Conditions: Coronary Artery Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2009
Healthy volunteers: no

Brief summary:
The EVOLVE Short DAPT Study is a prospective, multicenter, single-arm study designed to assess the safety of 3-month DAPT in subjects at high risk for bleeding undergoing PCI with a SYNERGY Stent System.

Detailed description:
The primary objective of the EVOLVE Short DAPT Study is to assess the safety of 3-month dual antiplatelet therapy (DAPT) in subjects at high risk for bleeding undergoing percutaneous coronary intervention (PCI) with the SYNERGY Stent System.

The study will be conducted up to 120 sites worldwide in the United States, Europe, Japan, and Brazil with planned enrollment of up to 2,250 subjects. Clinical follow-up will be required at the following time points: 3 months, 6 months, 12 months and 15 months post index procedure.

Subjects must be treated with one of the following P2Y12 inhibitors (clopidogrel, prasugrel, or ticagrelor) for 3 months following the index procedure. Subjects must be treated with aspirin for the duration of the trial. The minimum daily maintenance dose of aspirin should be 75-100 mg.

Subjects are eligible for discontinuation of P2Y12 inhibitor at 3 months if they meet both of the following criteria: subject was treated with 3 months of study required antiplatelet therapy post index procedure; and subject was free from events (stroke, MI, PCI, coronary artery bypass graft \[CABG\], and stent thrombosis) between the index procedure and the 3 month visit.

Subjects are not eligible for discontinuation of P2Y12 inhibitor at 3 months if any of the following criteria are met: subject who experiences a stroke, MI, PCI, CABG and/or stent thrombosis, during the 0-3 month period (between the date of the index procedure and the date of the 3-month follow-up visit); or subject who is non-compliant with study required antiplatelet therapy during the 0-3 month period (between the date of the index procedure and the date of the 3-month follow-up visit); or subject judged inappropriate for discontinuation from P2Y12 inhibitor use at 3 months due to another condition requiring chronic P2Y12 inhibitor use.

All enrolled subjects who receive a SYNERGY stent must be followed at all milestones through 15-months, regardless of eligibility to discontinue P2Y12 inhibitor. Following the 3-month milestone, subjects who experience MI or stent thrombosis events should be treated per the investigator's discretion and should be followed through the 15-month visit.

Arms:
arm 1: Subject with implantation of at least one SYNERGY stent within the preceding 3 calendar days that takes the required dual antiplatelet therapy (3 months of P2Y12 inhibitor, 15 months of aspirin)

Interventions: intervention 1: 3 months of dual antiplatelet therapy (DAPT) intervention 2: SYNERGY Stent System
Intervention descriptions: intervention 1: 3 months of P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) plus 15-months of aspirin intervention 2: SYNERGY Everolimus-Eluting Platinum Chromium Coronary Stent System

Protocol document:
Prot_SAP_000.pdf: 
IDE # G150194 
Confidential 
 
 
 
 
 
 
 
 
 
 
 
 
EVOLVE Short DAPT Study (S2073) 
 
A prospective, multicenter, single-arm study designed to assess the safety of 3-month dual 
antiplatelet therapy (DAPT) in subjects at high risk for bleeding undergoing percutaneous 
coronary intervention (PCI) with the SYNERGYTM Everolimus-Eluting Platinum Chromium 
Coronary Stent System (SYNERGY Stent System) 
 
CLINICAL PROTOCOL 
IDE # G150194 
 
Sponsored By 
Boston Scientific Corporation 
300 Boston Scientific Way 
 
Marlborough, MA 01752, United States 
 
European Authorized Representative 
Boston Scientific International S.A. 
Boston Scientific Limited 
Ballybrit Business Park 
Galway, Ireland 
 
Japanese Representative: 
Boston Scientific Japan K.K. 
Nakano Central Park South  
4-10-2 Nakano, Nakano-ku 
Tokyo,164-0001, Japan 
 
 
This protocol contains confidential information for use by the Investigators and their 
designated representatives participating in this clinical investigation. The protocol should be 
held confidential and maintained in a secure location. 
Do not copy or distribute without written permission from Boston Scientific Corporation. 
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Confidential 
 
 
1. 
Contact Information 
Role 
Contact  
Clinical Contacts 
Kellie Windle 
Senior Clinical Trial Manager 
Boston Scientific Corporation 
100 Boston Scientific Way 
Marlborough, MA 01752, United States 
 
Thomas Näschen, PhD 
Clinical Trial Manager 
Boston Scientific GmbH 
Daniel-Goldbach-Str. 17-27 
40880 Ratingen, Germany 
 
Hitomi Nagasawa 
Clinical Project Manager 
Boston Scientific Japan K.K. 
Nakano Central Park South  
4-10-2 Nakano, Nakano-ku 
Tokyo,164-0001, Japan 
Global Coordinating 
Principal Investigator 
Laura Mauri, MD, MSc 
Brigham and Women’s Hospital 
Division of Cardiovascular Medicine 
Department of Medicine 
75 Francis Street 
Boston, MA 02115, United States 
Coordinating 
Co-Principal 
Investigators 
Ajay J. Kirtane, MD, SM, FACC, FSCAI 
Columbia University Medical Center 
161 Fort Washington Avenue, 6th Floor 
New York, NY  10032, United States 
 
Stephan Windecker, MD 
Department of Cardiology 
Bern University Hospital 
3010 Bern, Switzerland  
Investigational Sites 
A list of investigational sites is maintained and will be made 
available to investigational sites 
Vendors 
A list of vendors involved in the trial is maintained and will be 
made available to investigational sites 
Original Release: August 27, 2015 
Current Version: April 12, 2017 
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IDE # G150194 
 
 
 
2. 
Protocol Synopsis 
EVOLVE Short DAPT Study (S2073) 
EVOLVE Short DAPT Study: A prospective, multicenter, single-arm study designed to assess 
the safety of 3-month dual antiplatelet therapy (DAPT) in subjects at high risk for bleeding 
undergoing percutaneous coronary intervention (PCI) with the SYNERGYTM Everolimus-
Eluting Platinum Chromium Coronary Stent System (SYNERGY Stent System) 
Primary 
Objective 
To assess the safety of 3-month DAPT in subjects at high risk for bleeding 
undergoing PCI with the SYNERGY Stent System 
Study Design 
Prospective, Multicenter, Single-Arm, Historical Control, Propensity Score 
Approach 
Planned Number 
of Subjects 
Up to 2,250 subjects will be enrolled in the EVOLVE Short DAPT Study  
Planned Number 
of Sites / 
Countries 
Up to 120 sites worldwide in the United States, Europe, Japan, and Brazil 
Test Device 
SYNERGY Everolimus-Eluting Platinum Chromium Coronary Stent System 
(SYNERGY Stent System) 
Device Sizes 
The SYNERGY commercial device matrix consists of the following sizes:  
 
Available Stent Lengths (mm): 
8, 12, 16, 20, 24, 28, 32, 38 
 
Available Stent Diameters (mm): 
2.25, 2.50, 2.75, 3.00, 3.50, 4.00 
 
 
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IDE # G150194 
 
 
 
Co-Primary 
Endpoints 
The study has two co-primary endpoints that will be assessed. They are: 
• Rate of death or myocardial infarction (MI) between 3 and 15 months  
• Rate of Academic Research Consortium (ARC) definite/probable stent 
thrombosis (ST) involving SYNERGY between 3 and 15 months  
Secondary 
Endpoint 
• Rate of bleeding, based upon the Bleeding Academic Research 
Consortium (BARC) classification (types 2, 3 and 5) between 3 and 15 
months in subjects not taking chronic anticoagulation. 
Additional 
Endpoints 
The following clinical endpoints will be measured at 3 months, 6 months, 12 
months and 15 months: 
• Rate of major adverse cardiac & cerebrovascular events (MACCE), 
defined as the composite of all death, MI, and stroke 
• Rate of major adverse cardiac events (MACE), defined as the composite 
of cardiac death, MI and TVR 
• Rate of target vessel failure (TVF), defined as the composite of TVR, 
cardiac death or target vessel related MI  
• Rate of cardiac death/MI 
• Rate of bleeding (GUSTO definition) 
• Rate of bleeding (BARC definition) 
• Rate of bleeding (TIMI definition) 
• Rate of stent thrombosis (ARC definite/probable) 
• Rate of cardiac death 
• Rate of non-cardiac death 
• Rate of all cause death 
• Rate of death/MI 
• Rate of MI (Q-wave and non–Q-wave) 
• Rate of stroke, ischemic and hemorrhagic 
• Rate of Target Vessel Revascularization (TVR) 
• Rate of Target Lesion Revascularization (TLR) 
• Rate of MI (ST-related and not ST-related) 
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Follow-up 
Schedule 
Follow-up will be performed (either by telephone or office visit) at the 
following milestones:  
• 3 months (90 days following the index or staged procedure, if 
applicable + 30 days or - 7 days) 
• 6 months (90 days following the 3-month visit date* ± 30 days) 
• 12 months (270 days following the 3-month visit date* ± 30 days) 
• 15 months (365 days following the 3-month visit date* + 30 days) 
All enrolled subjects are to be followed at all milestones through 15 months. 
The study will be considered complete with regard to the primary endpoints 
after all subjects have completed the 15-month follow-up.  
*If a 3-month visit is missed for a subject, the future follow-up windows at 
6, 12, and 15 months will be calculated based at 180, 360, and 455 days 
respectively following the index or staged procedure, if applicable. 
Study Duration 
Enrolled subjects who receive a SYNERGY stent will be followed for 15 
months following the index procedure. 
Required 
Medication 
Therapy 
• Aspirin: Subjects should be treated with aspirin for the duration of the 
trial. The minimum daily maintenance dose of aspirin should be 75–100 
mg. 
 
• P2Y12 inhibitor: Subjects must be treated with one of the following 
P2Y12 inhibitors (clopidogrel, prasugrel, or ticagrelor) for 3 months 
following the index procedure. 
 
• Enrolled subjects must take both aspirin and a P2Y12 inhibitor 
(clopidogrel, prasugrel, or ticagrelor) for 3 months following the index 
procedure. 
   
• Enrolled subjects will be evaluated at 3 months to confirm that 
discontinuation of P2Y12 inhibitor remains appropriate. 
 
• Subjects who are eligible for discontinuation of P2Y12 inhibitor therapy 
at 3 months are required to take aspirin starting at 3 months and 
continuing for the duration of the study. 
 
 
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Enrollment 
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 >3 months of DAPT outweighs the benefit,  
• 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 ≤100,000/μL 
2. Subject must be at least 18 years of age 
3. Subject must have had implantation of at least one SYNERGY stent 
within the preceding 3 calendar days 
4. Subject must be able to take study required antiplatelet therapy (as 
required per protocol) 
5. Subject is willing to comply with all protocol requirements, including 
agreement to stop taking P2Y12 inhibitor at the 3-month milestone, if 
eligible per protocol  
6. Subject (or legal guardian) understands the trial requirements and the 
treatment procedures and provides written informed consent before any 
study-specific procedures are performed 
7. For subjects less than 20 years of age enrolled at a Japanese site, the 
subject/ the subject’s legal representative must provide written informed 
consent before any study-specific tests or procedures are performed 
 
Enrollment 
Exclusion 
Criteria 
1. Subject who is taking (or is planning to take) chronic or lifelong 
anticoagulation within 15 months following index procedure. 
2. Subject with an indication for the index procedure of acute ST elevation 
MI (STEMI) 
3. Subject with an indication for the index procedure of Non ST elevation 
MI (NSTEMI), based on the 3rd Universal MI definition (1)  
4. Subject with treatment with another coronary stent, other than 
SYNERGY, during the index procedure 
5. Subject with planned staged procedures. (Note: Planned staged 
procedures are allowed if performed within 7 days and with only 
SYNERGY stents). 
6. Subject has a known allergy to contrast (that cannot be adequately pre-
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IDE # G150194 
 
 
 
medicated), the SYNERGY stent system or protocol-required 
concomitant medications (e.g., everolimus or structurally related 
compounds, polymer or individual components, all P2Y12 inhibitors and 
aspirin)  
7. Subject with implantation of a drug-eluting stent within 9 months prior 
to index procedure 
8. Subject previously treated at any time with intravascular brachytherapy 
9. Subject has an active peptic ulcer or active gastrointestinal (GI) bleeding 
10. 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) 
11. Subject intends to participate in an investigational drug or device clinical 
trial within 15 months following the index procedure (Note: registry, 
observational, data collection studies are not exclusionary) 
12. Subject judged inappropriate for discontinuation from P2Y12 inhibitor 
use at 3 months, due to another condition requiring chronic P2Y12 
inhibitor use 
13. Subject with planned surgery or procedure necessitating discontinuation 
of P2Y12 inhibitor within 3 months following index procedure 
14. Subject is a woman who is pregnant or nursing 
15. Subject with a current medical condition with a life expectancy of less 
than 15 months 
16. Target lesion(s) is located in the left main 
17. Target lesion(s) is located within 3 mm of the origin of the left anterior 
descending (LAD) coronary artery or left circumflex (LCx) coronary 
artery by visual estimate 
18. Subject has unprotected left main coronary artery disease ( > 50% 
diameter stenosis) 
19. Planned treatment of more than 3 lesions 
20. Planned treatment of lesions in more than 2 major epicardial vessels  
21. Target lesion(s) treated that involves a complex bifurcation (i.e. 
bifurcation lesion requiring treatment with more than one stent) 
22. Target lesion(s) is restenotic from a previous stent implantation 
23. Target lesion(s) is located within a saphenous vein graft or an arterial 
graft 
24. Target lesion(s) with a TIMI flow 0 (total occlusion) or TIMI flow 1 
prior to guide wire crossing 
25. Thrombus, or possible thrombus, present in the target vessel (by visual 
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estimate) 
Staged 
Procedure(s) 
• Planned staged procedures are allowed if performed ≤ 7 days from 
the index procedure and with only SYNERGY stents.  
• Subjects with a planned staged procedure > 7 days from the index 
procedure or with stents other than SYNERGY must not be enrolled 
in the study. 
• A staged procedure is only permitted when all enrollment inclusion 
criteria and no enrollment exclusion criteria are met for all lesions 
treated during both the initial procedure and the subsequent staged 
procedure.  
• The total number of lesions treated during the index and staged 
procedures combined must not exceed 3. 
• The total number of epicardial vessels treated during the index and 
staged procedures combined must not exceed 2.  
• In the case of a staged procedure meeting these criteria, the subject 
should return for the 3-month visit (i.e. assessment for eligibility to 
discontinue P2Y12 inhibitor) 90 days following the staged procedure 
+ 30 days or - 7 days. 
 
