purpose, a unique subject ID 
code (ID number and subject name code) will be used that allows identification of all data reported 
for each subject. 
Subject information collected in this study will comply with the standards for protection of privacy 
of individually identifiable health information as promulgated by U.S. HIPAA and as mandated in 
Title 45 CFR Parts 160 and 164 (U.S.) and J-GCP (Japan). All records will be kept confidential, 
and the subject’s name will not be released at any time. Subject records will not be released to 
anyone other than OrbusNeich Medical or their delegate or its designees and responsible regulatory 
authorities when requested. In all cases, caution will be exercised to assure the data are treated 
confidentially and that the subject’s privacy is protected. 
 
Authorization for Use and Disclosure of Protected Health Information (HIPAA) 
An authorization for use and disclosure of protected health information (PHI) under the HIPAA 
Privacy Rule (45 CFR § 164.102 et seq) will be obtained from every trial subject before or at the 
time of enrollment. It will be presented to, and signed by, the subject at the same time as the ICF. 
The investigator is responsible for obtaining subjects’ (or their LARs’) authorizations and 
signatures and for explaining the elements of the HIPAA authorization form if necessary. 
HIPAA authorization may be either a separate form or included in the study ICF, dependent upon 
local requirements.  
The HIPAA authorization form will contain all elements required under the HIPAA Privacy Rule. 
By law, site IRB approval of the sponsor-provided authorization form for use in this study is not 
required, and no such approval will be sought or requested.. 
The investigator or the site will promptly inform OrbusNeich Medical or their delegate of any 
restrictions on the use or disclosure of PHI of any subject to which the site or the investigator have 
agreed under the Privacy Rule. The investigator or the site will also promptly inform OrbusNeich 
Medical or their delegate of any written revocation of any subject’s HIPAA authorization. 
 
Insurance 
This study is covered under the sponsor’s liability insurance policy. A certificate of insurance 
and/or an information leaflet containing essential information about the insurance coverage can be 
provided by study sites upon request. 
 
Human Subject Protections 
There will be no exclusion from participation in the study on the basis of ethnicity or race. Subjects 
younger than 20 years of age will be excluded from the study, as the target population is adults. 
Women of childbearing potential will have pregnancy testing before randomization to avoid 
potential fetal exposure. Cognitively impaired individuals, prisoners, or other institutionalized 
persons will be allowed to participate only after documented consultation with and approval by 
the EC/IRB. 

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Subjects who are admitted to the hospital for a planned (elective) percutaneous coronary artery 
intervention procedure will be referred to the investigator or authorized designee for screening. 
These subjects will then undergo a screening process, during which subjects will have multiple 
opportunities to ask questions. The investigator or authorized designee will provide a detailed 
discussion of the protocol and answer any remaining questions. The subject will be given time to 
consider study participation. No coercion or undue influence on this decision will be used. Only 
those subjects who give written informed consent and complete enrollment testing before the date 
of planned study device implantation will be considered for participation in the study.  
 
Institutional Review Board/Ethics Committee Review 
The appropriate EC/IRB must approve the protocol and informed consent documents, agree to 
monitor the conduct of the study, and agree to review study progress periodically, at intervals not 
to exceed 1 year. The investigator will provide OrbusNeich Medical or their delegate with 
documentation that the EC/IRB has approved the study before the study may begin. 
In addition, the investigator must provide the following documentation to OrbusNeich Medical or 
their delegate: 
 EC/IRB annual continuing review and reapproval of the protocol, per current regulations 
(Title 21 CFR 812.150 [a][3]), J-GCP guidelines, and 1997 ICH guidelines. 
 EC/IRB approval of revisions to the informed consent documents or any amendments to 
the protocol. Any revisions to the protocol that may increase subject risk exposure must be 
approved before implementation. Administrative changes (such as a change in address or 
phone number) must be sent to ECs/IRBs but do not require their approval. The investigator 
will provide OrbusNeich Medical or their delegate with documentation of all approvals. 
 
