Clinical trial NCT03606642
Conditions: Coronary Artery Disease Atherosclerosis Stent Placement
Keywords: Cardiovascular disease peripheral vascular disease (PVD) Ischemia
Sponsor: HonorHealth Research Institute
Start date: 2018-11-19; Completion date: 2022-08-08
Enrollment: 50 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to see if one month of dual antiplatelet therapy (DAPT) combined with the placement of the Synergy® Stent with IVUS (intravascular ultrasound) is safe for patients who are at high risk of bleeding (HBR).

Detailed description:
DAPT or Dual Antiplatelet Therapy is a combination of two medications given after a percutaneous coronary intervention (PCI) with a drug eluting stent. DAPT is used to help make the platelets in your blood slick so they don't clump or stick together. If the platelets stick together and form a blood clot in the stent it is called a stent thrombosis and will cause an immediate heart attack or MI.

The medications used for DAPT are low dose Aspirin (81mg) and one of three (3) antiplatelet medications: ticagrelor (Brilinta), clopidogrel (Plavix) or prasugrel (Effient) . The standard length of time to take DAPT after a stent placement is 6 months to 1 year. Dapt is associated with an increased risk of bleeding. Because you are considered to be at a high risk for bleeding due to one or a combination of reasons this study is trying to determine if a shorter use of DAPT in combination with the Synergy® stent and an imaging tool called IVUS used during your PCI procedure is safe and effective to reduce the potential for serious bleeding events and early stent thrombosis.

The Synergy® stent was chosen because of its enhanced method of healing and reduced inflammation of the artery after placement. Because of this the Synergy stent may be a better choice for patients who are at high risk for bleeding and could benefit from a shortened period of DAPT.

Intravascular ultrasound or IVUS provides a visual image of the inside of the coronary artery. It is used in patients undergoing PCI or stent placement for a few reasons; prior to placing the stent it is used to measure the artery's width to select the proper size diameter of a stent, also the length of the blockage to select the appropriate length of the stent and to visualize the amount of narrowing or blockage. After the stent is placed IVUS is used to make sure the stent itself is fully expanded and sits up against the wall of the artery. This is called apposition. If stents are not fully expanded and sit up against the wall of the artery early reblockage may occur. In short the IVUS aids in the ideal placement of the stent.

By using the combination of the Synergy® Stent with the IVUS the expectation is to safely decrease the length of time you take DAPT from 6-12 months to 1 month. With the benefit of decreasing the risk of bleeding events.

Arms: arm 1: Single group of patients undergoing IVUS stent placement for PCI with 30 day DAPT therapy regimen. DAPT therapy consists of Aspirin (325 mg loading dose \[if applicable\] and 81 mg for maintenance dose) and P2Y12 Inhibitor (INFO ABOUT THE DRUGS)
Interventions: intervention 1: Dual Antiplatelet (DAPT) Therapy intervention 2: The Synergy® stent
Intervention descriptions: intervention 1: DAPT - one of three (3) antiplatelet medications: ticagrelor (Brilinta), clopidogrel (Plavix) or prasugrel (Effient) with Aspirin.

Aspirin loading dose (LD) = 325 mg. Aspirin maintenance dose (MD) = 81 mg.

P2Y12 Inhibitor Loading Dose (investigator preference):

Clopidogrel 600 mg PO x 1 or 75 mg PO daily x 4; Prasugrel 60 mg PO x 1; Ticagrelor 180 mg PO x 1.

P2Y12 Inhibitor Maintenance Dose (investigator preference):

Clopidogrel 75 mg PO daily; Prasugrel 10 mg PO daily; Ticagrelor 90 mg PO BID. intervention 2: IVUS guided stent

Protocol documents:
Prot_SAP_000.pdf: 
 
Research Institute 
 
SYNIVUS-DAPT 
SYNergy™ Stent System Implantation with Mandatory 
Intra-Vascular Ultra-Sound Guidance to Examine the 
Safety of Cessation of Dual Anti-Platelet Therapy in High 
Bleeding Risk Patients at One Month  
National Clinical Trial (NCT) Identified Number:  NCT03606642 
IDE G180024-S002 
Principal Investigator: David G. Rizik, MD 
IDE Sponsor: David G. Rizik, MD 
Funded by: Boston Scientific Corporation 
Version Number: V4.1 
 9 September 2019 
 
 
 
 


 
Research Institute 
 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Study Design ........................................................................................................................................ 6 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 7 
2 
INTRODUCTION ............................................................................................................................................ 8 
2.1 
Study Rationale .................................................................................................................................... 8 
2.2 
Background........................................................................................................................................... 8 
2.3 
Risk/Benefit Assessment .................................................................................................................... 9 
2.3.1 
Known Potential Risks ..................................................................................................... 9 
2.3.2 
RiskS ASSOCIATED WITH SYNERGY STENT® IMPLANTATION: ....................... 9 
2.3.3 
Known Potential Benefits .............................................................................................. 13 
2.3.4 
Assessment of Potential Risks and Benefits .............................................................. 13 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 13 
4 
STUDY DESIGN ........................................................................................................................................... 14 
4.1 
Overall Design .................................................................................................................................... 14 
4.2 
Scientific Rationale for Study Design.............................................................................................. 15 
4.3 
End of Study Definition ..................................................................................................................... 15 
5 
STUDY POPULATION ................................................................................................................................ 15 
5.1 
Inclusion Criteria ................................................................................................................................ 15 
5.2 
Exclusion Criteria ............................................................................................................................... 16 
5.3 
Screen Failures .................................................................................................................................. 18 
6 
STUDY INTERVENTION ............................................................................................................................ 18 
6.1 
Study Intervention(s) Administration ............................................................................................... 18 
6.1.1 
Study Intervention Description ..................................................................................... 18 
6.1.2 
Dosing and Administration ............................................................................................ 20 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 21 
6.2.1 
Acquisition and accountability ...................................................................................... 21 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 21 
6.4 
Study Intervention Compliance ........................................................................................................ 22 
6.4.1 
Rescue Medicine ............................................................................................................ 22 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 22 
7.1 
Discontinuation of Study PARTICIPATION ................................................................................... 22 
7.2 
Lost to Follow-Up ............................................................................................................................... 23 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 23 
8.1 
Adverse Events and Serious Adverse Events ............................................................................... 23 
8.1.1 
Definition of Adverse Events (AE) ............................................................................... 23 
8.1.2 
Definition of Serious Adverse Events (SAE) .............................................................. 25 
8.1.3 
Classification of an Adverse Event .............................................................................. 26 
8.1.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 27 
8.1.5 
Adverse Event Reporting .............................................................................................. 27 


 
Research Institute 
8.1.6 
Serious Adverse Event Reporting ............................................................................... 28 
8.1.7 
Reporting Events to Participants ................................................................................. 28 
8.1.8 
Events of Special Interest ............................................................................................. 29 
8.1.9 
Reporting of Pregnancy ................................................................................................ 29 
8.2 
Unanticipated Problems .................................................................................................................... 29 
8.2.1 
Definition of Unanticipated Problems (UP) ................................................................. 29 
8.2.2 
Unanticipated Problem Reporting ................................................................................ 30 
8.2.3 
Reporting Unanticipated Problems to Participants ................................................... 30 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 30 
9.1 
Statistical Hypotheses ....................................................................................................................... 30 
9.2 
The alternative hypothesis states that patients undergoing SYNIVUS-DAPT treatment will 
have lower rates of myocardial infarction or cardiac death. Sample Size Determination .......................... 31 
9.3 
Populations for Analyses .................................................................................................................. 31 
9.4 
Statistical Analyses............................................................................................................................ 31 
9.4.1 
General Approach .......................................................................................................... 31 
9.4.2 
Analysis of the PRIMARY Endpoint ............................................................................ 32 
9.4.3 
Baseline Descriptive Statistics ..................................................................................... 32 
9.4.4 
Planned Interim Analyses ............................................................................................. 32 
9.4.5 
Sub-Group Analyses ..................................................................................................... 33 
9.4.6 
Tabulation of Individual participant Data .................................................................... 33 
9.4.7 
Exploratory Analyses ..................................................................................................... 33 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 33 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 34 
10.1.1 
Informed Consent Process ........................................................................................... 34 
10.1.2 
Study Discontinuation and Closure ............................................................................. 34 
10.1.3 
Confidentiality and Privacy ........................................................................................... 35 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 36 
10.1.5 
Key Roles and Study Governance .............................................................................. 36 
10.1.6 
Safety Oversight ............................................................................................................. 36 
10.1.7 
Clinical Monitoring .......................................................................................................... 36 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 37 
10.1.9 
Data Handling and Record Keeping ............................................................................ 37 
10.1.10 
Protocol Deviations ........................................................................................................ 38 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 38 
10.1.12 
Conflict of Interest Policy .............................................................................................. 39 
10.2 
Abbreviations ...................................................................................................................................... 40 
10.3 
data SAFETY MONITORING cOMMITTEE................................................................................... 42 
10.4 
IVUS ACQUISITION PROTOCOL .................................................................................................. 43 
Protocol Amendment History .............................................................................................................................. 44 
11 
REFERENCES ............................................................................................................................................. 45 
 


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STATEMENT OF COMPLIANCE 
 
(1) [The trial will be carried out in accordance with International Conference on Harmonization 
Good Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
SYNERGY™ Stent System Implantation with mandatory Intra-Vascular 
Ultra-Sound Guidance to Examine the Safety of Cessation of Dual Anti-
Platelet Therapy in High Bleeding Risk Patients  One Month (SYNIVUS-
DAPT) 
Study Description: 
This is a prospective multicenter single-arm study designed to characterize 
the safety of 1 month of dual antiplatelet therapy (DAPT) in a patient 
population who are at increased risk for bleeding who are undergoing iLab 
IVUS-guided percutaneous coronary intervention (PCI) with a SYNERGY 
Everolimus-Eluting Platinum Chromium Coronary Stent System (SYNERGY™ 
Stent System).   We hypothesize that the 1 to 13 month rates of Cardiac 
Death or Myocardial Infarction (SCAI definition), and Stent thrombosis 
after Boston Scientific IVUS-guided SYNERGY™ Stents implantation will be 
low and provide key hypothesis generating information to inform future 
larger-scale clinical studies 
Objectives: 
 
Primary Objectives:  
To determine the safety of 1-month DAPT in a High Bleeding Risk (HBR) 
patient population who are undergoing SYNERGY™ stent implantation. 
Endpoints: 
Primary Endpoint:  
• 
Rate of cardiac death or myocardial infarction (SCAI definition) from 1 
to 13 months post-index procedure in the “as treated” (eligible for 30 
day DAPT cessation) population. 