Eligible for 
Discontinuation 
of P2Y12 
Inhibitor at 3 
Months 
Subjects are eligible for discontinuation of P2Y12 inhibitor at 3 months if 
they meet both of the following criteria: 
• Subject was treated with 3 months of P2Y12 inhibitor/aspirin post index 
procedure. (Note: Subjects enrolled under a prior version of the protocol 
who were on chronic anticoagulation between 0-3 months are eligible if 
they were also taking P2Y12 inhibitor or P2Y12 inhibitor/aspirin 
between 0-3 months). 
• Subject was free from events (stroke, MI, PCI, CABG, and stent 
thrombosis) between the index procedure and the 3 month visit 
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Not Eligible for 
Discontinuation 
of P2Y12 
Inhibitor at 3 
Months 
Subjects are not eligible for discontinuation of P2Y12 inhibitor at 3 months 
if any of the following criteria are met: 
• Subject who experiences a stroke, MI, PCI, CABG and/or stent 
thrombosis, during the 0-3 month period (between the date of the index 
procedure and the date of the 3-month follow-up visit) 
• Subject who is non-compliant with P2Y12 inhibitor or aspirin during the 
0-3 month period (between the date of the index procedure and the date 
of the 3-month follow-up visit). (Note: Subjects enrolled under a prior 
version of the protocol who were on chronic anticoagulation between 0-3 
months are not eligible if they were not taking P2Y12 inhibitor or P2Y12 
inhibitor/aspirin between 0-3 months).  
Non-compliant defined as: 
o Taking less than 80% or greater than 120% (subject reported); 
and/or  
o Interruption for 14 or more consecutive days 
• Subject judged inappropriate for discontinuation from P2Y12 inhibitor 
use at 3 months due to another condition requiring chronic P2Y12 
inhibitor use 
Note: All enrolled subjects who receive a SYNERGY stent must be 
followed at all milestones through 15-months, regardless of eligibility to 
discontinue P2Y12 inhibitor. 
Note: Compliance to the use of P2Y12 inhibitor and aspirin will be 
ascertained from the subject interview at the 3-month follow-up visit and 
will be used to determine if the subject is eligible for discontinuation of 
P2Y12 inhibitor. During the interview, the subject will also be asked about 
any significant interruptions (3 days or greater) in the prescribed treatment 
since the last follow-up visit. 
Management of 
Endpoint Events 
after 3 months 
Following the 3-month milestone, subjects who experience MI or stent 
thrombosis events should be treated per the investigator’s discretion and 
should be followed through the 15-month visit. 
Safety 
Parameters 
• All serious adverse events (SAE), adverse device effects (ADE), death, 
MI, TVR, stroke, stent thrombosis, and bleeding events will be collected 
for all enrolled subjects through end of study 
• A clinical events committee (CEC) will adjudicate all endpoint events, as 
specified in the CEC Charter 
 
 
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Statistical Methods 
Co-Primary 
Endpoint 
(Death/MI) 
Statistical 
Hypothesis 
The 3 to 15 month death/MI rate for SYNERGY with 3-month DAPT (test 
group) is non-inferior compared to historical drug-eluting stents (DES) with 
12-month DAPT (control group) in subjects at high risk for bleeding. 
Co-Primary 
Endpoint 
(Death/MI) 
Statistical Test 
Method 
A Propensity Score (PS) Model using quintile adjustment will be used to test 
the hypothesis of non-inferiority of SYNERGY with 3-month DAPT (test 
group) compared to historical DES with 12-month DAPT (control group) 
H0: PDeath/MI-3M – PDeath/MI-12M ≥ Δ 
H1: PDeath/MI-3M – PDeath/MI-12M < Δ 
where PDeath/MI-3M and PDeath/MI-12M are the 3 to 15-month  death/MI rates for 
the 3-month DAPT test group and 12-month DAPT group (historical 
control), respectively, and Δ is the non-inferiority margin. 
 
Co-Primary 
Endpoint 
(Death/MI)  
Sample Size 
Parameters 
• Expected 3 to 15 month death/MI rate in subjects at high risk for 
bleeding with 12-month DAPT (control) = 5.6%a 
• Expected 3 to 15 month death /MI rate in subjects at high risk for 
bleeding with 3-month DAPT (test) = 5.6%a 
• Non-inferiority margin = 2.52% (45% relative to the expected rate) 
• Test significance level = 0.025 (1-sided) 
• Power = 85% 
• The unadjusted comparison requires a minimum of 1,500 evaluable 
subjects per group, which is based on equal allocation using 2-group test 
of equivalence in proportions in nQuery Advisor 
• Control subjects are historical -limus DES subjects who were at high risk 
for bleeding extracted from Boston Scientific (BSC) sponsored trials 
PROMUS Element Plus US Post Approval Study (PE+PAS), PE 
PROVE European Post Approval Study, and the HCRI DAPT Study 
minus TAXUS subjects. The number of available historical control 
subjects is approximately 1,643 (403 from BSC + 1,240 from HCRI 
DAPT) 
• Number of evaluable test subjects required in the propensity score model 
is 1,650 (1,500 *1.1) including additional 10% subjects accounting for 
model variability 
• Expected drop out rate due to ineligibility for 3 month DAPT in 0 to 3 
months = 15% 
• Expected attrition rate in 3 to 15 months = 3% 
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• N = 2,000b subjects enrolled  
aThe expected rate of 5.6% for 3 to 15-month death/MI is estimated from BSC 
PROMUS subjects at high risk for bleeding extracted from the HCRI DAPT Study 
(13/253), PE+ US Post Approval Study (14/318), and PE PROVE European Post 
Approval Study (11/85). 
bThe enrollment may be terminated early if the observed dropout rate in 0 to 3 
months is projected to be <15%. Enrollment may be continued beyond 2,000 
subjects (up to a maximum of 2,250 subjects) if the observed dropout rate in 0 to 3 
months is projected to be >15%. 
Co-Primary 
Endpoint (Stent 
Thrombosis) 
Statistical 
Hypothesis 
Rate of Academic Research Consortium (ARC) definite/probable stent 
thrombosis (ST) involving SYNERGY between 3 and 15 months in subjects 
at high risk for bleeding is less than the performance goal (PG) of 1% 
Co-Primary 
Endpoint (Stent 
Thrombosis) 
Statistical Test 
Method 
An exact test will be used to test the hypothesis of one sample proportion 
compared to a PG: 
H0: PST-3M ≥ PG 
H1: PST-3M < PG 
where PST-3M is the 3 to 15-month ARC-defined (definite/probable) ST 
(involving SYNERGY) rate for the 3-month DAPT group and PG is the 
performance goal. 
Co-Primary 
Endpoint (Stent 
Thrombosis) 
Sample Size 
Parameters 
• Expected 3 to 15-month rate of ST (involving SYNERGY) in subjects at 
high risk for bleeding from 3-month DAPT (test) < 0.4%  
• PG = 1% 
• Test significance level = 0.025 (1-sided) 
• Power = 80% 
• Number of evaluable subjects = 1,650  
• Expected drop out rate due to ineligibility for 3 month DAPT in 0 to 3 
months = 15%a 
• Expected attrition rate in 3 to 15 months = 3% 
• N = 2,000b enrolled subjects required  
 
aThe enrollment may be terminated early if the observed dropout rate in 0 to 
3 months is projected to be <15%. Enrollment may be continued beyond 
2,000 subjects (up to a maximum of 2,250 subjects) if the observed dropout 
rate in 0 to 3 months is projected to be >15%. 
Secondary 
Endpoint 
(Bleeding) 
Statistical 
Hypothesis 
The 3 to 15 month rate of bleeding, based upon the Bleeding Academic 
Research Consortium (BARC) classification (types 2, 3 and 5) for 
SYNERGY in subjects at high risk for bleeding (excluding subjects on 
chronic anticoagulants)-  following 3 month DAPT (test group) is superior 
compared to historical DES with 12-month DAPT (control group) 
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Secondary 
Endpoint 
(Bleeding) 
Statistical Test 
Method 
A Propensity Score (PS) Model using quintile adjustment will be used to test 
the one-sided hypothesis of superiority of SYNERGY with 3-month DAPT 
(test group) compared to historical DES with 12-month DAPT (control 
group) 
H0: PMB-3M – PMB-12M ≥ 0 
H1: PMB-3M – PMB-12M < 0 
where PMB -3M and PMB-12M are the 3 to 15-month bleeding rates for the 3-
month DAPT test group and the 12-month DAPT control group, 
respectively. 
Secondary 
Endpoint 
(Bleeding) 
Sample Size 
Parameters 
• Expected 3 to 15 month bleeding rate from 12-month DAPT (control) = 
4%a 
• Expected 3 to 15 month bleeding rate from 3-month DAPT (test) = 
2.19% 
• Test significance level = 0.025 (1-sided) 
• Control subjects are historical -limus DES treated subjects at high risk 
for bleeding obtained from the HCRI DAPT study, number of available 
historical control subjects is approximately 1,240 
• Number of evaluable test subjects in the propensity score model is 1,650 
(including additional 10% subjects accounting for model variability) 
• Power = 80% using chi-square test (unadjusted power for 1,240 vs 
1,650) 
• Expected drop out rate due to ineligibility for 3 month DAPT in 0 to 3 
months = 15% 
• Expected attrition rate in 3 to 15 months = 3% 
• N = 2,000b subjects enrollment 
aThe expected rate for 3 to 15-month bleeding rate is estimated from the 
BSC PROMUS subjects at high risk for bleeding enrolled in the HCRI 
DAPT study (10/253). 
bThe enrollment may be terminated early if the observed dropout rate in 0 to 
3 months is projected to be <15%. 
Study Success 
Criteria 
The study will be considered a success if both the co-primary endpoints of 
death/MI and ARC definite/probable stent thrombosis are met. 
 
 
 