Financial Disclosure 
In compliance with 21 CFR 812.110(d), any listed or identified investigator or subinvestigator 
(including the spouse and any dependent children of said individuals) directly involved in the 
treatment or evaluation of research subjects will disclose the following information for the time 
period during which the investigator is participating in the study and for 1 year following 
completion of the study: 
1. Any financial arrangement entered into between OrbusNeich Medical and the investigator, 
whereby the value of the compensation to the investigator for conducting the study could 
be influenced by the outcome of the study. 
2. Any significant payments of other sorts made by OrbusNeich Medical to the investigator 
(or their institution) to support the activities of the investigator that totals more than 
$25,000, exclusive of the costs of conducting this or other clinical studies. 
3. Any proprietary interest held by the investigator in the product being evaluated. 
4. Any significant equity interest in OrbusNeich Medical, including any ownership interest, 
stock options, or other financial interest whose value cannot be readily determined through 
reference to public prices (eg, nonpublicly traded corporation), or any equity interest in a 
publicly traded corporation that exceeds $50,000. 

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REFERENCES 
1.  
Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. 
European Heart Journal. 2012;33(20):2551–2567. doi:10.1093/eurheartj/ehs184. 
2.  
Mehran R, Dangas GD, Kobayashi Y, et al. Short- and long-term results after multivessel 
stenting 
in 
diabetic 
patients. 
J 
Am 
Coll 
Cardiol. 
2004;43(8):1348–1354. 
doi:10.1016/j.jacc.2003.04.004. 
3.  
Rodriguez A, Bernardi V, Navia J, et al. Argentine Randomized Study: Coronary 
Angioplasty with Stenting versus Coronary Bypass Surgery in patients with Multiple-Vessel 
Disease (ERACI II): 30-day and one-year follow-up results. ERACI II Investigators. J Am Coll 
Cardiol. 2001;37(1):51–58. 
4.  
Serruys PW, Unger F, Sousa JE, et al. Comparison of coronary-artery bypass surgery and 
stenting for the treatment of multivessel disease. N Engl J Med. 2001;344(15):1117–1124. 
doi:10.1056/NEJM200104123441502. 
5.  
Coronary artery bypass surgery versus percutaneous coronary intervention with stent 
implantation in patients with multivessel coronary artery disease (the Stent or Surgery trial): a 
randomised 
controlled 
trial. 
Lancet. 
2002;360(9338):965–970. 
doi:10.1016/S0140-
6736(02)11078-6. 
6.  
Nobuyoshi M, Kimura T, Nosaka H, et al. Restenosis after successful percutaneous 
transluminal coronary angioplasty: serial angiographic follow-up of 229 patients. J Am Coll 
Cardiol. 1988;12(3):616–623. 
7.  
Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent 
placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis 
Study Investigators. N Engl J Med. 1994;331(8):496–501. doi:10.1056/NEJM199408253310802. 
8.  
Sousa JE, Costa MA, Abizaid AC, et al. Sustained suppression of neointimal proliferation 
by sirolimus-eluting stents: one-year angiographic and intravascular ultrasound follow-up. 
Circulation. 2001;104(17):2007–2011. 
9.  
Sousa JE, Costa MA, Abizaid A, et al. Lack of neointimal proliferation after implantation 
of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and 
three-dimensional intravascular ultrasound study. Circulation. 2001;103(2):192–195. 
10.  
Morice M-C, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting 
stent with a standard stent for coronary revascularization. N Engl J Med. 2002;346(23):1773–1780. 
doi:10.1056/NEJMoa012843. 
11.  
Stone GW, Ellis SG, Cox DA, et al. One-year clinical results with the slow-release, 
polymer-based, 
paclitaxel-eluting 
TAXUS 
stent: 
the 
TAXUS-IV 
trial. 
Circulation. 
2004;109(16):1942–1947. doi:10.1161/01.CIR.0000127110.49192.72. 