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Secondary Endpoints 
• 
Rate of cardiac death or myocardial infarction (SCAI definition) from 1 
to 13 months post-index procedure in the overall enrolled “intent-to-
treat” patient population  
 
• 
Rate of Academic Research Consortium (ARC) definite/probable stent 
thrombosis (ST) involving SYNERGY ™Stents from 1 to 13 months post-
index procedure  
• 
Rate of major bleeding (GUSTO severe/life threatening + moderate) 
from 1 to 13 months post-index procedure 
• 
Ischemia-Driven (ID) Target Lesion Revascularization,  
• 
ID Target Vessel Revascularization,  
• 
Target Lesion Failure,  
• 
Target Vessel Failure,  
• 
All-Cause Death, and  
• 
All-Cause Death or MI. 
 
Study Population: 
Approximately 100 evaluable patients will be enrolled in this study with 
the possibility to expand enrollment to two hundred thirty one (231). 
 
General Inclusion Criteria:  
1. Subject is considered at high risk for bleeding, defined as meeting one 
or more of the following criteria at the time of enrollment:   
• 
≥ 75 years of age and, in the opinion of the investigator, the risk of 
bleeding associated with >1 months of DAPT outweighs the 
benefit,  
• 
Need for chronic or lifelong anticoagulation therapy 
• 
History of major bleeding (severe/life threatening or moderate 
bleeding based on the GUSTO classification) within 12 months of 
the index procedure, 
• 
History of stroke (ischemic or hemorrhagic),  
• 
Renal insufficiency (creatinine ≥2.0 mg/dl) or failure (dialysis 
dependent),  
• 
Platelet count >20,000/µL to ≤100,000/μL 
• 
In the opinion of investigator, patient is at significant risk of falling 
• 
Patient abuses drugs or alcohol 
• 
Hemoglobin <11.0 u/dl 
2. Subject must be 18 years of age 
3. Subject must be able to take study required dual antiplatelet therapy 
(1 month of P2Y12 inhibitor and aspirin, 13 months of antiplatelet 
monotherapy) 


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4. Subject is willing to comply with all protocol requirements, including 
agreement to stop taking P2Y12 inhibitor at the 1-month milestone if 
eligible per protocol  
5. Subject (or legal guardian) understands the trial requirements and the 
treatment procedures and provides written informed consent before 
any trial-specific procedures are performed 
 
Angiographic Inclusion Criteria 
1. Subject must have had implantation of at least one SYNERGY™ Stent 
and the use of Boston Scientific IVUS for guided stent implantation 
2. All implanted stents must be post dilated and  must meet the 
following IVUS success criteria: 
a) Treated lesions in which the stent cross sectional area exceeds 
the distal reference cross sectional area 
b) If the stent cross sectional area is less than the distal reference 
cross sectional area additional post-dilatation must be 
performed, followed by repeat IVUS.  
c) Above IVUS criteria must be met after the 2nd post dilatation 
Note: if the IVUS criteria is not met after the 2nd post dilatation the 
patient is excluded 
3. Stent procedure performed by an approved investigator 
4. Vessel diameter > 2.25 mm and < 4.0 mm  and lesion length < 34mm  
5. Pre-dilatation is up to the discretion of the investigator 
 
General Exclusion criteria:  
1. Subject with an indication for the index procedure of acute ST 
elevation MI (STEMI) 
2. Subject with an indication for the index procedure of Non ST elevation 
MI (NSTEMI), based on the 3rd Universal MI definition 
3. Subject with treatment with another coronary stent, other than a 
SYNERGY™ stent during the index procedure 
4. Subject with a planned staged procedure > 7 days following the index 
procedure. (Note: Planned staged procedures are allowed if 
performed within 7 days of the index procedure and only when 
SYNERGY™ stents are used for both the index and staged procedures). 
Discontinuation of DAPT should occur 1 month after the last PCI 
procedure is completed 
5. A staged procedure cannot be in a 3rd epicardial vessel if 2 epicardial 
vessels were treated during the index procedure  
6. Subject has a known allergy to: 
• 
 Contrast (that cannot be adequately pre-medicated)  


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• 
 SYNERGY™ Stent system (e.g., everolimus. structurally 
related compounds, polymer or individual components) or  
• 
Protocol-required concomitant medications( all P2Y12 
inhibitors and aspirin)  
7. Subject previously treated at any time with intravascular 
brachytherapy 
8. Subject has an active peptic ulcer or active gastrointestinal (GI) 
bleeding 
9. Subject is participating in an investigational drug or device clinical trial 
that has not reached its primary endpoint (Note: registry, 
observational, data collection studies are not exclusionary) 
10. Subject intends to participate in an investigational drug or device 
clinical trial within 12 months following the index procedure (Note: 
registry, observational, data collection studies are not exclusionary) 
11. Subject is judged inappropriate for discontinuation from P2Y12 
inhibitor use at 1 month, due to another condition requiring chronic 
P2Y12 inhibitor use  
• 
If at the 30 day visit the patient has had a peri-procedural 
NSTEMI with an enzyme elevation >5% of the upper 99th 
percentile of either CK-MB or Troponin, the subject should 
not be taken off DAPT. 
12. Subject with planned surgery or procedure necessitating 
discontinuation of P2Y12 inhibitor within (<)1 month following index 
procedure 
13. Subject is a woman who is pregnant or nursing 
14. Subject with a current medical condition with a life expectancy of less 
than 12 months 
15. Subject with implantation of a drug-eluting stent other than 
SYNERGY™ Stents within 11 months prior to index procedure 
16. Have been previously consented for this trial and screen failed 
17. Any other clinically significant comorbidities, which in the judgment of 
the Investigator, could compromise compliance with the protocol, 
interfere with interpretation of the study results, or predispose the 
patient to safety risks. 
 
Angiographic Exclusion Criteria 
1. Target lesion(s) is located within a saphenous vein graft or an arterial 
graft 
2. TIMI flow 0 (total occlusion)  
3. Target lesion(s) is located in the left main 


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4. Potential Target lesion(s) that involve a complex bifurcation (i.e. 
bifurcation lesion requiring treatment with more than one stent) 
5. Thrombus, or possible thrombus, present in the target vessel (by visual 
estimate) 
6. Patients requiring a treatment of more than two native epicardial 
vessels  
7. More than three lesions in two epicardial vessels unless they can be 
covered by one stent.  
8. In-stent restenosis of target lesion 
9. Treatment of non-target lesions or lesions not treated with a Synergy™ 
stent 
10. Subject who did not receive Boston Scientific IVUS guided stent 
implantation and assessment 
11. Any target lesion that has not been post dilated and has not had post 
dilatation IVUS 
12.  Patients who do not meet the following IVUS success criteria:  
• 
Target lesion(s) in which the stent cross sectional area is less than 
the distal reference cross sectional area and additional post-
dilatation is not performed, followed by repeat IVUS. 
** Note: If the  IVUS criteria is not met after the 2nd post dilatation 
the patient is excluded 
 
Phase 
Pilot 
Description of 
Sites/Facilities Enrolling 
Participants: 
The study will be conducted at HonorHealth System within the Phoenix, 
Arizona metropolitan area, and two institutions outside of the 
HonorHealth System. All Institutions within the HonorHealth system will 
collectively be considered a single “site”.    All sites have recognized 
expertise with Boston Scientific IVUS guided stent implantation and will 
use IVUS to perform the procedures. The study will not be conducted 
outside the United States and its territories. Additional sites may be added 
pending enrollment rates.   
Description of Study 
Intervention: 
This is a study designed to follow patients whom have received IVUS-
guided Implantation of the SYNERGY™ Stents and discontinued DAPT at 1 
month.  
Study Duration: 
24 Months 
Participant Duration: 
13 Months 
Total Number of Patients: 
      231 
 