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3. 
Table of Contents 
1. 
CONTACT INFORMATION .................................................................................................... 2 
2. 
PROTOCOL SYNOPSIS .......................................................................................................... 3 
3. 
TABLE OF CONTENTS ........................................................................................................ 13 
3.1. Table of Figures ...................................................................................................... 17 
3.2. Table of Tables ....................................................................................................... 17 
4. 
INTRODUCTION ................................................................................................................. 18 
4.1. Clinical Development Program for SYNERGY .................................................. 19 
4.1.1. 
EVOLVE First Human Use (FHU) Clinical Trial ..................................... 19 
4.1.2. 
EVOLVE II Clinical Program ................................................................... 19 
4.1.3. 
Summary .................................................................................................... 21 
5. 
DEVICE DESCRIPTION ....................................................................................................... 21 
5.1. SYNERGY Stent System Description .................................................................. 21 
5.1.1. 
Device Component Description ................................................................. 22 
5.1.2. 
Drug/Polymer Component Description ..................................................... 22 
5.1.2.1. 
Everolimus ................................................................................ 22 
5.1.2.2. 
Polymer Carrier ......................................................................... 22 
5.2. Device Matrix ......................................................................................................... 23 
5.3. Device Labeling ...................................................................................................... 23 
6. 
PRIMARY OBJECTIVE ........................................................................................................ 24 
7. 
ENDPOINTS ........................................................................................................................ 24 
7.1. Co-Primary Endpoints .......................................................................................... 24 
7.2. Secondary Endpoint ............................................................................................... 24 
7.3. Additional Endpoints ............................................................................................. 24 
8. 
DESIGN .............................................................................................................................. 25 
8.1. Scale and Duration ................................................................................................. 25 
8.2. Treatment Assignment .......................................................................................... 27 
8.2.1. 
Treatment ................................................................................................... 27 
8.3. Justification for the Study Design ......................................................................... 27 
9. 
SUBJECT SELECTION ......................................................................................................... 27 
9.1. Study Population and Eligibility ........................................................................... 27 
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9.2. Inclusion Criteria ................................................................................................... 28 
9.3. Exclusion Criteria .................................................................................................. 29 
10. SUBJECT ACCOUNTABILITY .............................................................................................. 31 
10.1. Point of Enrollment ................................................................................................ 31 
10.2. Withdrawal ............................................................................................................. 31 
11. STUDY METHODS .............................................................................................................. 32 
11.1. Data Collection ....................................................................................................... 32 
11.2. Study Candidate Screening ................................................................................... 33 
11.3. Informed Consent .................................................................................................. 33 
11.4. Antiplatelet Medications ........................................................................................ 33 
11.4.1. Loading Dose (P2Y12 inhibitor) ............................................................... 33 
11.4.2. Loading Dose (Aspirin) ............................................................................. 33 
11.5. Laboratory Procedures .......................................................................................... 34 
11.6. Cardiac Catheterization ........................................................................................ 34 
11.6.1. Index Procedure ......................................................................................... 34 
11.6.1.1. Stent Placement ......................................................................... 34 
11.7. End of the Index Procedure .................................................................................. 34 
11.8. Postprocedure/Prehospital Discharge .................................................................. 34 
11.9. Staged Procedures .................................................................................................. 35 
11.10. 
Follow-Up ................................................................................................. 35 
11.10.1. 3-Month Follow-up (90 days following the index or staged procedure, if 
applicable + 30 days or – 7 days) .............................................................. 36 
11.10.1.1. Eligible for Discontinuation of P2Y12 Inhibitor at 3 Months .. 36 
11.10.1.2. Not Eligible for Discontinuation of P2Y12 Inhibitor at 3 Months
................................................................................................... 36 
11.10.2. 6-Month Follow-up (90 days following the 3-month visit date ± 30 days)37 
11.10.3. 12-Month Follow-up (270 days following the 3-month visit date ± 30 days)
 37 
11.10.4. 15-Month Follow-up (365 days following the 3-month visit date* + 30 days)
 37 
11.10.5. Procedure for Determining When a Subject is Lost to Follow-Up ........... 38 
12. STATISTICAL CONSIDERATIONS ....................................................................................... 39 
12.1. Endpoints ................................................................................................................ 39 
12.1.1. Co-Primary Endpoints ............................................................................... 39 
12.1.1.1. Hypotheses ................................................................................ 39 
12.1.1.2. Sample Size ............................................................................... 40 
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12.1.1.3. Statistical Methods .................................................................... 41 
12.1.2. Secondary Endpoint ................................................................................... 43 
12.1.2.1. Hypothesis................................................................................. 43 
12.1.2.2. Sample Size ............................................................................... 43 
12.1.2.3. Statistical Methods .................................................................... 44 
12.2. General Statistical Methods .................................................................................. 44 
12.2.1. Analysis Sets .............................................................................................. 44 
12.2.2. Control of Systematic Error/Bias ............................................................... 45 
12.2.3. Number of Subjects per Investigative Site ................................................ 46 
12.3. Data Analyses ......................................................................................................... 46 
12.3.1. Post-procedure Endpoints .......................................................................... 46 
12.3.2. Interim Analyses ........................................................................................ 46 
12.3.3. Subgroup Analyses .................................................................................... 46 
12.3.4. Justification of Pooling .............................................................................. 47 
12.3.5. Multivariate Analyses ................................................................................ 47 
12.3.6. Other Analyses ........................................................................................... 48 
12.3.7. Changes to Planned Analyses .................................................................... 48 
13. DATA MANAGEMENT ........................................................................................................ 48 
13.1. Data Collection, Processing, and Review ............................................................. 48 
13.2. Data Retention ........................................................................................................ 48 
14. AMENDMENTS ................................................................................................................... 49 
15. DEVIATIONS ...................................................................................................................... 49 
16. DEVICE/EQUIPMENT ACCOUNTABILITY .......................................................................... 49 
17. COMPLIANCE ..................................................................................................................... 49 
17.1. Statement of Compliance ....................................................................................... 49 
17.2. Investigator Responsibilities ................................................................................. 50 
17.2.1. Delegation of Responsibility ..................................................................... 51 
17.3. Institutional Review Board/ Independent Ethics Committee ............................ 51 
17.4. Sponsor Responsibilities ........................................................................................ 52 
17.5. Insurance ................................................................................................................. 52 
18. MONITORING ..................................................................................................................... 52 
19. POTENTIAL RISKS AND BENEFITS .................................................................................... 53 
19.1. Risks Associated with the Implantation of Coronary Stents ............................. 53 
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19.2. Risks Associated with Everolimus ........................................................................ 54 
19.3. Risks Associated with the Study Device(s) ........................................................... 55 
19.4. Sex-Specific Risks Associated with the Study Device(s) ..................................... 55 
19.5. Risks Associated with Participation in the Clinical Study ................................. 56 
19.6. Possible Interactions with Concomitant Medical Treatments ........................... 56 
19.7. Risk Minimization Actions .................................................................................... 56 
19.8. Anticipated Benefits ............................................................................................... 56 
19.9. Risk to Benefit Rationale ....................................................................................... 56 
20. SAFETY REPORTING .......................................................................................................... 56 
20.1. Definitions and Classification ............................................................................... 56 
20.2. Relationship to Study Device(s) ............................................................................ 59 
20.3. Investigator Reporting Requirements .................................................................. 61 
20.4. Boston Scientific Device Deficiencies .................................................................... 62 
20.5. Reporting to Regulatory Authorities /IRBs /IECs /Investigators ...................... 62 
21. INFORMED CONSENT ......................................................................................................... 62 
22. COMMITTEES .................................................................................................................... 64 
22.1. Steering Committee ................................................................................................ 64 
22.2. Dynamic Safety Monitoring Committee .............................................................. 64 
22.2.1. Clinical Events Committee ........................................................................ 64 
22.2.2. Data Monitoring Committee ...................................................................... 64 
23. SUSPENSION OR TERMINATION ......................................................................................... 65 
23.1 Premature Termination of the Study ................................................................... 65 
23.1.1 
Criteria for Premature Termination of the Study ....................................... 65 
23.2 Termination of Study Participation by the Investigator or Withdrawal of IRB/EC 
Approval ................................................................................................................. 65 
23.3 Requirements for Documentation and Subject Follow-up ................................. 65 
23.4 Criteria for Suspending/Terminating a Study Center ........................................ 66 
24. PUBLICATION POLICY ....................................................................................................... 66 
25. REIMBURSEMENT AND COMPENSATION FOR SUBJECTS (JAPAN ONLY) ......................... 66 
25.1. Subject Reimbursement ........................................................................................ 66 
25.2. Compensation for Subject’s Health Injury ......................................................... 66 
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26. BIBLIOGRAPHY .................................................................................................................. 67 
27. ABBREVIATIONS AND DEFINITIONS .................................................................................. 72 
27.1. Abbreviations ......................................................................................................... 72 
27.2. Definitions ............................................................................................................... 75 
28. APPENDICES ...................................................................................................................... 89 
28.1. Clinical Trial Organization (Japan) ..................................................................... 89 
28.2. Revision History ..................................................................................................... 90 
 
3.1. Table of Figures 
Figure 8.1-1: EVOLVE Short DAPT Study ................................................................................. 26 
 
3.2. Table of Tables 
Table 4.1-1:  Summary of the EVOLVE II Global Clinical Program .......................................... 21 
Table 9.2-1: Inclusion Criteria ...................................................................................................... 28 
Table 9.3-1: Exclusion Criteria ..................................................................................................... 30 
Table 12.1-1: Propensity Score Model Covariates ....................................................................... 42 
Table 20.1-1: Adverse Event Definitions ..................................................................................... 58 
Table 20.2-1: Criteria for Assessing Relationship of Study Device and Procedure to Adverse 
Event .......................................................................................................................... 60 
Table 20.3-1: Investigator Reporting Requirements ..................................................................... 61 
Table 27.1-1: Abbreviations ......................................................................................................... 72 
 
 
 
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4. 
Introduction 
The EVOLVE Short DAPT Study is designed to assess the safety of 3-month dual antiplatelet 
therapy (DAPT) in subjects who are at high risk for bleeding undergoing percutaneous coronary 
intervention (PCI) with the SYNERGY Stent System. The SYNERGY Stent System represents 
the next-generation drug-eluting stent (DES) from Boston Scientific Corporation (BSC, 
Marlborough, Massachusetts, United States). The stent system is based on the well-characterized 
Element™ stent platform and utilizes a bioabsorbable poly(DL-lactide-co-glycolide) (PLGA) 
polymer to deliver everolimus. 
Drug-eluting stents delivering anti-proliferative drugs from a durable polymer have significantly 
reduced angiographic and clinical measures of restenosis compared with bare metal stents 
(BMS), with no apparent increase in the risk of adverse events (AEs) including death and 
myocardial infarction (MI) (2-20).  However, durable polymers have been associated with  
hypersensitivity reactions, delayed healing and incomplete endothelialization which, compared 
to BMS, may contribute to an increased risk of late (30 days to 1 year) and very late (beyond 1 
year) stent thrombosis (ST), especially with first generation DES (21-23). Although newer 
durable polymers may have enhanced biocompatibility and appear to be associated with 
improved clinical outcomes, they have still been incriminated in the occurrence of inflammation, 
neoatherosclerosis, and thrombosis (24,25).  
To reduce the risk of stent thrombosis, clinical guidance documents recommend DAPT 
following DES implantation. The American College of Cardiology/American Heart Association 
recommends that, following DES implantation, patients with stable ischemic heart disease 
should receive clopidogrel (or an alternative P2Y12 inhibitor) in addition to aspirin for a 
minimum of 6 months, unless there is a high bleeding risk. Following DES implantation, patients 
with stable ischemic heart disease who develop a high risk of bleeding (e.g., treatment with oral 
anticoagulant therapy), are at high risk of severe bleeding complication (e.g., major intracranial 
surgery), or develop significant overt bleeding, discontinuation of P2Y12 inhibitor therapy after 
3 months may be reasonable (26) Due to the potential for increased risk of ST with durable 
polymer DES, the recommended duration of DAPT is typically longer with DES compared to 
BMS (26,27). The recent DAPT study suggested that even longer duration DAPT therapy (≥30 
months) provide additional ischemic event reduction (28). However, this study only included 
durable polymer DES and BMS and patients with high risk of bleeding were mainly excluded. A 
number of meta-analyses have been performed examining the impact of prolonged DAPT after 
DES implantation on clinical outcomes (pooling data from 10 trials with >30,000 
participants)(29-33). The meta-analyses concluded that a longer duration of DAPT was 
associated with a lower risk of definite/probable ST and MI compared with a shorter duration of 
DAPT, however, the benefit of longer-term DAPT on ST was significantly attenuated with use of 
second-generation DES compared with first generation DES (31). Longer DAPT duration was 
associated with a significantly higher risk of bleeding and all-cause mortality compared with 
shorter DAPT (29-33). The optimal duration of DAPT in patients at high risk of bleeding 
remains unknown.  
The SYNERGY stent incorporates a number of features designed to improve vascular healing 
and, thus, potentially reduce the risk of late stent thrombosis and the need for prolonged dual 
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antiplatelet therapy. First, the polymer coating, with low initial polymer load, is only applied to 
the abluminal surface of the stent. The inside surface of the stent - the side in contact with the 
bloodstream – is bare metal. Second, the polymer degrades within 4 months leaving only the 
biologically inert bare-metal platform behind (34,35).   
  
4.1. Clinical Development Program for SYNERGY 
The safety and effectiveness of the Element stent platform in combination with everolimus in the 
form of the PROMUS Element stent has been established in the PLATINUM Clinical Trial 
Program (36-51). The EVOLVE series of trials including EVOLVE, EVOLVE II, and EVOLVE 
II QCA, have established the safety and effectiveness of the SYNERGY Stent System 
demonstrating that SYNERGY is comparable in performance to the commercially available 
PROMUS Element stent for the treatment of coronary artery lesions. 
4.1.1. EVOLVE First Human Use (FHU) Clinical Trial 
The EVOLVE trial is a prospective, randomized, multicenter, single-blind, non-inferiority trial 
evaluating the safety and performance of two dose formulations of the SYNERGY stent, 
SYNERGY FHU sent (dose and release profile similar to PROMUS Element) and SYNERGY 
FHU (1/2 Dose) stent (similar release profile and half the dose of PROMUS Element) in 291 
subjects for the treatment of de novo lesions ≤28 mm in length in a native coronary artery 2.25–
3.5 mm (visual estimate). The primary clinical endpoint of the EVOLVE trial was the 30-day 
TLF rate defined as a composite of cardiac death or MI related to the target vessel, or ischemia-
driven TLR. The primary angiographic endpoint was in-stent late loss as measured by QCA at 6 
months. The 30-day TLF rate was 0%, 1.1%, and 3.1% in the PROMUS Element, SYNERGY 
FHU, and SYNERGY FHU (1/2 Dose) groups respectively. All TLF events in the SYNERGY 
groups were attributable to target vessel related periprocedural non-Q-wave MIs. At 6 months, 
the TLF rate was 3.1%, 2.2%, and 4.1% in the PROMUS Element, SYNERGY FHU, and 
SYNERGY FHU (1/2 Dose) groups respectively. Through 6 months, there were no Q-wave MIs, 
cardiac deaths, or stent thromboses in any group. The 6-month primary angiographic endpoint of 
in-stent late loss was 0.15±0.34 mm, 0.10±0.25 mm, and 0.13±0.26 mm for PROMUS Element, 
SYNERGY FHU, and SYNERGY FHU (1/2 Dose) respectively. The upper one-sided 95.2% 
confidence limit of the difference between test and control for SYNERGY FHU was 0.02 and 
SYNERGY FHU (1/2 Dose) was 0.05; both lower than the pre-specified non-inferiority margin 
of 0.20 mm (P for non-inferiority <0.001)(34). At 12-months, there were no significant 
differences between groups in TLF, MI, and revascularization rates and there were no cardiac 
deaths, Q-wave MIs, or stent thromboses in any group (52,53). The study is now considered 
complete with regard to the primary endpoint and follow-up through 4 years is complete (54). 
There were no significant differences between PROMUS Element and either SYNERGY stent 
for any major cardiac endpoint through 4 years (52,54,55)_ENREF_35_ENREF_35. Additional 
follow-up is ongoing to 5 years. 
4.1.2. EVOLVE II Clinical Program 
The SYNERGY stent is currently being evaluated in the EVOLVE II global clinical program for 
the treatment of subjects with a maximum of 3 de novo atherosclerotic lesions. The program 
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includes the EVOLVE II trial, which comprises a randomized controlled trial (RCT) with single-
arm diabetic (DM) and pharmacokinetic (PK) substudies, and the EVOLVE II Quantitative 
Coronary Angiography (QCA) study as detailed below and in Table 4.1-1. 
• The randomized controlled trial (RCT) at 125 global centers enrolled 1,684 subjects (1:1 
randomization of SYNERGY to PROMUS Element Plus) with a maximum of 3 
atherosclerotic lesions ≤34 mm in length (by visual estimate) in native coronary arteries 
≥2.25 mm to ≤4.0 mm in diameter (by visual estimate).  This study completed enrollment 
in August, 2013 and follow-up continues through 5 years.  
The RCT primary endpoint of 12-month target lesion failure (TLF), defined as ischemia-
driven target lesion revascularization (TLR), target vessel-related MI, or cardiac death, 
was observed in 6.7% of SYNERGY and 6.5% PROMUS Element Plus treated subjects 
by intention-to-treat analysis (p=0.0005 for non-inferiority) and 6.4% in both groups by 
per protocol analysis (p=0.0003 for non-inferiority). With respect to 1-year TLF 
SYNERGY is non-inferior to PROMUS Element Plus. Clinically-indicated TLR and 
definite/probable stent thrombosis were observed in 2.6% vs 1.7% (p=0.21) and 0.4% vs 
0.6% (p=0.50) of SYNERGY vs. PROMUS Element Plus treated subjects, respectively 
(56). 
• A concurrent, non-randomized, diabetic (DM) substudy at 48 global centers enrolled an 
additional 203 SYNERGY diabetic subjects with atherosclerotic lesions ≤ 34 mm in 
length (by visual estimate) in native coronary arteries ≥ 2.25 mm to ≤ 4.0 mm in diameter 
(by visual estimate).  Enrollment was complete in December, 2013 and follow-up 
continues through 5 years.  
In the EVOLVE II Diabetes Substudy, diabetic subjects randomized to the SYNERGY 
arm in the EVOLVE II RCT (263 subjects) were pooled with diabetic subjects enrolled in 
the single-arm DM substudy (203 subjects) for a total of 466 diabetic subjects treated 
with SYNERGY stents. The primary endpoint of 12-month TLF was met. In the 
intention-to-treat analysis, the rate of TLF was 7.5% in SYNERGY treated diabetic 
subjects which is significantly less than the performance goal (14.5%; P<0.0001). 
Definite or probable stent thrombosis occurred in 1.1% of subjects (57).  
• A concurrent, non-randomized, pharmacokinetic (PK) substudy at 6 centers enrolled 21 
subjects with atherosclerotic lesions ≤ 34 mm in length (by visual estimate) in native 
coronary arteries ≥ 2.25 mm to ≤ 4.0 mm in diameter (by visual estimate) to evaluate 
everolimus blood levels following stent implantation.  Enrollment was complete in 
October, 2013. 
• The EVOLVE II QCA study was a prospective, single-arm, multicenter, observational 
study that enrolled 100 subjects at 12 centers with atherosclerotic lesion(s) ≤34 mm in 
length (by visual estimate) in native coronary arteries ≥2.25 mm to ≤4.0 mm in diameter 
(by visual estimate).  Enrollment was complete in October, 2013 and the final follow-up 
visit occurred in October 2014; the trial is now complete.  
The EVOLVE II QCA primary endpoint analysis of in-stent late loss at 9 months post-
index procedure, was 0.23±0.34 mm (in 95 subjects) which was significantly less than the 
performance goal of 0.40 mm (p<0.0001). There were no deaths and no subject 
experienced a definite, probable or possible stent thrombosis through 12 months. Five 
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subjects had peri-procedural non-Q-wave myocardial infarctions (5.0%) according to the 
protocol definition (with peri-procedural MI defined based on CK-MB >3x URL) (58).   
 