OrbusNeich Medical 
 
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12.  
Morice M-C, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting 
stent with a standard stent for coronary revascularization. N Engl J Med. 2002;346(23):1773–1780. 
doi:10.1056/NEJMoa012843. 
13.  
Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients 
with coronary artery disease. N Engl J Med. 2004;350(3):221–231. doi:10.1056/NEJMoa032441. 
14.  
Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed 
healing 
and 
late 
thrombotic 
risk. 
J 
Am 
Coll 
Cardiol. 
2006;48(1):193–202. 
doi:10.1016/j.jacc.2006.03.042. 
15.  
Mauri L, Hsieh W, Massaro JM, Ho KKL, D’Agostino R, Cutlip DE. Stent thrombosis in 
randomized clinical trials of drug-eluting stents. N Engl J Med. 2007;356(10):1020–1029. 
doi:10.1056/NEJMoa067731. 
16.  
Finn AV, Joner M, Nakazawa G, et al. Pathological correlates of late drug-eluting stent 
thrombosis: strut coverage as a marker of endothelialization. Circulation. 2007;115(18):2435–
2441. doi:10.1161/CIRCULATIONAHA.107.693739. 
17.  
Finn AV, Nakazawa G, Joner M, et al. Vascular responses to drug eluting stents: 
importance of delayed healing. Arterioscler Thromb Vasc Biol. 2007;27(7):1500–1510. 
doi:10.1161/ATVBAHA.107.144220. 
18.  
Ong ATL, McFadden EP, Regar E, de Jaegere PPT, van Domburg RT, Serruys PW. Late 
angiographic stent thrombosis (LAST) events with drug-eluting stents. J Am Coll Cardiol. 
2005;45(12):2088–2092. doi:10.1016/j.jacc.2005.02.086. 
19.  
Chevalier B, Silber S, Park S-J, et al. Randomized comparison of the Nobori Biolimus A9-
eluting coronary stent with the Taxus Liberté paclitaxel-eluting coronary stent in patients with 
stenosis in native coronary arteries: the NOBORI 1 trial--Phase 2. Circ Cardiovasc Interv. 
2009;2(3):188–195. doi:10.1161/CIRCINTERVENTIONS.108.823443. 
20.  
Stone GW, Midei M, Newman W, et al. Comparison of an everolimus-eluting stent and a 
paclitaxel-eluting stent in patients with coronary artery disease: a randomized trial. JAMA. 
2008;299(16):1903–1913. doi:10.1001/jama.299.16.1903. 
21.  
Leon MB, Mauri L, Popma JJ, et al. A randomized comparison of the ENDEAVOR 
zotarolimus-eluting stent versus the TAXUS paclitaxel-eluting stent in de novo native coronary 
lesions 12-month outcomes from the ENDEAVOR IV trial. J Am Coll Cardiol. 2010;55(6):543–
554. doi:10.1016/j.jacc.2009.08.067. 
22.  
Fajadet J, Wijns W, Laarman G-J, et al. Randomized, double-blind, multicenter study of 
the Endeavor zotarolimus-eluting phosphorylcholine-encapsulated stent for treatment of native 
coronary artery lesions: clinical and angiographic results of the ENDEAVOR II trial. Circulation. 
2006;114(8):798–806. doi:10.1161/CIRCULATIONAHA.105.591206. 
23.  
Kandzari DE, Mauri L, Popma JJ, et al. Late-term clinical outcomes with zotarolimus- and 
sirolimus-eluting stents. 5-year follow-up of the ENDEAVOR III (A Randomized Controlled Trial 