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1.2 
STUDY DESIGN  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Scheduled for Cardiac Cath with PCI 
Draw protocol required labs. Administration of P2y12 and 
ASA loading dose prior to the procedure per study 
Successful PCI with Synergy Stent and Post Procedure IVUS 
imaging. Post procedure required labs, ekg and 2 sets of 
cardiac enzymes 6-8 hours apart 
Complex or unsuccessful PCI (meets 
exclusion criteria) 
Known to have HBR (High Bleeding Risk) as indicated by the 
inclusion criteria  
Discharged on daily dose of DAPT 
Follow up at 60 days post PCI to assess for adverse events, 
SAEs and targeted endpoints 
Exclusion from study and is placed on 
DAPT according to investigators standard 
of practice 
Continue on Antiplatelet Monotherapy 
(ASA preferred) 
Follow up at 7 months and 13 months post PCI to 
assess for adverse events, SAEs and targeted 
endpoints 
30 days post PCI: Evaluated for cardiac events: 
recurring angina, unstable angina, revascularization 
(TLR or other) or another condition in the opinion of 
the investigator would prevent stopping DAPT 
Consent for SynIVUS study 


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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Screening/ 
Baselinea 
Index 
Procedure 
(Day 1) 
Post-Index 
Procedureb 
(Prior to 
discharge) 
30 Days       
(+ 7 days  
Post PCI ) 
(in office) 
60 days  
(+7 days) 
Post PCI  
(In office 
or via 
phone) 
7 months 
(+14 daysi) 
Post PCI 
(In office 
or via 
phone) 
13 Months   
(+ 30 daysj)   
Post PCI 
(In office or 
via phone) 
Informed 
Consent 
X 
 
 
 
 
 
 
H&Pc 
X 
 
 
 
 
 
 
CBC w Diff, 
platelets 
X 
 
X 
 
 
 
 
BMP 
X 
 
X 
 
 
 
 
PT/INR 
(only if on 
warfarin, liver 
disease or 
severe 
anemia 
X 
 
X 
 
 
 
 
CPK, CK-MB 
or Troponin-I 
X 
 
Xd 
 
 
 
 
EKG 
X 
 
X 
 
 
 
 
ConMeds 
(Only Cardiac  
X 
 
X 
X 
X 
X 
X 
Cardiac Cath 
w PCI 
 
X 
 
 
 
 
 
ASA LD 
Xe 
 
 
 
 
 
 
ASA MD 
 
Xf 
 
X 
 
X 
X 
P2Y12 LD 
 
Xg 
 
 
 
 
 
P2Y12 MD 
 
 
Xh 
X 
 
X 
X 
AE 
assessment 
 
X 
X 
X 
X 
X 
X 
Angina 
assessment k 
 
 
 
X 
X 
X 
X 
Angina  
Questionnaire 
 
 
 
X 
 
 
 
EDC 
Completion 
X 
X 
X 
X 
X 
X 
X 
 
 


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a to be completed < 7 days prior to Index procedure 
b To be completed within 24 hours after Index procedure 
c Determination of high risk of bleeding (HRB) 
d Perform 2, 6-8 hours apart, if cardiac enzyme levels are elevated (i.e. exceed the upper limits of normal 
as defined by local guidelines), serial measurements be performed until a decline is noted. If same day 
discharge draw one set immediately post PCI then 2nd set @ 6-8 hours after 
e Aspirin loading dose (LD) = 325 mg.  Start day of procedure (if not on chronic ASA) 
f Aspirin maintenance dose (MD) = 81 mg.  Start the day after aspirin loading dose 
g P2Y12 Inhibitor Loading Dose (investigator preference): clopidogrel 600 mg PO x 1 or 75 mg PO daily x 
4; prasugrel 60 mg PO x 1; ticagrelor 180 mg PO x 1.  Start within 7 days of procedure. 
h P2Y12 Inhibitor Maintenance Dose (investigator preference): clopidogrel 75 mg PO daily; prasugrel 10 
mg PO daily; ticagrelor 90 mg PO BID.  Start day after P2Y12 inhibitor loading dose 
i 6 months post DAPT cessation 
j 12 months post DAPT cessation 
k  Angina Assessment only at 60 days, 7 months and 13 months  
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 The purpose of this study is to examine whether discontinuation of Dual Anti-platelet Therapy (DAPT) at 
1 month after IVUS-guided implantation of the SYNERGY™Stent is feasible. 
 
2.2 
BACKGROUND  
 
Numerous preclinical studies have shown enhanced healing and reduced inflammation with the 3rd 
generation SYNERGY™ Stents relative to second generation Permanent Polymer DES1, 2, and 3.  Optical 
Coherence Tomography (OCT) findings suggest complete or near-complete endothelialization of the 
SYNERGY™ Stent at 1, 2, and 3 months4,5,6.  Mounting clinical evidence suggests a favorable safety and 
efficacy profile in selected patient populations7,8, real-world patient populations9,10, complex patients 
where DAPT has been discontinued at 3-months11 and elderly patients (over 74 years of age) in which 
DAPT was discontinued at 1 month. Of particular note for the group of elderly patients studied with 1 
month DAPT discontinuation is that no patient who received a SYNERGY stent implant experienced a 
Stent Thrombosis after discontinuing DAPT at 1 month.12 
Additionally, numerous studies have demonstrated the benefit of IVUS-guided implantation of coronary 
stents13,14 in terms of the safety and efficacy benefits.  
 
The goal of this study would be to combine the pro-healing design features of the SYNERGY™ Stents 
with a known procedural predictor of good outcomes (IVUS) and test the two in combination in an 
environment where dual antiplatelet therapy is discontinued at one month.  


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Boston Scientific is currently undertaking a well-powered study of DAPT discontinuation (EVOLVE Short 
DAPT) in EVOLVE II anatomically similar patients that are at high risk of bleeding. This study intends to 
supplement these data and is substantially different from EVOLVE SHORT DAPT in the following ways:  
 
1. The study is intended to provide important evidence regarding the role of IVUS-guided stenting to 
facilitate the early cessation of DAPT. 
 
2. SYNIVUS-DAPT examines DAPT cessation at 1 month as opposed to 3 months. To our knowledge, 
there are no other U.S. studies addressing this time course of DAPT discontinuation with any currently 
approved stents. 
 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS 
2.3.2 RISKS ASSOCIATED WITH SYNERGY STENT® IMPLANTATION: 
 
The SYNERGY™ Everolimus-Eluting Platinum Chromium Coronary Stent System (SYNERGY Stent® System) 
is a device/drug combination product consisting of a drug/polymer-coated balloon expandable stent, 
pre-mounted on a Monorail (MR) or Over-The-Wire (OTW) delivery catheter.  The stent is made from a 
platinum chromium alloy (PtCr), which consists of platinum, chromium, iron, nickel, and molybdenum.  
It is indicated for improving luminal diameter in patients, including those with diabetes mellitus, with 
symptomatic heart disease, stable angina, unstable angina, non-ST elevation MI or documented silent 
ischemia due to atherosclerotic lesions in native coronary arteries ≥2.25 mm to ≤4.0 mm in diameter in 
lesions ≤34 mm in length.  The use of this product carries the risks associated with coronary artery 
stenting, including stent thrombosis, vascular complications, and/or bleeding events.  Therefore this 
product should not be used in patients who are not likely to comply with recommended antiplatelet 
therapy. 
 
Potential adverse events (in alphabetical order) which may be associated with the use of a coronary 
stent in native coronary arteries include but are not limited to: 
Abrupt stent closure 
Acute myocardial infarction 
Allergic reaction to anti-coagulant and/or antiplatelet therapy, contrast medium, or stent materials 
Angina 
Arrhythmias, including ventricular fibrillation and ventricular tachycardia 
Arteriovenous fistula 
Bleeding 
Cardiac tamponade 
Cardiogenic shock/pulmonary edema 


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Coronary aneurysm 
Death 
Dissection 
Emboli, distal (air, tissue or thrombotic material or material from device(s) used in the procedure) 
Heart failure 
Hematoma 
Hemorrhage, which may require transfusion 
Hypotension/hypertension 
Infection, local or systemic 
Ischemia, myocardial 
Pain, access site 
Perforation or rupture of coronary artery 
Pericardial effusion 
Pseudo aneurysm, femoral 
Renal insufficiency or failure 
Respiratory failure 
Restenosis of stented segment 
Stent embolization or migration 
Stent deformation, collapse, or fracture 
Stent thrombosis/occlusion 
Stroke/cerebrovascular accident/transient ischemic attack 
Total occlusion of coronary artery 
Vessel spasm 
Vessel trauma requiring surgical repair or re-intervention 
 
Zortress™, the oral formulation of everolimus developed by Novartis Pharmaceuticals Corporation, has 
been evaluated in clinical trials and is approved in the United States for the prevention of organ 
rejection in adult kidney transplant recipients at the dose of 1.5 mg/day. Outside the U.S., 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 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 following list includes the known risks of everolimus at the oral doses listed above: 
Abdominal pain (including upper abdominal pain 
Anemia 
Angioedema 
Anorexia 
Asthenia 
Constipation 
Cough 
Delayed wound healing/fluid accumulation 
Diarrhea 
Dyslipidemia (including hyperlipidemia and hypercholesterolemia) 


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Dysgeusia 
Dyspepsia 
Dyspnea 
Dysuria 
Dry skin 
Edema (peripheral) 
Epistaxis 
Fatigue 
Headache 
Hematuria 
Hyperglycemia (may include new onset of diabetes) 
Hyperkalemia 
Hyperlipidemia 
Hypertension 
Hypokalemia 
Hypomagnesemia 
Hypophosphatemia 
Increased serum creatinine 
Infections and serious infections: bacterial, viral, fungal, and protozoal infections (may include herpes 
virus infection, polyoma virus infection which may be associated with BK virus associated nephropathy, 
and/or other opportunistic infections) 
Insomnia 
Interaction with strong inhibitors and inducers of CYP3A4 
Leukopenia 
Lymphoma and other malignancies (including skin cancer) 
Male infertility (azospermia and/or oligospermia) 
Mucosal inflammation (including oral ulceration and oral mucositis) 
Nausea 
Neutropenia 
Non-infectious pneumonitis 
Pain; extremity, incision site and procedural, back, chest, musculoskeletal 
Proteinuria 
Pruritus 
Pyrexia 
Rash 
Stomatitis 
Thrombocytopenia 
Thrombotic microangiopathy (TMA)/Thrombotic thrombocytopenic purpura (TTP)/Hemolytic uremic 
syndrome (HUS) 
Tremor 
Upper respiratory tract infection 
Urinary tract infection 


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Vomiting 
 
The amount of drug that circulates in the bloodstream following implantation of a SYNERGY™ Stentis 
several folds lower than that obtained with oral doses (1.5 mg to 20 mg/day). 
 