Table 4.1-1:  Summary of the EVOLVE II Global Clinical Program 
Trial Name 
EVOLVE II RCT 
EVOLVE II 
DM substudy 
EVOLVE II 
PK substudy 
EVOLVE II 
QCA 
Design 
1:1 
Randomization 
SYNERGY vs. 
PROMUS 
Element Plus 
Single Arm 
Single Arm 
Single Arm 
Vessel  (mm) 
≥2.25 to ≤4.0 
≥2.25 to ≤4.0 
≥2.25 to ≤4.0 
≥2.25 to ≤4.0 
Lesion Length 
(mm) 
≤34 
≤34 
≤34 
≤34 
Sample Size 
1684 
(846 SYNERGY;  
838 PROMUS 
Element Plus) 
203 
21 
100 
Primary 
Endpoint 
12 Month TLF 
12 Month TLF 
Observational 
9 month In-Stent 
Late Loss (mm) 
Primary 
Endpoint 
Result 
(SYNERGY)1 
6.7% (55/826) 
7.5% (34/451) 
Not Applicable 
0.23±0.34 
Abbreviations: DM=diabetic, PK=pharmacokinetics; QCA=quantitative coronary angiography; 
RCT=randomized controlled trial; TLF=target lesion failure (target vessel-related cardiac death, 
target vessel-related myocardial infarction, or ischemia-driven target lesion revascularization) 
1: Based on intent-to-treat analysis  
 
4.1.3. Summary 
Safety and efficacy of the SYNERGY Stent System has been demonstrated in the EVOLVE 
Clinical Program.  The SYNERGY stent has unique characteristics, and is designed to complete 
resorption of the polymer shortly following the drug elution at 90 days.  The EVOLVE Short 
DAPT Study is designed to assess the safety of a 3 month DAPT regimen following implantation 
of the SYNERGY stent in a population of patients at high risk for bleeding where a longer 
DAPT duration might not be appropriate. 
5. 
Device Description 
5.1. 
SYNERGY Stent System Description 
The SYNERGY Everolimus-Eluting Platinum Chromium Coronary Stent System (SYNERGY 
Stent System) is a device/drug combination product comprised of two regulated components: a 
device (coronary stent system) and a drug product (a formulation of everolimus contained in a 
bioabsorbable polymer coating).  
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5.1.1. Device Component Description 
The SYNERGY Stent System consists of a platinum chromium stent platform with an abluminal 
drug/polymer coating mounted onto a Monorail or Over-the-Wire Delivery System.  There are 
three stent models available for the SYNERGY stent:  
• Small Vessel (SV): 2.25 mm, 2.50 mm and 2.75 mm 
• Workhorse (WH): 3.00 mm, 3.50 mm 
• Large Vessel (LV): 4.00 mm 
5.1.2. Drug/Polymer Component Description 
5.1.2.1. 
Everolimus 
Everolimus is the active pharmaceutical ingredient in the SYNERGY stent. Everolimus 
possesses anti-fungal, immunosuppressive and anti-proliferative properties. At the cellular level, 
everolimus inhibits growth factor-stimulated cell proliferation in a reversible manner. 
Everolimus binds to cytosolic FKBP12 and subsequently inhibits activation of the regulatory 
kinase mTOR (mammalian target of rapamycin). This inhibition results in cell arrest at the late 
G1 phase in the cell cycle and thereby impedes functions that govern cell metabolism, growth, 
and proliferation. Everolimus has been evaluated in clinical trials in the United States (US) and 
Europe for use in conjunction with other medications to prevent heart and renal transplant 
rejection. Everolimus used as an active ingredient on coronary stents has been shown to prevent 
restenosis in clinical trials. 
5.1.2.2. 
Polymer Carrier 
The SYNERGY stent is coated on the abluminal stent surface with a bioabsorbable drug matrix. 
The bioabsorbable drug matrix is composed of PLGA mixed with everolimus.  
 
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5.2. 
Device Matrix 
The SYNERGY stent system is approved and commercially available. In the EVOLVE Short 
DAPT Study, clinical sites will select devices from the commercial inventory. The SYNERGY 
device matrix consists of the following sizes (stent diameter and stent length): 
 
 
Length 
8  
mm 
12 
mm 
16 
mm 
20 
mm 
24 
mm 
28 
mm 
32 
mm 
38 
Mm 
Diameters 
2.25 
mm 
X 
X 
X 
X 
X 
X 
X 
X 
2.50 
mm 
X 
X 
X 
X 
X 
X 
X 
X 
2.75 
mm 
X 
X 
X 
X 
X 
X 
X 
X 
3.00 
mm 
X 
X 
X 
X 
X 
X 
X 
X 
3.50 
mm 
X 
X 
X 
X 
X 
X 
X 
X 
4.00 
mm 
X 
X 
X 
X 
X 
X 
X 
X 
 
5.3. 
Device Labeling  
A basic description of the SYNERGY device and a comprehensive set of Directions for Use 
(DFU) are contained in each product package or are available electronically, per local regulation, 
on a Boston Scientific website.   
 
 
 
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6. 
Primary Objective 
The primary objective of the EVOLVE Short DAPT Study is to assess the safety of 3-month dual 
antiplatelet therapy (DAPT) in subjects at high risk for bleeding undergoing percutaneous 
coronary intervention (PCI) with the SYNERGY Stent System. 
7. 
Endpoints 
7.1. 
Co-Primary Endpoints 
• Rate of death or myocardial infarction (MI) between 3 and 15 months 
• Rate of Academic Research Consortium (ARC) definite/probable stent thrombosis (ST) (8) 
involving SYNERGY between 3 and 15 months 
7.2. 
Secondary Endpoint 
• Rate of bleeding, based upon the Bleeding Academic Research Consortium (BARC) 
classification (types 2, 3 and 5) (59),between 3 and 15 months in subjects not taking chronic 
anticoagulation. 
7.3. 
Additional Endpoints 
The following clinical endpoints will be measured at 3 months, 6 months, 12 months and 15 
months: 
• Rate of major adverse cardiac & cerebrovascular events (MACCE), defined as the composite 
of all death, MI, and stroke 
• Rate of major adverse cardiac events (MACE), defined as the composite of cardiac death, MI 
and TVR 
• Rate of target vessel failure (TVF), defined as the composite of TVR, cardiac death or target 
vessel related MI  
• Rate of cardiac death/MI 
• Rate of bleeding (GUSTO definition) (60) 
• Rate of bleeding (BARC definition) (59) 
• Rate of bleeding (TIMI definition) (61) 
• Rate of stent thrombosis (ARC definite/probable) 
• Rate of cardiac death 
• Rate of non-cardiac death 
• Rate of all cause death 
• Rate of death/MI 
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• Rate of MI (Q-wave and non–Q-wave) 
• Rate of stroke, ischemic and hemorrhagic 
• Rate of Target Vessel Revascularization (TVR) 
• Rate of Target Lesion Revascularization (TLR) 
• Rate of MI (ST-related and not ST-related) 
 
8. 
Design 
The EVOLVE Short DAPT Study is a prospective, multicenter, single-arm study, using a 
historical control and a propensity score approach to assess the safety of 3-month DAPT in 
subjects at high risk for bleeding undergoing PCI with a SYNERGY Stent System  
 
8.1. 
Scale and Duration 
The EVOLVE Short DAPT Study will be conducted at up to 120 sites worldwide in the United 
States, Europe, Japan, and Brazil with planned enrollment of up to 2,250 subjects. Follow-up 
will be required at the following time points: 3 months, 6 months, 12 months and 15 months.  
 
A schematic of the EVOLVE Short DAPT Study is shown on the following page in Figure 8.1-1. 
 
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Figure 8.1-1: EVOLVE Short DAPT Study 
 
 
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8.2. Treatment Assignment 
A subject is considered enrolled once the Institutional Review Board (IRB)/Ethics Committee 
(EC) approved study informed consent form (ICF) has been signed and the subject has received 
at least one commercial SYNERGY stent. Enrolled subjects must meet all inclusion and no 
exclusion criteria. Enrollment should occur within 3 calendar days of the index procedure date.  
8.2.1. Treatment  
Subjects should be treated per physician discretion and standard of care with the exception of the 
protocol requirement for DAPT.  The sites’ commercial device supply will be used.  
8.3. Justification for the Study Design 
Based on the novel design feature of the SYNERGY stent (polymer resorption occurring soon 
after completion of drug release at 90 days), it is expected that planned treatment with 3 months 
of DAPT in in the defined population of patients at high risk of bleeding will be safe, and may 
result in benefits such as avoidance of bleeding, cost and delay of non-cardiac procedures 
relative to a strategy of longer-term DAPT in the setting of current durable polymer drug-eluting 
stents. 
Given that the predictors of the key outcomes of interest are well-understood and there is limited 
residual between-trial variation, a prospective single arm study has been proposed for the 
EVOLVE Short DAPT Study. The design includes a large historical control cohort, instead of a 
traditional randomized trial, resulting in a smaller overall sample size, without sacrificing 
sensitivity to detect adverse events in the experimental arm. 
 
9. 
Subject Selection  
9.1. Study Population and Eligibility  
Inclusion and exclusion criteria for the EVOLVE Short DAPT Study are included in Table 9.2-1 
and Table 9.3-1 respectively. Prior to enrollment in the trial, a subject must meet all of the 
inclusion criteria and none of the exclusion criteria. 
 
 
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9.2. Inclusion Criteria 
Subjects who meet all of the following criteria (see Table 9.2-1) may be given consideration for 
inclusion in this clinical investigation, provided no exclusion criteria (see Section 9.3) are met 
Table 9.2-1: Inclusion Criteria 
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 >3 months of DAPT 
outweighs the benefit,  
• 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 ≤100,000/μL 
2. Subject must be at least 18 years of age 
3. Subject must have had implantation of at least one SYNERGY stent 
within the preceding 3 calendar days 
4. Subject must be able to take study required antiplatelet therapy (as 
required per protocol) 
5. Subject is willing to comply with all protocol requirements, 
including agreement to stop taking P2Y12 inhibitor at the 3-month 
milestone, if eligible per protocol  
6. Subject (or legal guardian) understands the trial requirements and the 
treatment procedures and provides written informed consent before 
any study-specific procedures are performed 
7. For subjects less than 20 years of age enrolled at a Japanese site, the 
subject/ the subject’s legal representative must provide written 
informed consent before any study-specific tests or procedures are 
performed 
 
 
 
 
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9.3. Exclusion Criteria 
Subjects who meet any one of the following criteria (Table 9.3-1) will be excluded from this 
clinical investigation. 
 
1. Subject who is taking (or is planning to take) chronic or lifelong 
anticoagulation within 15 months following index procedure. 
 