OrbusNeich Medical 
 
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of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Cypher 
Sirolimus-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions). JACC 
Cardiovasc Interv. 2011;4(5):543–550. doi:10.1016/j.jcin.2010.12.014. 
24.  
Saito S, Prpic R, Popma JJ, Alexander J, Krucoff MW. The clinical evaluation of the 
Endeavor zotarolimus-eluting coronary stent in Japanese patients with de novo native coronary 
artery lesions: primary results and 3-year follow-up of the Endeavor Japan study. Cardiovasc 
Revasc Med. 2011;12(5):273–279. doi:10.1016/j.carrev.2010.12.007. 
25.  
Planer D, Smits PC, Kereiakes DJ, et al. Comparison of everolimus- and paclitaxel-eluting 
stents in patients with acute and stable coronary syndromes: pooled results from the SPIRIT (A 
Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System) and 
COMPARE (A Trial of Everolimus-Eluting Stents and Paclitaxel-Eluting Stents for Coronary 
Revascularization in Daily Practice) Trials. JACC Cardiovasc Interv. 2011;4(10):1104–1115. 
doi:10.1016/j.jcin.2011.06.018. 
26.  
Kereiakes DJ, Sudhir K, Hermiller JB, et al. Comparison of everolimus-eluting and 
paclitaxel-eluting coronary stents in patients undergoing multilesion and multivessel intervention: 
the SPIRIT III (A Clinical Evaluation of the Investigational Device XIENCE V Everolimus 
Eluting Coronary Stent System [EECSS] in the Treatment of Subjects With De Novo Native 
Coronary Artery Lesions) and SPIRIT IV (Clinical Evaluation of the XIENCE V Everolimus 
Eluting Coronary Stent System in the Treatment of Subjects With De Novo Native Coronary 
Artery Lesions) randomized trials. JACC Cardiovasc Interv. 2010;3(12):1229–1239. 
doi:10.1016/j.jcin.2010.09.014. 
27.  
Stone GW, Rizvi A, Newman W, et al. Everolimus-eluting versus paclitaxel-eluting stents 
in 
coronary 
artery 
disease. 
N 
Engl 
J 
Med. 
2010;362(18):1663–1674. 
doi:10.1056/NEJMoa0910496. 
28.  
Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells 
for angiogenesis. Science. 1997;275(5302):964–967. 
29.  
Hill JM, Zalos G, Halcox JPJ, et al. Circulating endothelial progenitor cells, vascular 
function, 
and 
cardiovascular 
risk. 
N 
Engl 
J 
Med. 
2003;348(7):593–600. 
doi:10.1056/NEJMoa022287. 
30.  
Novel anti-restenosis therapies. The American Journal of Cardiology. 2003;92(6, 
Supplement 1):94–97. doi:10.1016/S0002-9149(03)00922-6. 
31.  
Aoki J, Serruys PW, van Beusekom H, et al. Endothelial progenitor cell capture by stents 
coated with antibody against CD34: the HEALING-FIM (Healthy Endothelial Accelerated Lining 
Inhibits Neointimal Growth-First In Man) Registry. J Am Coll Cardiol. 2005;45(10):1574–1579. 
doi:10.1016/j.jacc.2005.01.048. 
32.  
Duckers HJ, Silber S, de Winter R, et al. Circulating endothelial progenitor cells predict 
angiographic and intravascular ultrasound outcome following percutaneous coronary interventions 

OrbusNeich Medical 
 
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HARMONEE 
 
Protocol Number: VP-0601 
 
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Amendment 1.02/March 16, 2015 
 