There may be other potential adverse events that are unforeseen at this time. 
 
RISKS ASSOCIATED WITH DUAL ANTIPLATELET THERAPY 
P2Y12 Inhibitors: 
The main adverse event of this class of agents is bleeding. 
The choice of P2Y12 inhibitor is at the investigator’s discretion. 
 
Clopidogrel (Plavix®) 
For more information on clopidogrel please see clopidogrel or Plavix® package insert. 
 
Prasugrel (Effient®) 
Prasugrel can cause significant, sometimes fatal, bleeding. 
Do not use prasugrel in patients with active pathological bleeding or a history of transient ischemic 
attack or stroke. 
In patients who are ≥ 75 years of age, prasugrel is generally not recommended because of the increased 
risk of fatal and intracranial bleeding and uncertain benefit, except in high-risk patients (diabetes or 
prior MI), where its effect appears to be greater and its use may be considered. 
Do not start prasugrel in patients likely to undergo urgent coronary artery bypass graft surgery (CABG). 
When possible, discontinue prasugrel at least 7 days prior to any surgery. 
Additional risk factors for bleeding include: 
• Body weight < 60 kg 
• Propensity to bleed 
• Concomitant use of medications that increase the risk of bleeding 
 
Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, 
percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of prasugrel. 
If possible, manage bleeding without discontinuing prasugrel. Stopping prasugrel, particularly in the first 
few weeks after acute coronary syndrome, increases the risk of subsequent cardiovascular events. 
For more information on pasugrel please see Effient® package insert. 
 
Ticagrelor (Brilinta®) 
Ticagrelor, like other anti-platelet agents, can cause significant, sometimes fatal bleeding. 
Do not use ticagrelor in patients with active pathological bleeding or a history of intracranial 
hemorrhage. 
Do not start ticagrelor in patients undergoing urgent coronary artery bypass graft surgery (CABG). 
If possible, manage bleeding without discontinuing ticagrelor.  Stopping ticagrelor increases the risk of 
subsequent cardiovascular events. 


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Maintenance doses of aspiring above 100 mg reduce the effectiveness of ticagrelor and should be 
avoided. 
For more information on ticagrelor please see Brilinta® package insert. 
 
RISKS ASSOCIATED WITH STUDY PARTICIPATION: 
In addition to the aforementioned risks associated with the implantation of coronary stents, the use of 
everolimus, and the use of dual antiplatelet therapy after stent implantation may increase the risk of 
bleeding. Conversely, discontinuation of P2Y12 inhibitor may have additional risks, including stent 
thrombosis or myocardial infarction.  There may be additional risks linked to the procedure which are 
unforeseen at this time.   
2.3.3 KNOWN POTENTIAL BENEFITS  
Anticipated benefits include the effective treatment of coronary artery stenosis and improvement in the 
symptoms of coronary artery disease. Subjects who receive the SYNERGY™ Stent may have better vessel 
healing, a lower risk of stent thrombosis, and less of a need for prolonged dual antiplatelet therapy.  A 
shortened duration of dual antiplatelet therapy after stent implantation may decrease the risk of 
bleeding reduce cost, and reduce delays in non-cardiac procedures that require cessation of DAPT.  This 
clinical trial has been designed to investigate potential benefits of the SYNERGY™ Stent with a shortened 
duration of dual antiplatelet therapy.  
2.3.4 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
Evaluation of the risks and benefits that are expected to be associated with use of the SYNERGY™ Stent 
demonstrate that when used under the conditions intended, the benefits associated with use of the 
SYNERGY™ Stent should outweigh the risks and the SYNERGY™ Stent is suitable for its intended purpose.  
Based on the healing profile of the SYNERGY™ Stent near-complete endothelialization of the stent 
occurs at 30 days), it is expected that treatment with  30 days of DAPT will be safe in the patient 
population defined by the study selection criteria and more specifically in patients at high risk for 
bleeding, and may result in benefits such as avoidance of additional bleeding, cost and delay of non-
cardiac procedures relative to a strategy of longer-term DAPT in the setting of current durable polymer 
drug. 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
 
 
 
To determine the safety of 1-
month DAPT in a HBR patient 
population who are undergoing 
SYNERGY stent implantation. 
Primary Endpoint:  
• 
Rate of cardiac death or 
myocardial infarction (SCAI 
definition) from 1 to 13 months 
post-index procedure in the “as 
The specific endpoints 
are in accordance with 
EVOLVE Short DAPT (an 
approved FDA Trial). 
The 13 month endpoint 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
treated” (eligible for 30 day 
DAPT cessation) population. 
Secondary Endpoints 
• 
Rate of cardiac death or 
myocardial infarction (SCAI 
definition) from 1 to 13 months 
post-index procedure in the 
overall enrolled “intent-to-treat” 
patient population  
• 
Rate of Academic Research 
Consortium (ARC) 
definite/probable stent thrombosis 
(ST) involving the SYNERGY 
Stent’s at 1 to 13 months post-
index procedure  
• 
Rate of major bleeding (GUSTO 
severe/life threatening + 
moderate) at 1 to 13months post-
index procedure 
• 
Ischemia-Driven (ID) Target 
Lesion Revascularization,  
• 
ID Target Vessel 
Revascularization,  
• 
Target Lesion Failure,  
• 
Target Vessel Failure,  
• 
All-Cause Death, and  
• 
All-Cause Death or MI. 
is also in accordance 
with EVOLVE Short 
DAPT, in that the 
primary outcome is 
measured 12 months 
following DAPT 
cessation. 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
SYNIVUS-DAPT is a prospective multicenter single-arm pilot study designed to characterize the safety of 
1 month of dual antiplatelet therapy (DAPT) in a high bleeding risk (HBR) patient population who are 
undergoing iLab™ IVUS-guided percutaneous coronary intervention (PCI) with a SYNERGY™ Stent 
System.  
 


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Hypothesis – one (1) to thirteen (13) month rates of cardiac death or myocardial infarction (SCAI 
definition), and Stent thrombosis after Boston Scientific IVUS-guided SYNERGY™ Stents implantation will 
be low and provide key hypothesis-generating information to inform future larger scale clinical studies. 
 
Patients will be screened as per standard of care (please see Section 1.3 Schedule of Activities). Eligible 
patients will undergo iLab™ IVUS-guided PCI with SYNERGY™ Stent System on Day 1 followed by safety 
laboratories (CBC w Diff, Platelets, Basic Metabolic Panel, PT/INR, CPK/CK-MB or troponin) and EKG 
within 24 hours of procedure completion.  At 30 days (+ 7 days) patient will return to clinic for 
evaluation, followed by phone follow up at 30 days post DAPT cessation (60 days post PCI) 6 months     
(+ 14 Days) and at 12 months (+ 30 days) post-DAPT cessation (7 and 13 months post-procedure) for 
evaluation of adverse events and endpoints. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
The proposed trial is designated as a prospective, single arm pilot investigation to assess safety 
endpoints following the application of DAPT in HRB patients undergoing iLab IVUS-guided PCI with the 
SYNERGY® Stent System.  
 
The trial is designed as an observational, single arm, proof of concept study to determine if patients at 
high bleeding risk (HBR) who have IVUS guided SYNERGY™ Stent implantation can safely undergo DAPT 
cessation at 30 days post implantation. This is felt to be a prudent environment to appropriately and 
safely study this hypothesis and potentially enlighten future larger clinical trials.  
 