2. Subject with an indication for the index procedure of acute ST 
elevation MI (STEMI) 
3. Subject with an indication for the index procedure of Non ST 
elevation MI (NSTEMI), based on the 3rd Universal MI definition (1)  
4. Subject with treatment with another coronary stent, other than 
SYNERGY, during the index procedure 
5. Subject with planned staged procedures. (Note: Planned staged 
procedures are allowed if performed within 7 days and with only 
SYNERGY stents). 
6. Subject has a known allergy to contrast (that cannot be adequately 
pre-medicated), the SYNERGY stent system or protocol-required 
concomitant medications (e.g., everolimus or structurally related 
compounds, polymer or individual components, all P2Y12 inhibitors 
and aspirin)  
7. Subject with implantation of a drug-eluting stent within 9 months 
prior to index procedure 
8. Subject previously treated at any time with intravascular 
brachytherapy 
9. Subject has an active peptic ulcer or active gastrointestinal (GI) 
bleeding 
10. 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) 
11. Subject intends to participate in an investigational drug or device 
clinical trial within 15 months following the index procedure (Note: 
registry, observational, data collection studies are not exclusionary) 
 
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Table 9.3-1: Exclusion Criteria 
Exclusion 
Criteria 
12. Subject judged inappropriate for discontinuation from P2Y12 
inhibitor use at 3 months, due to another condition requiring chronic 
P2Y12 inhibitor use 
13. Subject with planned surgery or procedure necessitating 
discontinuation of P2Y12 inhibitor within 3 months following index 
procedure 
14. Subject is a woman who is pregnant or nursing  
15. Subject with a current medical condition with a life expectancy of 
less than 15 months 
16. Target lesion(s) is located in the left main 
17. Target lesion(s) is located within 3 mm of the origin of the left 
anterior descending (LAD) coronary artery or left circumflex (LCx) 
coronary artery by visual estimate 
18. Subject has unprotected left main coronary artery disease ( > 50% 
diameter stenosis) 
19. Planned treatment of more than 3 lesions 
20. Planned treatment of lesions in more than 2 major epicardial vessels 
21. Target lesion(s) treated that involves complex bifurcation (i.e. 
bifurcation lesion treated with more than one stent) 
22. Target lesion(s) is restenotic from a previous stent implantation 
23. Target lesion(s) is located within a saphenous vein graft or an arterial 
graft 
24. Target lesion(s) with a TIMI flow 0 (total occlusion) or TIMI flow 1 
prior to guide wire crossing 
25. Thrombus, or possible thrombus, present in the target vessel (by 
visual estimate) 
 
 
 
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10. 
Subject Accountability 
10.1. 
Point of Enrollment 
A subject is considered enrolled once the Institutional Review Board (IRB)/Ethics Committee 
(EC) approved study informed consent form (ICF) has been signed and the subject has received 
at least one commercial SYNERGY stent. Enrolled subjects must meet all inclusion and no 
exclusion criteria. Enrollment should occur within 3 calendar days of the index procedure date. 
10.2. Withdrawal 
All subjects enrolled in the clinical trial (including those withdrawn from the clinical trial or lost 
to follow-up) shall be accounted for and documented. While trial withdrawal is discouraged, 
subjects may choose to withdraw from the trial at any time, with or without reason and without 
prejudice to further treatment. Withdrawn subjects will not undergo any additional trial follow-
up, nor will they be replaced (the justified sample size considers an estimated allowance for 
attrition). The reason for withdrawal will be recorded (if given) in all cases of withdrawal. All 
applicable case report forms (CRFs) up to the point of subject withdrawal, including the End of 
Study CRF must be completed. Subjects who are “lost to follow-up” should have documented 
attempts to contact them prior to the completion of the End of Study CRF. Additional data will 
no longer be collected after the point at which a subject withdraws his/her consent. Data 
collected up to the point of subject withdrawal may be used. 
 
 
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11. 
Study Methods 
11.1. Data Collection 
The data collection schedule for the EVOLVE Short DAPT Study is summarized below: 
 
 
 
Pre-
Index 
Proced
ure 
Index 
Proc-
edure 
Post-
Procedure
/Pre 
Discharge 
Follow-Up Visits 
3-month   
Office or 
Telephone 
6-month 
Office or 
Telephone 
12-month  
Office or 
Telephone 
15-month  
Office or 
Telephone 
Informed Consent1 
X 
 
 
 
 
Demography 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Cardiac 
Biomarkers (CK, 
CK-MB, and/or 
troponin) 
X2 
 
X3 
 
 
 
 
Angiography/ 
Stent Implantation  
 
X 
 
 
 
 
 
Assessment of 
Eligibility to 
Discontinue 
P2Y12 Inhibitor 
 
 
 
X 
 
 
 
DAPT Medication 
Data Collection  
X 
X 
X 
X 
X 
X 
X 
ADE, SAE, 
SADE, UADE, 
USADE, and 
device deficiency 
assessment 
 
X 
X 
X 
X 
X 
X 
Endpoint Event 
(MACCE, ST, 
bleeding) 
Assessment 
 
X 
X 
X 
X 
X 
X 
 
1 Consent can be obtained either pre-procedure or post-procedure (up to 3 calendar days after the index procedure). If the study Informed 
Consent Form is modified during the course of the trial, study subjects will be re-consented, if necessary. 
 
2 If performed per standard of care, pre-procedure cardiac enzymes (CK, CK-MB, and/or troponin within 72 hours prior to the index 
procedure) should be recorded in the EDC system. If more than one draw was performed within 72 hours, only the most recent value 
should be recorded in EDC. 
 
3 If performed per standard of care, post-procedure cardiac enzymes (CK, CK-MB, and/or troponin between 12-24 hours following index 
procedure or prior to discharge, if discharged prior to the 12 hours) should be recorded in the EDC system. Only peak values should be 
recorded in EDC.  
 
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11.2. Study Candidate Screening 
Study investigators are expected to follow standard of care testing to diagnose and screen 
subjects for inclusion in the study.  
A screening log will be maintained to document selected information about consented subjects 
who fail to meet the EVOLVE Short DAPT Study criteria, including the reason for screen 
failure. 
11.3. Informed Consent 
Subjects who meet the enrollment eligibility criteria will be asked to sign the IRB/EC-approved 
study informed consent form (ICF). Subjects must be given ample time to review the ICF and 
have questions answered before signing. Informed consent must be obtained prior to the 
subject’s index procedure or within 3 calendar days following the index procedure, prior to any 
subject data entry into EDC.  The date of index procedure is considered day 0 and enrollment can 
occur as late as day 3. 
Refer to section 10.1 for definition of point of enrollment. 
11.4. Antiplatelet Medications 
Antiplatelet medications (aspirin + P2Y12 inhibitor) must be reported in the electronic case 
report form (eCRF) from 72 hours prior to the index procedure through the end of the study. 
Information pertaining to the use of antiplatelet medications including dose changes, medication 
interruptions (3 days or greater), and medication cessation, must be documented.  
11.4.1. Loading Dose (P2Y12 inhibitor) 
• For subjects who have been taking a P2Y12 inhibitor for ≥ 72 hours at the time of the index 
procedure, a loading dose is not required. 
 
• For subjects who have not been taking a P2Y12 inhibitor for ≥ 72 hours at the time of the 
index procedure, a loading dose is recommended. It is recommended that the loading dose be 
administered prior to the index procedure or not more than 2 hours after the index procedure.  
The following loading doses are recommended:  
o Clopidogrel: A peri-procedural loading dose of ≥ 300 mg is recommended.  
o Prasugrel: A peri-procedural loading dose of 60 mg is recommended. 
o Ticagrelor: A peri-procedural loading dose of 180 mg is recommended. 
11.4.2. Loading Dose (Aspirin) 
• For subjects who have been taking aspirin daily for ≥ 72 hours at the time of the index 
procedure, a loading dose is not 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 is recommended prior to the index procedure. The 
dosage of the loading dose is at the discretion of the Investigator. It is recommended that the 
loading dose be administered prior to the index procedure. 
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11.5. Laboratory Procedures 
If performed per standard of care, results of the following laboratory tests will be recorded in the 
study electronic data capture system (EDC): 
• Before the index procedure (within 72 hours prior to the index procedure), a CK, CK-MB, 
and/or troponin. If more than one draw was performed within 72 hours, only the most recent 
value should be recorded in EDC. 
• A post-procedural (12 - 24 hours post-index procedure or prior to discharge, if hospitalized < 
12 hours) CK, CK-MB, and/or troponin. Only peak enzyme values should be recorded in 
EDC. 
11.6. Cardiac Catheterization 
11.6.1. Index Procedure 
The start of the index procedure is defined as the time of sheath insertion. If a previously placed 
sheath is used (i.e., from a separate diagnostic procedure), index procedure start time is defined 
as the time of guide catheter insertion into sheath for the interventional procedure. 
 
11.6.1.1. 
Stent Placement 
Stent placement should be performed per local standard practice. Refer to the DFU for detailed 
instructions about preparation and placement of the SYNERGY stent. 
 
11.7. End of the Index Procedure 
The end of the index procedure is defined as the time the guiding catheter was removed (post 
final angiography). The introducer(s) sheaths should be removed as per standard local practice.  
 
The following procedures must be completed:  
• Document baseline, procedural, target lesion and SYNERGY stent information on the 
appropriate eCRFs. 
• Record antiplatelet medications 
• Complete AE assessment and collect source documents as described in Section 20.  
11.8. Postprocedure/Prehospital Discharge 
• Aspirin: Subjects must be treated with aspirin for the duration of the trial. The minimum 
daily maintenance dose of aspirin should be 75–100 mg. 
 
• P2Y12 inhibitor: Subjects should be treated with one of the following P2Y12 inhibitors 
(clopidogrel, prasugrel, or ticagrelor) for 3 months following the index procedure. 
 
• Enrolled subjects must take both aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, or 
ticagrelor) for 3 months following the index procedure. 
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• Enrolled subjects will be evaluated at 3 months to confirm that discontinuation of P2Y12 
inhibitor remains appropriate. 
 
• Subjects who are eligible for discontinuation of P2Y12 inhibitor therapy at 3 months are 
required to take aspirin starting at 3 months and continuing for the duration of the study. 
• The subject may be discharged from the hospital when clinically stable at the Investigator’s 
discretion. Generally, this is ≤ 24 hours post index procedure but standard, local practice 
should be followed. 
• Complete AE assessment and collect source documents as described in Section 20. 
• It is important that trial site personnel review the trial requirements with the subject to 
maximize compliance with the follow-up schedule and required medication regimen. It is 
also important that trial site personnel instruct subjects to return/respond for follow-up 
assessments according to the trial event schedule. Study staff should establish a date for the 
follow-up visit with the subject and if possible, schedule the visit(s) at the time of hospital 
discharge. 
11.9. Staged Procedures 
• Planned staged procedures are allowed if performed ≤ 7 days from the index procedure 
and with only SYNERGY stents.  
• Subjects with a planned staged procedure > 7 days from the index procedure or with 
stents other than SYNERGY must not be enrolled in the study.  
• A staged procedure is only permitted when all enrollment inclusion criteria and no 
enrollment exclusion criteria are met for all lesions treated during both the initial 
procedure and the subsequent staged procedure.  
• The total number of lesions treated during the index and staged procedures combined 
must not exceed 3. 
• The total number of major epicardial vessels treated during the index and staged 
procedures combined must not exceed 2.  
• In the case of a staged procedure meeting these criteria, the subject should return for the 
3-month visit (i.e. assessment for eligibility to discontinue P2Y12 inhibitor) 90 days 
following the staged procedure + 30 days or - 7 days. 
11.10. Follow-Up 
All enrolled subjects who receive a SYNERGY stent will be evaluated in-hospital and at 
3 months, 6 months, 12 months and 15 months after the index procedure.  
All protocol-required follow-up assessments must be conducted with direct contact with the 
subjects by a trained study team member, documented on the Delegation of Authority log. In 
order to allow for flexibility to encourage subject retention, follow-up assessments may be 
performed via telephone interview or office visit as per local practice. At the time of each 
protocol required follow-up, study site personnel should answer any study-related questions the 
subject may have in addition to completing the required protocol assessments. 
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11.10.1.    3-Month Follow-up (90 days following the index or staged procedure, if 
applicable + 30 days or – 7 days) 
All enrolled subjects must be evaluated 3 months after the index or staged (if applicable) 
procedure. The follow-up assessment may be performed via telephone interview with the subject 
or during an office visit. During the 3-month follow-up, the following assessments must be 
completed.  
• AE assessment and source document collection as described in Section 20.  
• Documentation of current antiplatelet medications (P2Y12 inhibitor and aspirin). Information 
pertaining to dose changes, medication interruptions (3 days or greater), and medication 
cessation must be documented. 
• Assessment of subject’s eligibility to discontinue P2Y12 inhibitor. Investigator involvement 
in the assessment to discontinue P2Y12 inhibitor is required.  
• If a subject meets criteria, the subject should discontinue P2Y12 inhibitor at the time of the 
3-month follow-up visit and should continue taking aspirin through the end of the study. 
 