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in the HEALING-II trial: evaluation of an endothelial progenitor cell capturing stent. 
EuroIntervention. 2007;3(1):67–75. 
33.  
Klomp M, Beijk MAM, Tijssen JGP, de Winter RJ. One-year clinical outcome in an 
unselected patient population treated with the GenousTM endothelial progenitor cell capturing 
stent. Catheter Cardiovasc Interv. 2011;77(6):809–817. doi:10.1002/ccd.22795. 
34.  
De Bruyne B, Pijls NHJ, Kalesan B, et al. Fractional flow reserve-guided PCI versus 
medical therapy in stable coronary disease. N Engl J Med. 2012;367(11):991–1001. 
doi:10.1056/NEJMoa1205361. 
35.  
Sharkawi T, Cornhill F, Lafont A, Sabaria P, Vert M. Intravascular bioresorbable 
polymeric stents: a potential alternative to current drug eluting metal stents. J Pharm Sci. 
2007;96(11):2829–2837. doi:10.1002/jps.20957. 
36.  
Grube E, Buellesfeld L. BioMatrix Biolimus A9-eluting coronary stent: a next-generation 
drug-eluting stent for coronary artery disease. Expert Rev Med Devices. 2006;3(6):731–741. 
doi:10.1586/17434440.3.6.731. 
37.  
Di Mario C, Ferrante G. Biodegradable drug-eluting stents: promises and pitfalls. Lancet. 
2008;371(9616):873–874. doi:10.1016/S0140-6736(08)60389-X. 
38.  
Guan J, Sacks MS, Beckman EJ, Wagner WR. Synthesis, characterization, and 
cytocompatibility 
of 
elastomeric, 
biodegradable 
poly(ester-urethane)ureas 
based 
on 
poly(caprolactone) 
and 
putrescine. 
J 
Biomed 
Mater 
Res. 
2002;61(3):493–503. 
doi:10.1002/jbm.10204. 
39.  
Guan J, Sacks MS, Beckman EJ, Wagner WR. Biodegradable poly(ether ester 
urethane)urea elastomers based on poly(ether ester) triblock copolymers and putrescine: synthesis, 
characterization and cytocompatibility. Biomaterials. 2004;25(1):85–96. 
40.  
Asplund B, Aulin C, Bowden T, et al. In vitro degradation and in vivo biocompatibility 
study of a new linear poly(urethane urea). J Biomed Mater Res Part B Appl Biomater. 
2008;86(1):45–55. doi:10.1002/jbm.b.30986. 
41.  
Van Minnen B, van Leeuwen MBM, Kors G, Zuidema J, van Kooten TG, Bos RRM. In 
vivo resorption of a biodegradable polyurethane foam, based on 1,4-butanediisocyanate: a three-
year subcutaneous implantation study. J Biomed Mater Res A. 2008;85(4):972–982. 
doi:10.1002/jbm.a.31574. 
42.  
De Bruyne B, Pijls NHJ, Kalesan B, et al. Fractional flow reserve-guided PCI versus 
medical therapy in stable coronary disease. N Engl J Med. 2012;367(11):991–1001. 
doi:10.1056/NEJMoa1205361. 
43.  
Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for 
Percutaneous Coronary Intervention A Report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines and the Society for 