4.3 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), 
Section 1.3. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
General Inclusion criteria:  
1. Subject is considered at high risk for bleeding, defined as meeting one or more of the following 
criteria at the time of enrollment:   
• 
≥ 75 years of age and, in the opinion of the investigator, the risk of bleeding associated 
with >1 months of DAPT outweighs the benefit,  
• 
Need for chronic or lifelong anticoagulation therapy 


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• 
History of major bleeding (severe/life threatening or moderate bleeding based on the 
GUSTO classification) within 12 months of the index procedure, 
• 
History of stroke (ischemic or hemorrhagic),  
• 
Renal insufficiency (creatinine ≥2.0 mg/dl) or failure (dialysis dependent),  
• 
Platelet count >20,000/µL to ≤100,000/μL 
• 
In the opinion of investigator, patient is at significant risk of falling 
• 
Patient abuses drugs or alcohol 
• 
Hemoglobin < 11.0 
2. Subject must be 18 years of age 
3. Subject must be able to take study required dual antiplatelet therapy (1 month of P2Y12 inhibitor 
and aspirin, 13 months of antiplatelet monotherapy) 
4. Subject is willing to comply with all protocol requirements, including agreement to stop taking 
P2Y12 inhibitor at the 1-month milestone if eligible per protocol  
5. Subject (or legal guardian) understands the trial requirements and the treatment procedures and 
provides written informed consent before any trial-specific procedures are performed 
 
Angiographic Inclusion Criteria 
1. Subject must have had implantation of at least one SYNERGY™ Stent and the use of Boston Scientific 
IVUS for guided stent implantation 
2. All implanted stents must be post dilated and  must meet the following IVUS success criteria: 
a) Treated lesions in which the stent cross sectional area exceeds the distal reference cross 
sectional area 
b) The stent cross sectional area is less than the distal reference cross sectional area (if not 
additional post-dilatation must be performed, followed by repeat IVUS). 
c) Above IVUS success criteria must be met after the 2nd post dilatation   
Note: If IVUS success criteria is not met after the 2nd post dilatation then the patient is excluded 
3. Stent procedure performed by an approved investigator 
4. Vessel diameter > 2.25 mm and < 4.0 mm  and lesion length < 34mm  
5. Pre-dilatation is up to the discretion of the investigator 
 
5.2 
EXCLUSION CRITERIA 
 
 An individual who meets any of the following criteria will be excluded from participation in this study: 
General Exclusion criteria:  
1. Subject with an indication for the index procedure of acute ST elevation MI (STEMI) 
2. Subject with an indication for the index procedure of Non ST elevation MI (NSTEMI), based on the 
3rd Universal MI definition 
3. Subject with treatment with another coronary stent, other than SYNERGY, during the index 
procedure 
4. Subject with a planned staged procedure > 7 days following the index procedure. (Note: Planned 
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SYNERGY™ stents are used for both the index and staged procedures). Discontinuation of DAPT 
should occur 1 month after the last PCI procedure is completed 
5. A staged procedure cannot be in a 3rd epicardial vessel if 2 epicardial vessels were treated during the 
index procedure  
6. Subject has a known allergy to: 
a. 
 Contrast (that cannot be adequately pre-medicated),  
b. 
 SYNERGY™ Stent system (e.g., everolimus. structurally related compounds, polymer or 
individual components) or  
c. 
Protocol-required concomitant medications ( all P2Y12 inhibitors and aspirin)  
7. Subject previously treated at any time with intravascular brachytherapy 
8. Subject has an active peptic ulcer or active gastrointestinal (GI) bleeding 
9. Subject is participating in an investigational drug or device clinical trial that has not reached its 
primary endpoint (Note: registry, observational, data collection studies are not exclusionary) 
10. Subject intends to participate in an investigational drug or device clinical trial within 12 months 
following the index procedure (Note: registry, observational, data collection studies are not 
exclusionary) 
11. Subject is judged inappropriate for discontinuation from P2Y12 inhibitor use at 1 month, due to 
another condition requiring chronic P2Y12 inhibitor use  
a. 
If at the 30 day visit the patient has had a peri-procedural NSTEMI with an enzyme 
elevation >5% of the upper 99th percentile of either CK-MB or Troponin, the subject 
should not be taken off DAPT. 
12. Subject with planned surgery or procedure necessitating discontinuation of P2Y12 inhibitor within 
(<)1 month following index procedure 
13. Subject is a woman who is pregnant or nursing 
14. Subject with a current medical condition with a life expectancy of less than 12 months 
15. Subject with implantation of a drug-eluting stent other than SYNERGY™ Stents within 11 months 
prior to index procedure 
16. Have been previously consented for this trial and screen failed 
17. Any other clinically significant comorbidities, which in the judgment of the Investigator, could 
compromise compliance with the protocol, interfere with interpretation of the study results, or 
predispose the patient to safety risks. 
 
Angiographic Exclusion Criteria 
1. Target lesion(s) is located within a saphenous vein graft or an arterial graft 
2. TIMI flow 0 (total occlusion) 
3. Target lesion(s) is located in the left main 
4. Potential Target lesion(s) that involve a complex bifurcation (i.e. bifurcation lesion requiring 
treatment with more than one stent) 
5. Thrombus, or possible thrombus, present in the target vessel (by visual estimate) 
6. Patients requiring a treatment of more than two native epicardial vessels. 
7. More than three lesions in two epicardial vessels unless they can be covered by one stent.  
8. Target lesion(s) with  in- stent restenosis 


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9. Treatment of non-target lesions or lesions not treated with a SYNERGY™ stent 
10. Subject who did not receive Boston Scientific IVUS guided stent implantation and assessment 
11. Any target lesion that has not been post dilated and has not received post dilatation IVUS 
12. Patients who do not meet the following IVUS success criteria:  
• 
Target lesion(s) in which the stent cross sectional area is less than the distal reference cross 
sectional area and additional post-dilatation is not performed, followed by repeat IVUS. 
** Note: If the IVUS  success criteria is not met after the 2nd post dilatation the patient is 
excluded 
 
5.3 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently entered in the study. Screen failure information will be reported to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. This will include demographic, screen failure details, eligibility criteria, and any 
serious adverse events (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) may not be 
rescreened.  
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Coordinators will be trained by the Coordinating Center at HonorHealth Research Institute. Participants 
will be screened for Eligibility, and Informed Consent will be obtained.  Detailed procedural data will be 
obtained by the Study Coordinator and Site Principal Investigator, and participants will undergo a Baseline 
Interview. These data will be entered into the electronic data capture system with stringent protections 
and quality controls.  
The SYNERGY™ Stent System is already FDA-approved for improving luminal diameter in patients with 
atherosclerotic lesions in native coronary arteries > 2.25 mm to < 4.0 mm in diameter in lesions < 34 mm 
in length. This includes those with diabetes mellitus, with symptomatic heart disease, stable angina, 
unstable angina, non-ST elevation MI or documented silent ischemia.  
 
Pre Procedure Tests and Procedures (Up to 7 days prior to the procedure) 
• 
Standard Laboratory Values: Basic Metabolic Panel, CBC w/ differential and platelets  
• 
Cardiac Enzymes: Total CPK/CK-MB or Troponin I 


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• 
PT-INR: If not part of standard of care draw only if patient is taking warfarin, has liver disease or 
severe anemia 
• 
12 Lead ECG  
 
Procedure  
Study subjects will undergo PCI using the SYNERGY™ Stent System with iLab IVUS-guidance following the 
SYNERGY™IFU (instructions for use). If bailout stenting is required, a SYNERGY™ stent should be used if a 
stent of appropriate length and diameter is available. If not available, an approved coronary stent should 
be used.  
Per the SYNERGY IFU: 
• 
Target lesion vessel diameter >2.25mm and < 4.0mm 
• 
Target lesion length < 34mm  
• 
No ostial lesions (within 5 mm of RCA ostium, 3 mm of left main) 
• 
No complex bifurcations 
• 
No TIMI flow < 1 distal to lesion 
• 
No In-stent restenosis 
• 
No CTOs 
• 
No Overlapping stents 
 
Per Protocol  
• 
Pre dilatation  per the investigators’ discretion 
• 
Post dilation is required for each implanted stent 
• 
No more than 3 target lesions in 2 epicardial vessels 
• 
Two target lesions in one epicardial vessel may be stented if at least 15mm apart or can be covered 
with one stent  
• 
Post dilatation is required for all stents implanted followed by IVUS (for each stent). Up to 2 post 
dilations and IVUS can be done for each implanted stent 
• 
If two target lesions are treated, post-procedure IVUS imaging must be done on the first target 
lesion after its successful treatment, and then after successful treatment of the 2nd target lesion  
  
IVUS Guide (see Amendment 1) 
• 
All target lesions must have IVUS post dilatation followed by IVUS 
• 
If the stent is not fully opposed the stent must be re-dilated and IVUS repeated after each dilatation 
• 
If the cross sectional area of the stent is less than the distal vessel diameter after the 2nd post dilatation 
and repeat IVUS, the patient is excluded 
 
Bailout Stenting 
IF a bailout stent is required it is recommended to use a SYNERGY™ Stent.  IVUS must be done per the 
IVUS protocol for any bailout stents used. 
 