All enrolled subjects should be followed at all milestones through 15-months, regardless of 
eligibility to discontinue P2Y12 inhibitor 
 
11.10.1.1. 
Eligible for Discontinuation of P2Y12 Inhibitor at 3 Months 
Subjects are eligible for discontinuation of P2Y12 inhibitor at 3 months if they meet both of the 
following criteria: 
• Subject was treated with 3 months of P2Y12 inhibitor/aspirin post index procedure. (Subjects 
enrolled under a prior version of the protocol who were on chronic anticoagulation between 
0-3 months are eligible if they were also taking P2Y12 inhibitor or P2Y12 inhibitor/aspirin 
between 0-3 months). 
• Subject was free from events (stroke, MI, PCI, CABG, and stent thrombosis) between the 
index procedure and the 3-month visit 
11.10.1.2. 
Not Eligible for Discontinuation of P2Y12 Inhibitor at 3 Months 
Subjects are not eligible for discontinuation of P2Y12 inhibitor at 3 months if any of the 
following criteria are met: 
• Subject who experiences a stroke, MI, PCI, CABG and/or stent thrombosis, during the 0-3 
month period (between the date of index procedure and the date of the 3-month follow-up 
visit) 
• Subject who is non-compliant with P2Y12 inhibitor or aspirin during the 0-3 month period 
(between the date of the index procedure and the date of the 3-month follow-up visit). 
Subjects enrolled under a prior version of the protocol who were on chronic anticoagulation 
between 0-3 months are not eligible if they were not taking P2Y12 inhibitor or P2Y12 
inhibitor/aspirin between 0-3 months. 
Non-compliant defined as: 
o Taking less than 80% or greater than 120% (subject reported); and/or  
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o Interruption for 14 or more consecutive days 
• Subject judged inappropriate for discontinuation from P2Y12 inhibitor use at 3 months due 
to another condition requiring chronic P2Y12 inhibitor use 
Compliance to the use of P2Y12 inhibitor and aspirin will be ascertained from the subject 
interview at the 3-month follow-up visit and will be used to determine if the subject is eligible 
for discontinuation of P2Y12 inhibitor. During the interview, the subject will also be asked about 
any significant interruptions (3 days or greater) in the prescribed treatment since the last follow-
up visit.  
Note: All enrolled subjects who receive a SYNERGY stent must be followed at all milestones 
through 15-months, regardless of eligibility to discontinue P2Y12 inhibitor. 
 
11.10.2.   6-Month Follow-up (90 days following the 3-month visit date ± 30 days) 
All enrolled subjects must be evaluated approximately 6 months after the index procedure (3 
months after the 3-month visit). The follow-up assessment may be performed via telephone 
interview with the subject or during an office visit. During the 6-month follow-up, the following 
assessments must be completed.  
• AE assessment and source document collection as described in Section 20. 
• Documentation of current antiplatelet medications (P2Y12 inhibitor and aspirin). Information 
pertaining to dose changes, medication interruptions (3 days or greater), and medication 
cessation must be documented. 
11.10.3.    12-Month Follow-up (270 days following the 3-month visit date ± 30 days) 
All enrolled subjects must be evaluated approximately 12 months after the index procedure (9 
months after the 3-month visit). The follow-up assessment may be performed via telephone 
interview with the subject or during an office visit. During the 12-month follow-up, the 
following assessments must be completed. 
• AE assessment and source document collection as described in Section 20.  
• Documentation of current antiplatelet medications (P2Y12 inhibitor and aspirin). Information 
pertaining to dose changes, medication interruptions (3 days or greater), and medication 
cessation must be documented. 
11.10.4.    15-Month Follow-up (365 days following the 3-month visit date* + 30 days) 
All enrolled subjects must be evaluated approximately 15 months after the index procedure (12-
months after the 3-month visit). The follow-up assessment may be performed via telephone 
interview with the subject or during an office visit. During the 15-month follow-up, the 
following assessments must be completed. 
• AE assessment and source document collection as described in Section 20.  
• Documentation of current antiplatelet medications (P2Y12 inhibitor and aspirin). Information 
pertaining to dose changes, medication interruptions (3 days or greater), and medication 
cessation must be documented. 
 
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11.10.5.     Procedure for Determining When a Subject is Lost to Follow-Up 
A subject will not be considered lost to follow-up unless the subject misses the 15-month follow-
up visit. A minimum of 3 attempts (i.e., 2 phone calls followed by a certified letter) should be 
made to contact the subject for each missed follow-up visit. This information should be 
documented in the source. 
 
 
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12. 
Statistical Considerations 
12.1. Endpoints 
12.1.1. Co-Primary Endpoints 
There are two powered co-primary endpoints: 
 
1. The rate of death or myocardial infarction (MI) between 3 and 15 months expressed as 
the proportion of subjects who experience death/MI between 3 and 15 months among all 
subjects who either experience death/MI between 3 and 15 months or survive free of 
death/MI for at least 425 days. 
 
2. The rate of Academic Research Consortium (ARC) definite/probable stent thrombosis 
(ST) involving SYNERGY between 3 and 15 months expressed as the proportion of 
subjects who experience ARC ST between 3 and 15 months among all subjects who 
either experience ARC ST between 3 and 15 months or survive free of ARC ST for at 
least 425 days. 
 
12.1.1.1. 
Hypotheses 
Death/MI: 
The null hypothesis that the difference of death/MI rates between SYNERGY with 3-month 
DAPT (test group) and historical DES with 12-month DAPT (control group) is greater than or 
equal to the non-inferiority margin will be tested against the alternative hypothesis that the 
difference between test group and control group is less than the non-inferiority margin in 
subjects at high risk for bleeding: 
H0: PDeath/MI-3M – PDeath/MI-12M ≥ Δ 
H1: PDeath/MI-3M – PDeath/MI-12M < Δ 
where PDeath/MI-3M and PDeath/MI-12M are the 3 to 15-month  death/MI rates for the 3-month DAPT 
test group and 12-month DAPT group (historical control), respectively, and Δ is the non-
inferiority margin. 
A propensity score model using quintile adjustment for death/MI will be used to test the 
hypothesis of non-inferiority of the test group compared to historical control group. 
 
ARC-defined ST: 
The null hypothesis that ARC ST rate is greater than or equal to the performance goal will be 
tested against the alternative hypothesis that ARC ST rate for the is less than the performance 
goal: 
H0: PST-3M ≥ PG 
H1: PST-3M < PG 
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where PST-3M is the rate of 3 to 15-month ARC-defined definite/probable ST involving 
SYNERGY for the 3-month DAPT group, and PG is the performance goal. 
 
12.1.1.2. 
Sample Size  
Death/MI: 
The expected rate of 5.6% for 3 to 15 month death/MI rates in subjects at high risk for bleeding 
for both test and control groups is estimated from BSC PROMUS subjects extracted from the 
HCRI DAPT, PE+ PAS, and PE PROVE studies. The non-inferiority margin is 2.52%, which is 
45% of the expected rate. With one-sided 2.5% significance level, the study will require a 
minimum of 1,500 evaluable subjects per group to provide 85% power to reject the null 
hypothesis when the alternative hypothesis is true. With consideration of additional 10% subjects 
accounting for model variability, number of evaluable subjects in the test group required in the 
propensity score model is 1,650 (1,500 *1.1). In the control group, there are approximately 1,643 
historical -limus DES high risk for bleeding subjects available from Boston Scientific sponsored 
trials (403) and the HCRI DAPT Study minus TAXUS (1,240). Assuming that the dropout rate 
due to the ineligibility between 0 and 3 months for 3-month DAPT test group is 15% and the 
expected attrition rate between 3 and 15 months is 3%, the study needs to enroll 2,000 subjects in 
the 3-month DAPT test group. 
The enrollment may be terminated earlier if the observed dropout rate between 0 and 3 months is 
projected to be less than 15%. Enrollment may be continued beyond 2,000 subjects (up to a 
maximum of 2,250 subjects) if the observed dropout rate in 0 to 3 months is projected to be 
>15%. 
The sample size calculation is based on 2-group test of equivalence in proportions with equal 
allocation using nQuery Advisor Version 5.0 
 
ARC-defined ST: 
The expected rate of 3 to 15-month rate of ARC-defined definite/probable ST in subjects at high 
risk for the test group is less than 0.4% based on HCRI DAPT, PE+ PAS, and PE PROVE 
studies. The performance goal is set to be 1%. With a one-sided 2.5% significance level, 1,650 
evaluable subjects will be required to provide 80% power to reject the null hypothesis when the 
alternative hypothesis is true. Assuming that the dropout rate due to the ineligibility between 0 
and 3 months for the test group is 15% and the expected attrition rate between 3 and 15 months 
is 3%, the study needs to enroll 2,000 subjects for the test group. 
The enrollment may be terminated earlier if the observed dropout rate between 0 and 3 months is 
projected to be less than 15%. Enrollment may be continued beyond 2,000 subjects (up to a 
maximum of 2,250 subjects) if the observed dropout rate in 0 to 3 months is projected to be 
>15%. 
The sample size is calculated using an exact test for single proportion using nQuery Advisor 
Version 5.0. 
 
 
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12.1.1.3. 
Statistical Methods 
Death/MI: 
A propensity score model with quintile adjustment will be used to address baseline imbalance 
between the test group and the historical control group. The null hypothesis will be tested against 
alternative hypothesis using the propensity score quintile adjusted death/MI co-primary endpoint 
for testing non-inferiority between the test group and the historical control group. 
 
The propensity score will be estimated by using logistic regression with inclusion of all pre-
specified baseline covariates in the model as the predictor variables and the treatment groups 
(test vs control) as the dependent variable. 
 
The entire study analysis set will be divided into propensity score quintiles. The death/MI co-
primary endpoints will be calculated by study group within each quintile. The adjusted measure 
for each study group is a simple mean of the five propensity score quintile estimates. Similarly, 
the stratified between-group difference estimate is the mean of the quintile difference estimates, 
and the adjusted standard error is obtained from the square root of the mean of the five quintile 
variances. 
 
Let 𝑑𝑑𝑖𝑖, i = 1, …, 5 be the quintile difference estimates, 𝑠𝑠𝑠𝑠𝑖𝑖, i = 1, …, 5 are the standard errors of 
the quintile difference estimates, and 𝑣𝑣𝑣𝑣𝑣𝑣𝑖𝑖, i = 1, …, 5 are the corresponding variances where 
𝑣𝑣𝑣𝑣𝑣𝑣𝑖𝑖=𝑠𝑠𝑠𝑠𝑖𝑖
2. The adjusted between-group difference estimate is 𝑑𝑑̅ =
1
5 ∑
(𝑑𝑑𝑖𝑖)
5
𝑖𝑖=1
, 𝑉𝑉𝑉𝑉𝑉𝑉൫𝑑𝑑̅൯=
1
52 ∑
𝑣𝑣𝑣𝑣𝑣𝑣(𝑑𝑑𝑖𝑖)
5
𝑖𝑖=1
, and 𝑆𝑆𝑆𝑆൫𝑑𝑑̅൯= ඥ𝑉𝑉𝑉𝑉𝑉𝑉(𝑑𝑑̅). 
 
The adjusted between-group difference estimate (𝑑𝑑̅) and the standard error (𝑆𝑆𝑆𝑆(𝑑𝑑̅)) of the 
adjusted between-group difference will be used to construct the 97.5% upper confidence bound 
of the adjusted between-group difference using normal approximation to binomial (z-test). If the 
97.5% upper confidence bound is less than the non-inferiority margin, the null hypothesis will be 
rejected for the death/MI co-primary endpoint and the test group will be concluded to be non-
inferior to historical control group. 
 
 
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The covariates for propensity score model will include the following variables in different 
categories, which are available in both the short DAPT study and the historical control studies:  
 
Table 12.1-1: Propensity Score Model Covariates 
Category 
Covariates 
Geographic Location 
region (US vs OUS) 
Demographics 
age, gender, race/ethnicity 
Physical Assessment 
height, weight 
Medical History 
smoking status, medically treated diabetic, hypertension 
requiring medication, hyperlipidemia requiring medication, 
history of CHF, history of MI, current angina status 
(stable/unstable/silent ischemia/none), history of PCI, history 
of CABG, LVEF, history of CVA, history of renal 
disease/insufficiency/failure, history of PVD, anticoagulant 
therapy, history of major bleeding 
Target Lesion/ Pre-
Procedure* 
CASS site, lesion length (visual), RVD (visual), %DS (visual), 
calcification, tortuosity, per-procedure TIMI flow 
Procedure/Post-
Procedure 
number of vessels treated (index + staged), number of lesions 
(index + staged), number of stents (index + staged), P2Y12 
inhibitor type (0-3 months) 
Additional 
angiographic data* 
post-procedure TIMI flow, post-procedure %DS, dissection, 
perforation 
*For subjects with multiple lesions, the worst case of the multiple lesion characteristics will be 
used in the propensity score. 
 
ARC-defined ST: 
For the co-primary endpoint of ARC-defined (definite/probable) ST, the one-sided exact test for 
single proportion comparing the observed ARC ST rate of the test group to the pre-specified 
performance goal will be performed.  Specifically, if the one-sided 97.5% upper confidence 
bound for the observed ARC ST rate of the test group is less than the performance goal, the test 
group will be considered to meet the performance goal. 
 
 
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12.1.2. Secondary Endpoint 
The rate of bleeding, based upon the Bleeding Academic Research Consortium (BARC) 
classification (types 2, 3 and 5), between 3 and 15 month expressed as the proportion of subjects 
who experience bleeding between 3 and 15 months among all subjects who either experience 
bleeding between 3 and 15 months or survive free of bleeding for at least 425 days (analysis 
excludes subjects on chronic anticoagulants). 
12.1.2.1. 
Hypothesis 
The null hypothesis that the difference of bleeding rates between test group and historical control 
group is greater than or equal to zero will be tested against the alternative hypothesis that the 
difference between test group and historical control group is less than zero: 
H0: PMB-3M – PMB-12M ≥ 0 
H1: PMB-3M – PMB-12M < 0 
where PMB -3M and PMB-12M are the 3 to 15-month bleeding rates for the 3-month DAPT test group 
and the 12-month DAPT historical control group, respectively. 
 