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Cardiovascular 
Angiography 
and 
Interventions. 
Circulation. 
2011;124(23):e574–e651. 
doi:10.1161/CIR.0b013e31823ba622. 
44.  
Patel MR, Dehmer GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AATS/AHA/ASNC 2009 
Appropriateness Criteria for Coronary Revascularization: a report by the American College of 
Cardiology Foundation Appropriateness Criteria Task Force, Society for Cardiovascular 
Angiography and Interventions, Society of Thoracic Surgeons, American Association for Thoracic 
Surgery, American Heart Association, and the American Society of Nuclear Cardiology Endorsed 
by the American Society of Echocardiography, the Heart Failure Society of America, and the 
Society of Cardiovascular Computed Tomography. J Am Coll Cardiol. 2009;53(6):530–553. 
doi:10.1016/j.jacc.2008.10.005. 
45.  
Novel anti-restenosis therapies. The American Journal of Cardiology. 2003;92(6, 
Supplement 1):94–97. doi:10.1016/S0002-9149(03)00922-6. 
46.  
Haude M, Lee SWL, Worthley SG, et al. The REMEDEE trial: a randomized comparison 
of a combination sirolimus-eluting endothelial progenitor cell capture stent with a paclitaxel-
eluting stent. JACC Cardiovasc Interv. 2013;6(4):334–343. doi:10.1016/j.jcin.2012.10.018. 
47.  
Kim J-S, Afari ME, Ha J, et al. Neointimal patterns obtained by optical coherence 
tomography correlate with specific histological components and neointimal proliferation in a 
swine 
model 
of 
restenosis. 
Eur 
Heart 
J 
Cardiovasc 
Imaging. 
2013:jet162. 
doi:10.1093/ehjci/jet162. 
48.  
Pocock SJ, Lansky AJ, Mehran R, et al. Angiographic surrogate end points in drug-eluting 
stent trials: a systematic evaluation based on individual patient data from 11 randomized, 
controlled trials. J Am Coll Cardiol. 2008;51(1):23–32. doi:10.1016/j.jacc.2007.07.084. 
49.  
Hwang WYK, Foote J. Immunogenicity of engineered antibodies. Methods. 2005;36(1):3–
10. doi:10.1016/j.ymeth.2005.01.001. 
50.  
DeNardo GL, Bradt BM, Mirick GR, DeNardo SJ. Human antiglobulin response to foreign 
antibodies: 
therapeutic 
benefit? 
Cancer 
Immunol 
Immunother. 
2003;52(5):309–316. 
doi:10.1007/s00262-002-0350-y. 
51.  
Mirick GR, Bradt BM, Denardo SJ, Denardo GL. A review of human anti-globulin 
antibody (HAGA, HAMA, HACA, HAHA) responses to monoclonal antibodies. Not four letter 
words. Q J Nucl Med Mol Imaging. 2004;48(4):251–257. 
52.  
Hwang WYK, Foote J. Immunogenicity of engineered antibodies. Methods. 2005;36(1):3–
10. doi:10.1016/j.ymeth.2005.01.001. 
53.  
Stone GW, Teirstein PS, Meredith IT, et al. A prospective, randomized evaluation of a 
novel everolimus-eluting coronary stent: the PLATINUM (a Prospective, Randomized, 
Multicenter Trial to Assess an Everolimus-Eluting Coronary Stent System [PROMUS Element] 
for the Treatment of Up to Two de Novo Coronary Artery Lesions) trial. J Am Coll Cardiol. 
2011;57(16):1700–1708. doi:10.1016/j.jacc.2011.02.016. 