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Post Procedure (Prior to Discharge) 
• 
Post procedure labs: BMP, CBC with diff and platelets, cardiac enzymes (CPK, CK–MB or Troponin I) 2 
sets 6-8 hours apart  
• 
Note: if patient is being discharged the same day draw one set of cardiac enzymes immediately post 
procedure and one set at 6 hours post procedure. 
• 
12 Lead ECG 
 
Post PCI Follow up Visits 
Follow up visits will occur at 30 and 60 days post PCI, and 7 and 13 months post PCI 
 
1. 30 Day Post PCI Visit (+ 7 days) in person Visit: 
Requirements:  
• 
Angina Assessment including completion of the angina assessment questionnaire 
o Evaluate for cardiac events: recurring angina, unstable angina, revascularization (TLR 
or other) or another condition in the opinion of the investigator would prevent 
stopping DAPT 
• 
Assessment of adherence to DAPT:  Interruptions, missed doses, changes in DAPT Medication 
• 
Adverse event assessment and reporting 
• 
Cardiac con medications (including Aspirin)  
• 
DAPT cessation 
 
2. 60 Day, 7 Month and 13 Month  Post PCI Visits 
• 
Angina Assessment  
• 
Assessment of adherence to Aspirin: Interruptions, missed doses, changes in DAPT 
Medication 
• 
Adverse Event assessment  including evaluation for cardiac events: Recurring angina, unstable 
angina, revascularization (TLR or other) or other conditions  
• 
Cardiac con medications (including Aspirin and any reintroduction of P2Y12) 
 
 
6.1.2 DOSING AND ADMINISTRATION 
 
Antiplatelet Medications  
DAPT Regimen (aspirin + P2Y12 inhibitor) will be reported in the electronic case report form (eCRF) to 
include the period of time 72 hours prior to the index procedure through the end of the study. Pertinent 
information regarding the use of antiplatelet medications including dose changes, medication 
interruptions (greater than 3 days), and medication cessation, must be documented. Post-PCI dosing 
should be administered in accordance with the individual agents’ directions for use (e.g., consistent 
with warning, precautions, and dose adjustments if needed) 


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 At the discretion of the Investigator patients on warfarin or NOAC may be discharged on the 
anticoagulant and a P2Y12 without Aspirin.  Additionally at the time of the 30 day visit, if the patient 
continues on the anticoagulant, the P2Y12 may be stopped and low dose Aspirin (81 mg) may be 
started. 
P2Y12 Inhibitor Loading and Discharge Dosing   
• 
For subjects who have been taking a P2Y12 inhibitor for > 72 hours prior to the time of the index 
procedure, a loading dose will not be required.   
• 
For subjects who have not been taking a P2Y12 inhibitor for < 72 hours at the time of the index 
procedure, a loading dose will be recommended to be administered prior to the index 
procedure or not more than 2 hours after the index procedure. The following  doses are 
recommended:   
Clopidogrel: A peri-procedural loading dose of 600 mg PO x 1 or 75 mg PO daily for 4 days is 
recommended. A post-procedural daily dose of 75mg will be recommended. 
Prasugrel: A peri-procedural loading dose of 60 mg is recommended. A post procedural daily 
dose of 10 mg will be recommended.   
Ticagrelor: A peri-procedural loading dose of 180 mg is recommended. A post procedural dose 
of 90mg BID will be recommended 
  Aspirin Loading Dose   
• 
For subjects who have been taking Aspirin daily (regardless of the dose) for ≥ 72 hours prior to 
the time of the index procedure, a loading dose will not be required.   
• 
For subjects who have not been taking Aspirin daily for ≥ 72 hours at the time of the index 
procedure, a loading dose of Aspirin (325mg) is recommended prior to the index procedure. The 
dosage of the loading dose is at the discretion of the Investigator with a recommendation that it 
is administered prior to the index procedure.  
• 
A post procedural dose of Aspirin 81mg is recommended. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
Study participants will undergo SYNERGY™ Stent implantation and receive prescriptions for aspirin and 
the investigator’s choice of P2Y12 inhibitor.  Antiplatelet agents and SYNERGY™ Stent are commercially 
available and will not be provided as part of this study. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 


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Not applicable.  This is not a randomized study. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Compliance to DAPT regimen will be ascertained at the 1-month follow-up visit and will be used to 
determine if the subject is eligible for discontinuation of P2Y12 inhibitor. During the 1-month follow-up 
visit, the subject will also be asked about any significant interruptions (greater than 3 days) in the 
prescribed index procedure.   
Follow up at 30 days post DAPT cessation either by phone or clinic visit to assess angina status and 
targeted endpoints. 
 Note: All enrolled subjects who receive a SYNERGY™ Stents must be followed at all milestones through 
13-months, regardless of eligibility to discontinue DAPT.   
6.4.1 RESCUE MEDICINE 
 
Not applicable. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY PARTICIPATION 
 
Subjects should not discontinue P2Y12 inhibitor (the patient will remain in the study until 13 months 
unless consent to participate is withdrawn) at 1 month if any of the following criteria are met:  
• 
Subject experiences a stroke, MI, PCI, CABG and/or stent thrombosis, during the 1 month period 
following the index procedure   
• 
Subject is non-compliant with DAPT regimen during the 1 month period following the index 
procedure.  Non-compliant is defined as: DAPT interruption for at least 3 days.   
• 
Subject judged to have another condition rendering them inappropriate for discontinuation 
from P2Y12 inhibitor at 1 month. 
An investigator may discontinue or withdraw a participant from the study if: 
• 
Pregnancy occurs 
• 
Significant study non-compliance beyond DAPT compliance issues 


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• 
Continued participation in the study would not be in the best interest of the participant due to 
other conditions 
• 
The participant is unwilling or unable to discontinue DAPT within 7 days after 30-day post-
procedure visit 
• 
Other unforeseen reason 
Additionally, participants may withdraw from participation in the study at any time upon their own 
discretion and a request to the site. 
The reason for participant discontinuation or withdrawal from the study will be recorded on Case Report 
Form (CRF). Subjects who sign the informed consent form but screen fail due to inclusion or exclusion 
criteria requirements will be replaced.   
7.2 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for any of the study follow-
up visits and/or is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit and counsel the 
participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
 
8.1 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
All serious adverse events (SAE), adverse device effects (ADE), death, MI, stent thrombosis, as well as 
bleeding events will be collected from the start of the index procedure (sheath insertion) through the 
13-month follow-up visit.  


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Specific Definitions of Adverse Events: 
DEATH 
All deaths are considered cardiac unless a non-cardiac cause can be documented. 
  
• 
Cardiac death: Any death due to immediate cardiac cause (e.g. MI, low-output failure, fatal 
arrhythmia). Unwitnessed death and death of unknown cause will be classified as cardiac death.  
• 
Non-cardiac death: Any death not covered by the above definition, including death due to 
pulmonary causes, accident, suicide, infection, sepsis, or trauma. 
 
STENT THROMBOSIS 
 
We intend to use the ARC Definite/Probable definition of stent thrombosis  
Definite Stent Thrombosis:  
• 
Angiographic or pathologic confirmation of intracoronary stent thrombosis either inside 
or 5mm proximal or distal to the stent. 
AND 
• 
Symptoms suggestive of an acute coronary syndrome:   
o New onset of ischemic symptoms at rest (typical chest pain with duration >20 
minutes) 
o New ischemic ECG changes suggestive of acute ischemia 
o Typical rise and fall in cardiac biomarkers (>2× ULN of CK) 
 
Probable Stent Thrombosis:   
 
• 
unexplained death within 30 days  
• 
target vessel myocardial infarction without angiographic confirmation of stent 
thrombosis 
GUSTO Severe/life-threatening or moderate bleeding 
• 
Severe or life-threatening: Either intracranial hemorrhage or bleeding that causes 
hemodynamic compromise and requires intervention 
• 
Moderate: Bleeding that requires blood transfusion but does not result in hemodynamic 
compromise 
MYOCARDIAL INFARCTION –SCAI Definition – Procedural Related MI 
Group  
Definition  


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Normal baseline CK-
MB  
CK-MB rise of >10x ULN or >5x ULN with new pathologic Q-waves in at least 2 
contiguous leads or new persistent left bundle branch block 
OR 
In the absence of baseline CK-MB, a cTn rise of >70x ULN or a rise of >35 ULN 
plus new pathologic Q-waves in at least 2 contiguous leads or new persistent 
left bundle branch block 
Elevated baseline 
biomarkers that are 
stable or falling  
A CK-MB or cTn rise that is equal (by an absolute increment) to the 
definitions described for patients with normal CK-MB at baseline. 
Elevated baseline 
biomarkers that 
have not been 
shown to be stable 
or falling  
A CK-MB or cTn rise that is equal (by an absolute increment) to the 
definitions described for patients with normal CK-MB at baseline 
Plus  
New ST-segment elevation or depression 
Plus  
New-onset or worsening heart failure or sustained hypotension or other signs 
of a clinically relevant MI. 
 
Spontaneous MI: 
Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac troponin (cTn)] with at 
least one value above the 99th percentile upper reference limit (URL) and with at least one of the 
following: 
• 
Symptoms of ischemia 
• 
New or presumed new significant ST-segment-T wave (ST-T) changes or new left bundle branch 
block (LBBB) 
• 
Development of pathological Q waves in the ECG 
• 
Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 
• 
Identification of an intracoronary thrombus by angiography or autopsy 
 
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes:  
• 
death, a life-threatening adverse event,  


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• 
inpatient hospitalization or prolongation of existing hospitalization,  
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions,  
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition.  
 
8.1.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.1.3.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”.] 
 
 
8.1.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the investigator 
who examines and evaluates the participant based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
 


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8.1.3.3 EXPECTEDNESS  
 
The principal investigator in consultation with the sponsor will be responsible for determining whether 
an adverse event (AE) is expected or unexpected.  An AE will be considered unexpected if the nature, 
severity, or frequency of the event is not consistent with the risk information previously described for 
the study intervention. 
8.1.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, investigator assessment of severity, relationship to study product (assessed only by those with 
the training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
Study team will record all reportable events with start dates occurring any time after informed consent 
is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation.  At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events 
will be followed for outcome information until resolution or stabilization. 
 
 
8.1.5 ADVERSE EVENT REPORTING  
 
Any adverse experience that occurs in this study that is serious, unexpected, and related or probably 
related to the study design must be reported to the IRB of record within 10 working days after the 
investigator first receives a report of the event by completing and submitting an adverse event report 
form as per IRB of record policy and procedures. 
 