The historical control group for the hypothesis testing for bleeding is only from HCRI DAPT 
Study minus TAXUS. A second propensity score model will be developed based on the same set 
of covariates used in the propensity score model for the death/MI co-primary endpoint. The 
second propensity score model using quintile adjustment for the bleeding will be used to test the 
one-sided hypothesis of superiority of the test group compared to historical control group. 
12.1.2.2. 
Sample Size 
The expected rate of 4% for 3 to 15 month bleeding rate in subjects at high risk for bleeding for 
control group is estimated from the BSC PROMUS subjects enrolled in the HCRI DAPT study. 
The expected rate for 3 to 15 month bleeding rate in subjects at high risk for bleeding for test 
group is set to be 2.19%. In the control group, there are approximately 1,240 historical -limus 
DES high risk for bleeding subjects available from HCRI DAPT Study minus TAXUS. The 
number of evaluable subjects available in the test group required in the propensity score model 
for the death/MI co-primary endpoint and the ARC ST co-primary endpoint is 1,650. Given the 
number of subjects of 1,650 in the test group and 1,240 in the historical control group, the 
unadjusted power is 80%. Assuming that the dropout rate due to the ineligibility between 0 and 3 
months for the test group is 15% and the expected attrition rate between 3 and 15 months is 3%, 
the study needs to enroll 2,000 subjects for the test group. 
The enrollment may be terminated earlier if the observed dropout rate between 0 and 3 months is 
projected to be less than 15%. Enrollment may be continued beyond 2,000 subjects (up to a 
maximum of 2,250 subjects) if the observed dropout rate in 0 to 3 months is projected to be 
>15%. 
The sample size calculation is based on unequal allocation using 2-group chi-square test compare 
two proportions using nQuery Advisor Version 5.0. 
 
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12.1.2.3. 
Statistical Methods 
The second propensity score model with quintile adjustment will be used to address baseline 
imbalance between the test group and the historical control group. The null hypothesis will be 
tested against alternative hypothesis using the propensity score quintile adjusted secondary 
endpoint of bleeding for testing superiority between the test group and the historical control 
group. 
 
 
The adjusted between-group difference estimate (𝑑𝑑̅) and the standard error (𝑆𝑆𝑆𝑆(𝑑𝑑̅)) of the 
adjusted between-group difference will be used to construct the 97.5% upper confidence bound 
of the adjusted between-group difference using normal approximation to binomial. If the 97.5% 
upper confidence bound is less than zero, the null hypothesis will be rejected for the secondary 
endpoint of bleeding and the test group will be concluded to be superior to historical control 
group. 
12.2. 
General Statistical Methods 
All statistical analyses will be performed using the SAS System software, version 9.3 or later 
(Copyright© 2002-2010 by SAS Institute Inc., Cary, North Carolina, USA. All rights reserved).  
All statistical analyses will be conducted according to applicable Standard Operating Procedures, 
Work Instructions, and the study-specific Statistical Analysis Plan.  
12.2.1. Analysis Sets 
For the EVOLVE Short DAPT Study, a subject is considered enrolled once an informed consent 
form has been signed and the subject has received at least one commercial SYNERGY stent. 
Enrolled subjects must meet all inclusion and no exclusion criteria. The analysis set for the test 
group includes enrolled subjects who meet criteria for discontinuation of P2Y12 inhibitor and 
who discontinue P2Y12 inhibitor at 3 months. The analysis set will be used as the test group in 
the propensity score model. 
For the death/MI co-primary endpoint analysis, the EVOLVE Short DAPT-like high risk for 
bleeding subjects will be extracted from HCRI DAPT, PE+ PAS, and PE PROVE studies to form 
the historical control group.  For the secondary bleeding endpoint analysis, the EVOLVE Short 
DAPT-like high risk for bleeding subjects will be extracted from HCRI DAPT study only to 
form the historical control group. Bleeding events were not adjudicated by the CEC in the 
PE+PAS or the PE-PROVE study. 
The EVOLVE Short DAPT-like subjects are defined as subjects who meet the EVOLVE Short 
DAPT Study inclusion criteria and do not meet any of the following exclusion criteria at the time 
of the index procedure: 
• indication for the index procedure of acute ST elevation MI (STEMI) or Non ST elevation 
MI (NSTEMI),  
• previously treated with intravascular brachytherapy,  
• left main target lesion,  
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• more than 3 lesions treated,  
• more than 2 vessels treated, 
• bifurcations,  
• in-stent restenosis,  
• saphenous vein graft,  
• TIMI flow 0 (total occlusion) or TIMI flow 1 prior to guide wire crossing, and  
• thrombus or possible thrombus present in the target vessel (by visual estimate). 
The high risk for bleeding subject set is defined as a set of subjects who meets 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 >3 months of DAPT outweighs the benefit, 
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, stroke (ischemic and hemorrhagic), or renal insufficiency (creatinine ≥2.0 mg/dl) or 
failure (dialysis dependent), and platelet count ≤100,000 µL. 
12.2.2. Control of Systematic Error/Bias 
An independent Clinical Events Committee (CEC) will review clinical events encountered 
during the study. The CEC will be blinded to the study center and subject identification to the 
extent possible.   
Handling of dropouts and missing data will depend on their frequency and the nature of the 
outcome measure. The distribution of prognostic factors between subjects with and without data 
will be examined. Adjustments for missing data will be performed if deemed necessary to 
eliminate or minimize bias and will be described completely.  Statistical models that account for 
censored data will be employed in appropriate circumstances, e.g., for time-to-event outcomes.  
Sensitivity analyses may be conducted to assess the impact of different assumptions on 
interpretation of the results.  Outlier values will be evaluated and values determined to be invalid 
will be queried.  All data will be included in the analysis. 
Propensity Scores Modeling Approach 
To avoid potential bias, an independent propensity score model team, who is blinded to the 
outcome data, will develop two propensity score models based on the same set of covariates with 
three historical studies used in the first model and one historical study used in the second model.  
The first propensity score model for the death/MI co-primary endpoint will be based on the 
analysis set for the test group from the EVOLVE Short DAPT Study and the EVOLVE Short 
DAPT-like high risk for bleeding subjects for the control group from HCRI DAPT, PE+ PAS, 
and PE PROVE studies.  
The second propensity score model for bleeding will be based on the analysis set for the test 
group from the EVOLVE Short DAPT Study and the EVOLVE Short DAPT-like high risk for 
bleeding subjects for the control group from HCRI DAPT study. Subjects who were on long-
term anticoagulation therapy and who were anticipated to still be on an anticoagulant at the time 
of randomization were not eligible for enrollment in HCRI DAPT study. In order to make a like-
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to-like comparison between test and control groups, subjects with a need for chronic or lifelong 
anticoagulation therapy in the test group will be excluded from the second propensity score 
model for the bleeding secondary endpoint. 
The independent propensity score model team will select the appropriate propensity score 
models prior to the endpoint analyses and file the propensity score baseline covariate modeling 
as an IDE supplement. The selected propensity score models will be delivered to an independent 
outcome reporting team for the endpoint analyses. The independent outcome reporting team will 
use these propensity score models to test the hypotheses of the test group compared to the control 
group and to compare other clinical outcomes between the test group and control group. 
The missing data for the propensity score model covariates will be imputed. The within-study 
median value of the non-missing covariate for the subjects used in the propensity score model 
will be used as the imputed value for the missing continues covariate. The within-study mode 
value of the non-missing covariate for the subjects used in the propensity score model will be 
used as the imputed value for the missing discrete covariate. 
12.2.3. Number of Subjects per Investigative Site 
The maximum number of subjects to be enrolled per site is 200. 
12.3. 
Data Analyses 
Baseline data will be summarized by treatment group. Subject demographics, clinical history, 
risk factors, and pre-procedure lesion characteristics will be summarized using descriptive 
statistics for continuous variables (mean, standard deviation, number of observations, minimum 
and maximum) and discrete variables (percentage and count/sample). 
The propensity score quintile adjusted baseline variables will be compared between the test 
group and control group. P-values will be provided using normal approximation.  
12.3.1. Post-procedure Endpoints 
Post-procedure information will be collected at regularly scheduled follow-up examinations as 
detailed in the clinical trial schedule and will be summarized using descriptive statistics for 
continuous variables (e.g., mean, standard deviation, n, minimum, maximum) and frequency 
tables or proportions for discrete variables. 
12.3.2. Interim Analyses  
No formal interim analyses are planned for the purpose of stopping this trial early for study 
success. A data monitoring committee (DMC) will monitor the safety events for the purpose of 
stopping the trial for futility. 
12.3.3. Subgroup Analyses 
For the test subjects with 3-month DAPT, planned subgroup analyses will include gender 
(female/male), diabetic status (medically treated diabetics/non medically treated diabetics), 
number of lesions (single lesion/multiple lesions), number of vessels (single vs multiple vessels 
treatment), long lesion, stent model (small vessel, workhorse, and large vessel), region (US vs 
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OUS), 0-3 month P2Y12 inhibitors (clopidogrel, prasugrel, or ticagrelor), DAPT Score (62) , or 
any subgroups identified in the univariate/multivariate model as significant predictors for co-
primary endpoints and secondary endpoint. 
12.3.4. Justification of Pooling 
An assessment of the poolability of 3-month eligible subjects across sites will be performed 
based on: 
1) the co-primary endpoint of all death/MI for the test group, 
2) the co-primary endpoint of all death/MI for the control group, 
3) the co-primary endpoint of ARC ST for the test group, 
4) the secondary endpoint of bleeding for the test group, and 
5) the secondary endpoint of bleeding for the control group 
using logistic regression with site as a factor and co-primary endpoints as the outcome. Sites with 
fewer than 10 subjects enrolled will be combined into “virtual sites” based on geographic regions 
within United States, Europe, Japan, and Brazil, so that “virtual sites” have at least 10 subjects 
but no more than the largest enrolling site. If the two-sided P value for the site effect is ≥ 0.15, it 
will be concluded that the site effect is not different across sites, and the site data can be pooled. 
If the two-sided P value for site effect is <0.15, site differences will be explored. 
The poolability assessment of the treatment-by-site interaction based on the common sites 
enrolling both the 3-month eligible test subjects and the historical control subjects will be 
performed: 
1) the co-primary endpoint of all death/MI for the 3-month eligible test/control subjects and 
2) the secondary endpoint of bleeding the 3-month eligible test/control subjects. 
An assessment of the poolability of subjects across sites will be made using logistic regression 
with treatment, site and the interaction of site by treatment as independent variables and co-
primary endpoints as the outcome. The same model will be assessed for the secondary endpoint 
as the outcome. Sites with fewer than 10 subjects enrolled will be combined into “virtual sites” 
based on geographic regions within United States, Europe, Japan, and Brazil, so that “virtual 
sites” have at least 10 subjects but no more than the largest enrolling site. If the two-sided P 
value for the interaction coefficient is ≥0.15, it will be concluded that the treatment effect is not 
different across sites, and the data can be pooled. If the two-sided P value for the interaction 
coefficient is <0.15, site differences will be explored. 
12.3.5. Multivariate Analyses 
Univariate and multivariate analyses may be performed to assess the effect of potential 
predictors on the co-primary endpoints and secondary endpoint using logistic regression as 
described in the Statistical Analysis Plan  
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12.3.6. Other Analyses 
Data collected for the follow-up period of 3 to 15 months will be analyzed using appropriate 
univariate and multivariate models. Kaplan-Meier plots of time-to-event variables will be 
constructed. The Cox proportional hazards regression model will be used to assess the effects of 
risk factors on the time-to-event variables. Multivariate models will be used to assess the 
predictability of outcome from the risk factors. 
12.3.7. Changes to Planned Analyses 
Any changes to the planned statistical analyses made prior to performing the analyses will be 
documented in an amended Statistical Analysis Plan approved before performing the analyses. 
Changes from the planned statistical methods after performing the analyses will be documented 
in the clinical study report along with a reason for the deviation. 
 