OrbusNeich Medical 
 
Protocol 
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54.  
Serruys PW, Silber S, Garg S, et al. Comparison of zotarolimus-eluting and everolimus-
eluting coronary stents. N Engl J Med. 2010;363(2):136–146. doi:10.1056/NEJMoa1004130. 
55.  
Windecker S, Serruys PW, Wandel S, et al. Biolimus-eluting stent with biodegradable 
polymer versus sirolimus-eluting stent with durable polymer for coronary revascularisation 
(LEADERS): a randomised non-inferiority trial. Lancet. 2008;372(9644):1163–1173. 
doi:10.1016/S0140-6736(08)61244-1. 
56.  
Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment 
comparisons. Stat Med. 2004;23(20):3105–3124. doi:10.1002/sim.1875. 
57.  
Lumley T. Network meta-analysis for indirect treatment comparisons. Stat Med. 
2002;21(16):2313–2324. doi:10.1002/sim.1201. 
58.  
Brooks SP, Gelman A. General Methods for Monitoring Convergence of Iterative 
Simulations. Journal of Computational and Graphical Statistics. 1998;7(4):434–455. 
doi:10.1080/10618600.1998.10474787. 
59.  
Kadota K, Muramatsu T, Iwabuchi M, et al. Randomized comparison of the Nobori 
biolimus A9-eluting stent with the sirolimus-eluting stent in patients with stenosis in native 
coronary arteries. Catheter Cardiovasc Interv. 2012;80(5):789–796. doi:10.1002/ccd.23280. 
60.  
Eddy DM, Hasselblad V, Shachter RD. Meta-analysis by the confidence profile method: 
the statistical synthesis of evidence. Boston: Academic Press; 1991. 
61.  
Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment 
comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol. 1997;50(6):683–
691. 
62.  
Fisher LD. Active control trials: what about a placebo? A method illustrated with 
clopidogrel, aspirin and placebo. Journal of the American College of Cardiology. 1998;31, 
Supplement 1:49. doi:10.1016/S0735-1097(98)80866-8. 
63.  
Hauck WW, Anderson S. Some Issues in the Design and Analysis of Equivalence Trials. 
Drug Information Journal. 1999;33(1):109–118. doi:10.1177/009286159903300114. 
64.  
Hasselblad V, Kong, DF. Statistical methods for comparison to placebo in active-control 
trials. Drug Information Journal. 2001;35:435–449. 
65.  
Simon R. Bayesian Design and Analysis of Active Control Clinical Trials. Biometrics. 
1999;55(2):484–487. doi:10.1111/j.0006-341X.1999.00484.x. 
66.  
Hedges LV, Olkin I. Statistical methods for meta-analysis. Orlando: Academic Press; 
1985. 
67.  
Eddy DM, Hasselblad V. FAST*PRO: Software for meta-analysis by the confidence profile 
method. Boston: Academic Press; 1992. 

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68.  
TAXUSTM Express 2TM Paclitaxel-Eluting Coronary Stent System (Monorail and Over-
the-Wire) - P030025. Available at:  
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfTopic/pma/pma.cfm?num=P030025. 
Accessed March 4, 2013. 
 

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APPENDIX 1: 
OPTICAL COHERENCE TOMOGRAPHY IMAGE 
ANALYSIS PARAMETERS 
 
Neointimal Quantification 
 Neointimal thickness: Strut level analysis of the neointimal thickness will be 
performed by the measuring the distance from the center of the stent blooming to 
the lumen centromere. This measurement will take into consideration every strut 
available in a cross-section image at every 0.6-mm longitudinal interval. 
 Neointimal area and neointimal volume (mm2 and mm3, respectively) will be 
obtained at 0.6-mm interval. 
 Binary strut coverage (%) obtained at 0.6-mm interval. 
 
Stent Apposition 
 Malapposition and how prevalent along the stent (defined as space greater than the 
strut thickness between stent strut and vessel wall) 
 Malapposition length (mm): Malapposition length is defined as the longitudinal 
length of the OCT pullback with consecutive cross sectional frame with at least 
1 malapposed strut in every frame. (Every frame interval is 0.2 mm.) 
 Longest malapposition distance (mm): Longest malapposition distance is defined 
as the longest distance from lumen contour to malapposed strut in each 
malapposition length. 
 Identification of the occurrence of segments with malapposition greater than 
20 microns in length (%). 
 
Lumen Quantification 
 Lumen area (mm2): Lumen area is defined as an inside area of luminal surface in 
cross sectional frame within stented segment. Lumen area of all analyzable cross 
sectional frames is measured. Maximum, minimum, and mean lumen area are 
collected in each pullback. 
o Stented segment is defined as the segment from distal stent edge to proximal 
stent edge. 
o Distal stent edge is defined as the first frame with stent struts visible in 3 
out of 4 quadrants. 
o Proximal stent edge is defined as the last frame with stent struts visible in 3 
out of 4 quadrants. 
 Lumen diameter (mm): Lumen diameter is defined a diameter of the lumen area. 
Lumen diameter of all analyzable cross sectional frames in stented segments is 
measured. Maximum, minimum, and mean lumen diameter are collected in each 
pullback. 