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Any unanticipated adverse device effects must be reported to the IRB within 10 working days after the 
investigator first learns of the event by completing and submitting an adverse event report for as per IRB 
of record policy and procedures. 
 
All adverse events that do not meet the above reporting requirements should be summarized and 
provided to the IRB at the time of continuing review. 
 
8.1.6 SERIOUS ADVERSE EVENT REPORTING  
 
The study investigator will immediately, but no longer than within 5 working days after investigator first 
becomes aware of the event, report to the sponsor any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol or investigator brochure and 
must include an assessment of whether there is a reasonable possibility that the study intervention 
caused the event. Study endpoints that are serious adverse events must be reported in accordance with 
the protocol unless there is evidence suggesting a causal relationship between the study intervention 
and the event. In that case, the investigator must immediately report the event to the sponsor. 
 
The study investigator shall complete an Unanticipated Adverse Device Effect Form and submit to the 
study sponsor and to the reviewing Institutional Review Board (IRB) as soon as possible, but in no event 
later than 5 working days after the investigator first learns of the effect.  The study sponsor is 
responsible for conducting an evaluation of an unanticipated adverse device effect and shall report the 
results of such evaluation to the Food and Drug Administration (FDA) and to all reviewing IRBs and 
participating investigators within 10 working days after the sponsor first receives notice of the effect. 
Thereafter, the sponsor shall submit such additional reports concerning the effect as FDA requests. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by the Data Coordinating Center (DCC)/study sponsor and should be 
provided as soon as possible. 
 
The study sponsor will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the sponsor's initial receipt of the information.  In addition, the sponsor must 
notify FDA and all participating investigators as soon as possible, but in no case later than 15 calendar 
days after the sponsor determines that the information qualifies for reporting. 
 
 
8.1.7 REPORTING EVENTS TO PARTICIPANTS  
 
Not applicable. 
 


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8.1.8 EVENTS OF SPECIAL INTEREST  
Not applicable. 
 
8.1.9 REPORTING OF PREGNANCY  
 
If a female patient becomes pregnant while participating in this study and receiving DAPT, a pregnancy 
report form should be completed and expeditiously submitted to the sponsor to facilitate outcome 
follow-up.  Information on the status of the mother and child will be forwarded to the sponsor.  
Generally, follow-up will be no longer than 6-8 weeks following the estimated delivery date.  Any 
premature termination of the pregnancy will be reported. 
 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication will be 
recorded as an AE or SAE. 
 
 
8.2 
UNANTICIPATED PROBLEMS 
 
8.2.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
This definition could include an unanticipated adverse device effect, 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 (21 CFR 812.3(s)). 
 
 


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8.2.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP report will 
include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study 
sponsor within 5 working days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within10 working days of 
the investigator becoming aware of the problem.  
 
An investigator shall submit to the sponsor and to the reviewing Institutional Review Board (IRB) a 
report of any unanticipated adverse device effect occurring during an investigation as soon as possible, 
but in no event later than 10 working days after the investigator first learns of the effect (21 CFR 
812.150(a)(1)), A sponsor who conducts an evaluation of an unanticipated adverse device effect under 
812.46(b) shall report the results of such evaluation to the Food and Drug Administration (FDA) and to 
all reviewing IRB's and participating investigators within 10 working days after the sponsor first receives 
notice of the effect. Thereafter the sponsor shall submit such additional reports concerning the effect as 
FDA requests (21 CFR 812.150(b) (1)).    
 
8.2.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Unanticipated problems that are determined to be related or probably related to the study intervention 
will be shared with the patients at the following visit after informed consent approved by IRB of record. 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
Outcome measures include 1-13 month post-procedure rates of cardiac death and myocardial 
infarction. This single-arm prospective design will compare rates on the dependent variables following 


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Boston Scientific IVUS-guided SYNERGY™ Stent implantations with standard of care rates in the target 
population.  The null and alternative hypotheses are as follows: 
H0 = p = p0 
The null hypothesis states that there is no difference on myocardial infarction or cardiac death rates. 
H1 : p < p0 
9.2 
THE ALTERNATIVE HYPOTHESIS STATES THAT PATIENTS UNDERGOING SYNIVUS-DAPT 
TREATMENT WILL HAVE LOWER RATES OF MYOCARDIAL INFARCTION OR CARDIAC 
DEATH. SAMPLE SIZE DETERMINATION 
An a priori power analysis was conducted for a one-sample binomial test with an alpha of .05 (one-
tailed), beta of .05, constant proportion (p) of .031, and assumed primary endpoint proportion of 0.0047 
resulting in a needed sample size of 231.  
The consideration of historical data on timing and incidence of myocardial infarction and stent 
thrombosis from published meta-analysis and related literature, the SCAAR registry and ACS subsets (De 
Luca, Dirksen, Spaulding, et al, 2012; Ellis, Colombo, Grube, et al, 2007; Palmerini, Biondi-Zoccai, Riva, et 
al, 2012; Palmerini, Kirtane, Serruys, et al, 2012; SCAAR registry and ACS subset, 2016). Historic rates at 
1-year follow up for ST showed variability ranging from 0.3 to 5.3%. Rates of MI range from 1.9 to 8.8%. 
A time-to-event bivariate exponential distribution function was used to determine criteria for sample 
sizes based on a 95% power determination resulting in a historic rate determination of 3.1%. Patients 
lost to follow-up will not be included in the final analysis, and additional patients will be recruited for 
study participation to reach the needed sample of 231. 
 
The FDA has approved an initial phase of the investigation for 100 U.S patients. Accordingly, the sample 
size of N=100 for the initial phase is not statically based. Should approvals for study continuation be 
granted, the total sample size for subsequent phases will remain at 231, inclusive of subjects enrolled on 
this initial phase. 
 
9.3 
POPULATIONS FOR ANALYSES 
 
The Intention-to-Treat (ITT) Analysis Dataset inclusive of all participants will be included in the analysis. 
This is inclusive of all safety endpoints and encompasses the safety analysis dataset. Patients lost to 
follow-up will not be included in planned analyses.  
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 


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All patients will be enrolled in the study with hospital IRB approval after consent. Preliminary data 
collected will include clinical history and demographic data. Descriptive statistics on patients’ 
demographic characteristics and echocardiographic parameters will be reported as means and standard 
deviations for continuous variables and frequency counts for categorical variables.  
 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT 
 
For primary endpoints: 
Prevalence rates of cardiac death and myocardial infarction will be determined for the sample. The 
binomial test will be conducted to test the significance of deviations from the expected distribution of 
observations dichotomized as “did not occur” or as “occurrence” for each outcome.  
For safety endpoints: 
Prevalence rates for safety outcomes including ischemia-driven (ID) target lesion revascularization, ID 
target vessel revascularization, target lesion failure, target vessel failure, all-cause death, and myocardial 
infarction will be evaluated with binomial tests. 
The test formula to be used is as follows: 
P(X) = Cnk  pk (1−p) n−k   
All data will be screened for non-parametric statistical test assumptions. Accordingly, all dichotomous 
outcomes will be screened for exclusivity and appropriateness for inclusion in data analysis. Missing 
data, nonadherence and data lost to follow-up will be excluded from the final analysis.  
The a priori alpha level for all statistical tests will be set at .05. To adjust for a potentially inflated family-
wise error rate, the Bonferroni correction (α/m) will be applied for multiple tests with the same sample.  
 
9.4.3 BASELINE DESCRIPTIVE STATISTICS 
Descriptive statistics on patients’ demographic characteristics and echocardiographic parameters will be 
reported as means and standard deviations for continuous variables and frequency counts for 
categorical variables. Rate to occurrence or prevalence data will be analyzed for this proposed study, 
and as such, repeated measures analysis from baseline are not applicable. 
 
9.4.4 PLANNED INTERIM ANALYSES  
 


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A 7 month planned interim analysis for the first 50 patients enrolled using the O’Brien-Fleming method 
will be conducted for cardiac death or myocardial infarction rate. Using an a priori alpha of .05, the 
adjusted alpha for the interim analysis will be 0.0054 and 0.0492 for the final analysis for consideration 
of frequency rates and obtained p-values at each analysis time point. Interim analysis outcomes will be 
used to assess trial efficacy, early evidence of harm, and safety to inform futility determinations and 
continuation considerations. Frequency rates on each outcome variable that exceed the non-inferiority 
margin of ±5% for the interim analysis will result in temporary halting for further safety evaluations. The 
project statistician will conduct the planned interim analysis results will be reviewed by the study PI and 
research team.  
 
 
9.4.5 SUB-GROUP ANALYSES 
 
The F test of stability (or Chow test) for the coefficients of a panel model will be used to examine 
outcomes according to site and region and to test for the presence of individual effects. 
 
F1−way = (ESSR − ESSU) / (N − 1)  
    ESSU/ ((T − 1) N − K) 
 
ESSR denotes the residual sum of squares under the null hypothesis and ESSU the residual sum of squares 
under the alternative. Under H0, the statistic F1−way is distributed as F with (N − 1, (T − 1)N − K) degrees 
of freedom. Accordingly, the null hypothesis is as follows: 
 
H0 : μi = 0, i = 1, . . .,N. 
 
Additional subgroup analyses will be conducted to examine potential differences in women and 
ethnic/racial minorities.  
 
9.4.6 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Individual participant data will be listed by each study outcome following the procedure to study 
cessation at 13 months. Any occurrence of cardiac death, myocardial infarction, and stent thrombosis 
prior to this time will be documented accordingly.  
 