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 Lumen volume (mm3): Lumen volume is defined as inside volume of luminal 
surface within stented segment. Lumen volume is calculated from lumen area and 
length of stented segment in each pullback. 
 Reference area (mm2): Reference area is defined as an inside area of luminal surface 
in cross sectional frame within reference segment. 
o Distal reference segment is defined as the segment of 5.0 mm distal from 
distal stent edge. 
o Proximal reference segment is defined as the segment of 5.0 mm proximal 
from proximal stent edge. 
o Reference area of all analyzable cross sectional frames in distal and 
proximal reference segment is measured. Maximum, minimum, and mean 
reference area are collected in each pullback. 
 Reference diameter (mm) 
o Reference diameter is defined as a diameter of the reference area. 
o Reference diameter of all analyzable cross sectional frames in distal and 
proximal reference segment is measured. 
o Maximum, minimum, and mean reference diameter are collected in each 
pullback. 
 Reference volume (mm3) 
o Reference volume is defined as inside volume of luminal surface within 
reference segment.  
o Reference volume is calculated from reference area and length of reference 
segment in each pullback. 
 
Stent Expansion 
 Stent expansion (%) vs reference vessel diameters. Optimal stent expansion is 
defined based on established intravascular ultrasound criteria of optimal stent 
expansion (in-stent minimal lumen area ≥ 90% of the average reference lumen area 
or ≥ 100 % of lumen area of the reference segment with the lowest lumen area). 
 
Intrastent Residual Stenosis  
 Maximal stenosis within the stent. The region of interest/reference will be defined 
between the proximal and distal stent edges, and the minimal cross-section area will 
be automatically detected.  
 
Minimal Lumen Area 
 Identification of cases with minimal lumen area < 4 mm2. 
 
Stent Length 
 Imaged stent length (mm): Imaged stent length is defined as the length from distal 
stent edge to proximal stent edge in the OCT pullback. 

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Edge Dissection  
 Edge dissection: Edge dissection is defined as a disruption of the luminal vessel 
surface in the distal or proximal reference segment.  
 Any dissection on adjacent stent edge is documented in each pullback. 
 Dissection length (mm): Dissection length is defined as longitudinal length with 
dissection on adjacent stent edge.  
 
Thrombus 
 Presence of thrombus: Thrombus is defined as intraluminal mass ≥ 200 µm, with 
no direct continuity with the surface of the vessel wall or a highly backscattered 
luminal protrusion in continuity with the vessel wall and resulting in signal-free 
shadowing. 
 
Stent Deformation/Gap 
 Stent elongation or compression will be evaluated primarily by comparing the 
longitudinal stent length vs the nominal size. 3D reconstructions may be 
informative as well as detail angiographic review.  
 Stent gap will be defined as the presence of any cross-section with at least 
2 quadrants without any stent strut in a region of supposed overlap.  
 
Presence of Neoatherosclerosis (Figure 15) 
 Qualitative analysis of the intrastent material will be performed in order to 
differentiate between homogeneous predominantly fibrotic tissue (neointima) vs 
the presence of neoatherosclerosis, defined as tissue with characteristics suggestive 
of lipid and/or calcium. 
 
 
Figure 15. Presence of Neoatherosclerosis 
A=NIH; B=neoatherosclerosis with predominantly calcified tissue, C=neoatherosclerosis with 
predominantly lipid tissue. 
 
 
Presence of Fibrin (Figure 16)  

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 Semi-quantitative approach for detecting fibrin by measuring the optical density 
(OD) of the tissue will be applied in representative frames of the proximal, mid, 
and distal thirds of the stent. Values of OD < 0.6 will be considered as positive for 
the presence of fibrin. 
 
 
Figure 16. Presence of Fibrin 
Optical density (pixel intensity) of the tissue covering the stent struts normalized for the optical 
density of the stent struts. Optical density =PItissue/PIstrut blooming. 
 

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APPENDIX 2:  INSTRUCTIONS FOR USE/INVESTIGATOR BROCHURE  
 
 
 

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