9.4.7 EXPLORATORY ANALYSES 
 
No additional exploratory or auxiliary analyses are planned for the investigation.  
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 


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10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS 
 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The following consent materials are submitted with this 
protocol: 
• 
Informed Consent Form 
• 
Angina Questionnaire 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator or designee will explain the research study to the participant and answer any questions that 
may arise. A verbal explanation will be provided in terms suited to the participant’s comprehension of 
the purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to investigators, funding agency, Investigational Device 
Exemption (IDE) sponsor and regulatory authorities.  If the study is prematurely terminated or 
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Review Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension.  Study 
participants will be contacted, as applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA).] 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at HonorHealth Research Institute. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
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password protected. At the end of the study, all study databases will be de-identified and archived at 
the HonorHealth Research Institute. 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at HonorHealth Research Institute.  
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Medical Monitor 
David G. Rizik, MD 
Bimal Padaliya, MD 
HonorHealth 
HonorHealth  
10510 N. 92nd Street 
Suite 300, Scottsdale, AZ 85258 
10200 N. 92nd Street Suite 150 
Scottsdale, AZ  85258 
480-882-7450 
490-882-7450 
DavidRizik@aol.com 
David.Rizik@HonorHealth.com  
bimalpadaliya@gmail.com 
Bimal.Padaliya@HonorHealth.com  
 
 
10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the appropriate expertise in cardiology, pharmacology and biostatistics. Members of the 
DSMB should be independent from the study conduct and free of conflict of interest, or measures 
should be in place to minimize perceived conflict of interest.  The DSMB will meet at least quarterly to 
assess safety and efficacy data of the study. The DMSB will operate under the rules of an approved 
charter that will be written and reviewed at the organizational meeting of the DSMB. At this time, each 
data element that the DSMB needs to assess will be clearly defined. The DSMB will provide its input to 
the study sponsor. 
 
10.1.7 CLINICAL MONITORING 
 
Clinical site monitoring will be conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial will be in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), Food & Drug Administration (FDA) and 
with applicable regulatory requirement(s).  HonorHealth will be responsible for monitoring of this study.  
One hundred percent of source documentation related to safety (AE-SAE) will be monitored.  Twenty-
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10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data, documentation and 
completion.  An individualized quality management plan will be developed to describe a site’s quality 
management. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), Food & Drug Administration (FDA) and applicable regulatory requirements.  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered in electronic case report forms (eCRF), a 21 CFR Part 
11-compliant data capture system provided by HonorHealth Research Institute. The data system 
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data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents. 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Study documents will be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harminosation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents will be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform 
the investigator when these documents no longer need to be retained. 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, Food and Drug Administration 
(FDA), International Conference on Harmonisation Good Clinical Practice (ICH GCP), or Manual of 
Procedures (MOP) requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be developed by 
the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 10 working days of identification of the protocol deviation, or within 10 working days 
of the scheduled protocol-required activity.  All deviations must be addressed in study source 
documents, reported to HonorHealth Research Institute.  Protocol deviations must be sent to the 
reviewing Institutional Review Board (IRB) per their policies. The site investigator is responsible for 
knowing and adhering to the reviewing IRB requirements.  
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
This study will comply with the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-


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reviewed journals.  Data from this study may be requested from other researchers 2 years after the 
completion of the primary endpoint by contacting David G Rizik, MD 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical or 
device industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the 
design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. 
Furthermore, persons who have a perceived conflict of interest will be required to have such conflicts 
managed in a way that is appropriate to their participation in the design and conduct of this trial.  The 
study leadership in conjunction with HonorHealth has established policies and procedures for all study 
group members to disclose all conflicts of interest and will establish a mechanism for the management 
of all reported dualities of interest. 
 
 
 


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10.2 ABBREVIATIONS 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
NOAC 
Novel Oral Anticoagulant 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 


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SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 


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10.3 DATA SAFETY MONITORING COMMITTEE 
An independent data safety and monitoring committee (DSMC) will be formed to evaluate the safety 
and effectiveness of the study intervention for each subject as well as study conduct of each site. The 
DSMC will also review all SAEs reported by each site. The DSMC will review study data to determine if 
endpoints are being met and if the study can continue with or without changes to the protocol or if the 
study should be terminated immediately due to safety concerns or lack of data to support study 
endpoints. Findings and recommendations of the DSMC will be reported to the sponsor after each 
meeting. The DSMC will also serve as the clinical events committee (CEC).  The DSMC will meet on a 
quarterly basis or more frequently as needed if safety concerns are raised. Data reported to 
HonorHealth will be received by the lead principal investigator on a regular basis and not less than once 
a month. In addition, SAEs will be reported to HonorHealth immediately and reviewed as they are 
received. Any unacceptable toxicities or severe toxicities that occur more frequently than expected will 
be discussed by the lead principal investigator, the medical monitor, and the site principal investigators 
who will decide jointly whether the study should be modified, interrupted, or stopped. A monthly 
conference call will be held with investigators participating in the study.  A planned interim analysis will 
be performed (Section 9.4.4). 
 


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10.4 IVUS ACQUISITION PROTOCOL 
Use of IVUS prior to stent implantation is not mandatory but encouraged.   
Post-stent-implantation IVUS examination with a Boston Scientific Opticross IVUS catheter and the 
POLARIS software system is mandatory for each implanted stent.   
Post-PCI IVUS criteria for stent optimization requires that the minimal stent cross-sectional area is 
greater than the lumen cross-sectional area at a distal reference segment.  
IVUS with any catheter frequency can be used but must be with a Boston Scientific catheter and on the 
Polaris system   
* After the final post stent dilatation:   
 
1) Place the IVUS catheter imaging sensor at least 10mm distal to the target lesion   
2) Perform an IVUS run by pulling back to at least 10mm proximal to the target lesion.  
3) Measure cross sectional area of the least diseased frame within 10mm distal to the stent (distal 
reference)  
4) Measure cross sectional area of the frame with the smallest diameter within the stent  
5) If the cross sectional area of the frame within the stent is greater than cross sectional area of the 
distal target, then the IVUS success criteria has been met  
6) If the cross sectional area of the frame within the stent is less than the cross sectional area of the 
distal target, then perform high pressure post dilatation of the stent and then repeat steps 1 through 6    
Note: If the stent cross sectional area is less than the target lesion distal reference diameter after the 2nd 
post dilatation and IVUS the patient is excluded. 
If two target lesions are treated, post-procedure imaging must be done on the first target lesion after its 
successful treatment, and then after successful treatment of the 2nd target lesion.  
* Administer 100-200 μg of intracoronary nitroglycerine before all IVUS examinations.  
Caution: It is important to place the IVUS catheter at the center of the vessel lumen to avoid disturbing 
the device struts.  
 
 
 


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PROTOCOL AMENDMENT HISTORY 
 
 
Version 
Date 
Description of Change  
Brief Rationale 
2.0 
9May2018 
Sections 1.1 Endpoints and 3.0 Objectives 
and Endpoints have been clarified 
Section 1.1 - Clarified multi-center study to 
reflect 2 other sites 
Section 1.3 – clarified Scheduled of Events to 
include cardiac troponin follow-up in case of 
elevated levels 
Section 4.1 – removal of post-procedure 
consenting and harmonize 12 months post-
DAPT = 13 months post-procedure 
Section 1.1 and 5.1 added inclusion criteria 
for a maximum of 2 native epicardial 
vessels/maximum 2 lesions/vessel. 
Section 5.2 – changes saphenous vein graft to 
index procedure SVG PCI 
Section 5.2 – clarified exclusion criteria #4, 
#7, #24, #25 
Section 6.1.2 – included tracking of all anti-
platelets interruptions greater than 1 day and 
post-index procedure recommendations on 
anti-platelet drugs dosages 
Section 7.1 – clarified language for 
replacement of consented/enrolled patients 
Section 8.1.1 – addition of definitions 
Section 9.1 – updated Statistical 
Considerations 
Section 9.4.2 and 10.1.8 – updated to include 
plan for handling missing data 
Section 10.1.7 – clarified monitoring plan 
Added IVUS Acquisition Protocol – 
Appendix A. 
Corrections requested by 
CDRH (FDA) 
3.0 
14Jul2018 
Section 7.1 – removed criteria for subject 
discontinuation 
Corrections requested by 
CDRH (FDA) 
4.0 
1Oct2018 
Added NCT number 
Section 1.1 Synopsis under Study Population 
Inclusion Criteria and Section 5.1 Inclusion 
Criteria 2nd bullet: Need for chronic or 
lifelong anticoagulation therapy.  An 
explanation for Atrial fibrillation patients has 
been added to clarify that these patients are 
eligible.    
Section 1.1 Synopsis under Study Population 
Exclusion Criteria and Section 5.2 Exclusion 
Criteria item #4: Clarification on the 
exclusion for patients undergoing peri-
 
Clarifications requested by 
the DSMC/CEC 


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procedural NSTEMI that states in patients 
with an enzyme elevation => 5% of the 
upper 99th percentile are excluded 
Sections 1.1 and 5.2 - Exclusion Criteria; 
added item #26 - Any other clinically 
significant co-morbidities, which in the 
judgement of the Investigator could 
compromise compliance, interfere with 
study results or predispose patient to safety 
risks. 
Section 1.3 Schedule of Events: Deleted 
CPK/CK-MB and replaced with Troponin.  
This is to reflect the standard monitoring. 
4.1 
09Sept2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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