13. 
Data Management 
13.1. Data Collection, Processing, and Review 
Subject data will be recorded in a limited access secure electronic data capture (EDC) system.  
The clinical database will reside on a production server hosted by Medidata. All changes made to 
the clinical data will be captured in an electronic audit trail and available for review by BSC or 
its representative. The associated RAVE software and database have been designed to meet 
regulatory compliance for deployment as part of a validated system compliant with laws and 
regulations applicable to the conduct of clinical studies pertaining to the use of electronic records 
and signatures. Database backups are performed regularly. 
The Investigator provides his/her electronic signature on the appropriate eCRFs in compliance 
with local regulations. A written signature on printouts of the eCRFs must also be provided if 
required by local regulation. Changes to data previously submitted to BSC require a new 
electronic signature by the Investigator acknowledging and approving the changes. 
Visual and/or electronic data review will be performed to identify possible data discrepancies. 
Manual and/or automatic queries will be created in the EDC system and will be issued to the site 
for appropriate response. Site staff will be responsible for resolving all queries in the database. 
13.2. Data Retention 
The Investigator or Investigational site will maintain, at the investigative site, in original format 
all essential study documents and source documentation that support the data collected on the 
study subjects in compliance with ISO 14155 or International Conference on Harmonization 
(ICH)/Good Clinical Practice (GCP) guidelines.  Documents must be retained for at least 2 years 
after the last approval of a marketing application or until at least 2 years (at least 3 years in 
Japan) have elapsed since the formal discontinuation of the clinical investigation of the product. 
These documents will be retained for a longer period of time by agreement with BSC or in 
compliance with pertinent individual country laws and regulations.  
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It is BSC’s responsibility to inform the Investigator and site when these documents no longer 
need to be maintained. The Investigator will take measures to ensure that these essential 
documents are not accidentally damaged or destroyed. If for any reason the Investigator 
withdraws responsibility for maintaining these essential documents, custody must be transferred 
to an individual who will assume responsibility and BSC must receive written notification of this 
custodial change.  
In Japan, BSC must maintain necessary essential documents for 5 years from the date of the 
marketing application approval (or until completion of re-examination, if applicable and if longer 
than 5 years) or until 3 years have elapsed since the formal discontinuation of the clinical 
investigation of the device, whichever is longer. 
14. 
Amendments  
If a protocol revision is necessary which affects the rights, safety or welfare of the subject or 
scientific integrity of the data, an amendment is required. Appropriate approvals and/or 
notifications (e.g., IRB/EC/regulatory body) of the revised protocol must be obtained prior to 
implementation. 
15. 
Deviations 
An Investigator should not make any changes or deviate from this protocol, except to protect the 
life and physical well-being of a subject in an emergency. An Investigator shall notify the 
sponsor, and the reviewing IRB/EC where applicable, of any deviation from the investigational 
plan to protect the life or physical well-being of a subject in an emergency, and those deviations 
which affect the scientific integrity of the clinical investigation. Such notice shall be given as 
soon as possible, but no later than 5 working days after the emergency occurred, or per 
prevailing local requirements, if sooner than 5 working days.  
All deviations from the protocol, with the reason for the deviation and the date of occurrence, 
must be documented and reported to the sponsor using EDC. Sites may also be required to report 
deviations to the IRB/EC, per local guidelines and government regulations.  
Deviations will be reviewed and evaluated on an ongoing basis and, as necessary, appropriate 
corrective and preventive actions (including, but not limited to,  notification, site re-training, or 
discontinuation) will be put into place by the sponsor. 
16. 
Device/Equipment Accountability 
Device identification should be entered into the eCRF for all SYNERGY devices used.   
Local procedures should be followed to return unused, expired, or malfunctioning commercial 
devices, if applicable. 
17. 
Compliance 
17.1. Statement of Compliance 
This study will be conducted in accordance with ISO 14155 Clinical Investigation of Medical 
Devices for Human Subjects- GCP, or the relevant parts of the ICH Guidelines for GCP, ethical 
principles that have their origins in the Declaration of Helsinki, Japan Medical Device GCP and 
pertinent individual country laws and regulations. The study shall not begin until the required 
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approval/favorable opinion from the IRB/EC and/or regulatory authority has been obtained, if 
appropriate. Any additional requirements imposed by the IRB/EC or regulatory authority shall be 
followed, if appropriate. 
17.2. Investigator Responsibilities 
The Principal Investigator of an investigational center is responsible for ensuring that the study is 
conducted in accordance with the Clinical Study Agreement, the protocol, ISO 14155, ethical 
principles that have their origins in the Declaration of Helsinki, any conditions of approval 
imposed by the reviewing IRB/EC, and prevailing local and/or country laws and/or regulations, 
whichever affords the greater protection to the subject. 
The Principal Investigator’s responsibilities include, but are not limited to, the following.  
• Prior to beginning the study, sign Clinical Study Agreement and protocol Signature Page 
documenting his/her agreement to conduct the study in accordance with the protocol. 
• Provide his/her qualifications and experience to assume responsibility for the proper conduct 
of the study and that of key members of the center team through up-to-date curriculum vitae 
or other relevant documentation and disclose potential conflicts of interest, including 
financial, that may interfere with the conduct of the clinical study or interpretation of results. 
• Make no changes in or deviate from this protocol, except to protect the life and physical 
well-being of a subject in an emergency; document and explain any deviation from the 
approved protocol that occurred during the course of the clinical investigation. 
• Create and maintain source documents throughout the clinical study and ensure their 
availability with direct access during monitoring visits or audits; ensure that all clinical-
investigation-related records are retained per requirements. 
• Ensure the accuracy, completeness, legibility, and timeliness of the data reported to the 
sponsor in the CRFs and in all required reports. 
• Record, report, and assess (seriousness and relationship to the device) every adverse event 
(as reportable per protocol) and observed device deficiency. 
• Report to BSC, per the protocol requirements, all SAEs and device deficiencies that could 
have led to a SADE. 
• Report to the IRB/EC and regulatory authorities any SAEs and device deficiencies that could 
have led to a SADE, if required by the national regulations or this protocol or by the IRB/EC, 
and supply BSC with any additional requested information related to the safety reporting of a 
particular event. 
• Allow BSC to perform monitoring and auditing activities, and be accessible to the monitor 
and respond to questions during monitoring visits. 
• Allow and support regulatory authorities and the IRB/EC when performing auditing 
activities. 
• Ensure that informed consent is obtained in accordance with applicable laws, this protocol 
and local IRB/EC requirements. 
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• Provide adequate medical care to a subject during and after a subject’s participation in a 
clinical study in the case of AEs, as described in the ICF. 
• Inform the subject of the nature and possible cause of any AEs experienced. 
• Inform the subject of any new significant findings occurring during the clinical investigation, 
including the need for additional medical care that may be required. 
• Provide the subject with well-defined procedures for possible emergency situations related to 
the clinical study, and make the necessary arrangements for emergency treatment. 
• Ensure that clinical medical records are clearly marked to indicate that the subject is enrolled 
in this clinical study. 
• Ensure that, if appropriate, subjects enrolled in the clinical investigation are provided with 
some means of showing their participation in the clinical investigation, together with 
identification and compliance information for concomitant treatment measures (contact 
address and telephone numbers shall be provided). 
• Inform, with the subject’s approval or when required by national regulations, the subject’s 
personal physician about the subject’s participation in the clinical investigation. 
• Make all reasonable efforts to ascertain the reason(s) for a subject’s premature withdrawal 
from clinical investigation while fully respecting the subject’s rights. 
• Ensure that an adequate investigation site team and facilities exist and are maintained and 
documented during the clinical investigation. 
• Ensure that maintenance and calibration of the equipment relevant for the assessment of the 
clinical investigation is appropriately performed and documented, where applicable. 
17.2.1. Delegation of Responsibility 
When specific tasks are delegated by an Investigator, included but not limited to conducting the 
informed consent process, the Investigator is responsible for providing appropriate training and 
adequate supervision of those to whom tasks are delegated. The Investigator is accountable for 
regulatory violations resulting from failure to adequately supervise the conduct of the clinical 
study.  
17.3. Institutional Review Board/ Independent Ethics Committee 
Prior to gaining Approval-to-Enroll status, the investigational center will provide to BSC 
documentation verifying that their IRB/EC is registered or that registration has been submitted to 
the appropriate agency, as applicable according to national/regulatory requirements.   
Annual IRB/EC approval and renewals will be obtained throughout the duration of the study as 
required by local/country or IRB/EC requirements. Copies of the Investigator’s reports and the 
IRB/EC continuance of approval must be provided to the sponsor.  
A copy of the written IRB/EC and/or regulatory authority approval (if applicable) of the protocol 
(or permission to conduct the study) and ICF, must be received by BSC before recruitment of 
subjects into the study.   
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17.4. Sponsor Responsibilities 
All information and data sent to BSC concerning subjects or their participation in this study will 
be considered confidential by BSC. Only authorized BSC personnel or a BSC representative 
including a Contract Research Organization (CRO) will have access to these confidential 
records. Authorized regulatory personnel have the right to inspect and copy all records pertinent 
to this study. Study data collected during this study may be used by BSC for the purposes of this 
study, publication, and to support future research and/or other business purposes. All data used in 
the analysis and reporting of this study will be without identifiable reference to specific subject 
name. 
 
BSC will keep subjects’ health information confidential in accordance with all applicable laws 
and regulations. BSC may use subjects’ health information to conduct this research, as well as 
for additional purposes, such as overseeing and improving the performance of its device, new 
medical research and proposals for developing new medical products or procedures, and other 
business purposes. Information received during the study will not be used to market to subjects; 
subject’s identifying data will not be placed on any mailing lists or sold to anyone for marketing 
purposes.  
17.5. Insurance  
Where required by local/country regulation, proof and type of insurance coverage, by BSC for 
subjects in the study will be obtained. 
18. 
Monitoring 
Monitoring will be performed during the study, according to the study Monitoring Plan, to assess 
continued compliance with the current, approved protocol/amendment(s) and applicable 
regulations. In addition, the monitor verifies that informed consent is obtained from all enrolled 
study subjects, study records are adequately maintained, that data are reported in a satisfactory 
manner with respect to timeliness, adequacy, and accuracy, and that the Investigator continues to 
have sufficient staff and facilities to conduct the study safely and effectively. Monitoring 
strategies will be tailored to risks, and will be focused on critical processes and critical data. 
Monitoring activities will be adjusted based on the issues and risks identified throughout the 
study. Pre-defined thresholds for protocol deviation and compliance once met or exceeded, can 
also trigger increased monitoring frequency and/or the implementation of corrective action plans 
at clinical sites. Source documents include, at a minimum but not limited to, the ICF; subject 
medical records, including nursing records and catheterization laboratory records; diagnostic 
imaging records; laboratory results; and reports of SAEs. The monitoring plan will include 
source data verification for an approximate sampling of 10% of subjects enrolled. A risk-based 
approach to source data verification will be implemented as described in the Monitoring Plan.  
The Investigator/institution guarantees direct access to original source documents (electronic or 
paper) by BSC personnel, their designees, and appropriate regulatory authorities. In the event 
that the original medical records cannot be obtained for a subject that is seen by a non-study 
physician at a non-study institution, photocopies of the original source documents must be made 
available for review. Photocopies of original source documents related to SAEs (from either the 
study site or a non-study institution, if applicable) must also be made available for submission to 
the BSC Safety Office as described in Section 21. 
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The study may also be subject to a quality assurance audit by BSC or its designees, as well as 
inspection by appropriate regulatory authorities. It is important that the Investigator and relevant 
study personnel are available during on-site monitoring visits or audits and that sufficient time is 
devoted to the process. 
19. 
Potential Risks and Benefits 
19.1. Risks Associated with the Implantation of Coronary Stents 
Potential AEs (in alphabetical order) which may be associated with the implantation of a 
coronary stent or the associated cardiac catheterization are listed below: 
• Abrupt stent closure 
• Acute MI 
• Allergic reaction to anticoagulant 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 
• Coronary aneurysm 
• Death 
• Dissection 
• Emboli, distal ( air, tissue, or thrombotic material or material from devices(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 
• Pseudoaneurysm, femoral 
• Renal insufficiency or failure 
• Respiratory failure 
• Restenosis of stented segment 
• Stent deformation, collapse or fracture 
• Stent embolization or migration 
• Stent thrombosis/occlusion 
• Stroke/cerebrovascular accident/transient ischemic attack 
• Total occlusion of coronary artery 
• Vessel spasm 
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• Vessel trauma requiring surgical repair or reintervention 
19.2.  Risks Associated with Everolimus  
Zortress®, the oral formulation of everolimus developed by Novartis Pharmaceuticals 
Corporation, has been evaluated in clinical trials and is approved in the US 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 US 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(63). The amount of drug that circulates in the bloodstream following implantation of 
SYNERGY stent is significantly lower than that obtained with oral doses.  
• Abdominal pain (including upper abdominal pain) 
• Anemia 
• Angioedema 
• Anorexia 
• Asthenia 
• Constipation 
• Cough 
• Delayed wound healing/fluid accumulation 
• Diarrhea 
• Dyslipidemia (including hyperlipidemia and hypercholesterolemia) 
• 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 
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• 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 
• Vomiting 
Live vaccines should be avoided and close contact with those that have had live vaccines should 
be avoided. Fetal harm can occur when administered to a pregnant woman. There may be other 
potential adverse events that are unforeseen at this time. 
19.3. Risks Associated with the Study Device(s)  
The SYNERGY stent releases everolimus via a bioabsorbable PLGA polymer. This polymer 
formulation has previously been used to achieve controlled release of everolimus in the 
SYNERGY FHU stent in the EVOLVE trial. The SYNERGY stent has also been used in the 
EVOLVE II program, for which primary endpoint results are available. Several clinical trials 
have demonstrated the safety and performance of other drug-eluting stents that use similar 
polymer formulations to control the release of pharmaceutical agents from a coronary stent (64-
66). These clinical trials, in combination with the EVOLVE trials, suggest that the risk 
associated with the SYNERGY stent is comparable to other drug-eluting coronary stents.  
19.4. Sex-Specific Risks Associated with the Study Device(s)  
An Analysis of subjects treated with everolimus-eluting stents in the EVOLVE II RCT study was 
performed to assess the impact of gender on outcomes.  Difference in treatment and gender are 
observed.  Despite these differences, the overall conclusions of the trial regarding both safety and 
effectiveness of the SYNERGY Stent can be generalized to males and females.  However, the 
influence of gender on long-term drug-eluting stent outcomes has not been fully elucidated.  
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19.5. Risks Associated with Participation in the Clinical Study 
In addition to the aforementioned risks associated with the implantation of coronary stents and 
the use of everolimus, 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. 
19.6. Possible Interactions with Concomitant Medical Treatments 
Refer to the SYNERGY DFU for information on known drug interactions with everolimus.  
19.7. Risk Minimization Actions 
Additional risks may exist. Risks can be minimized through compliance with this protocol, 
performing procedures in the appropriate hospital environment, adherence to subject selection 
criteria, adherence to eligibility criteria for discontinuation of P2Y12 inhibitor at 3-months, close 
monitoring of the subject's physiologic status during research procedures and/or follow-ups and 
by promptly supplying BSC with all pertinent information required by this protocol. 
19.8. Anticipated 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. This clinical trial has been designed to investigate potential 
benefits of SYNERGY with a shortened duration of dual antiplatelet therapy.  
19.9. Risk to Benefit Rationale 
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 design feature of the SYNERGY stent (polymer resorption occurring soon after 
completion of drug release at 90 days), it is expected that treatment with 3 months 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-eluting stents.   
 
20. 
Safety Reporting  
20.1. Definitions and Classification 
All serious adverse events (SAE), adverse device effects (ADE), death, MI, TVR, stroke, 
stent thrombosis, as well as bleeding events will be collected from the start of the index 
procedure (sheath insertion) through the 15-month follow-up visit.  
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Adverse event definitions are provided in Table 20.1-1. Administrative edits were made on the 
definition of serious adverse event to combine definitions from ISO 14155-2011 and MEDDEV 
2.7/3 (2015) for clarification purposes. 
Table 20.1-1: Adverse Event Definitions 
Term 
Definition 
Adverse Event (AE) 
 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3 
Any untoward medical occurrence, unintended disease or injury, or any 
untoward clinical signs (including an abnormal laboratory finding) in subjects, 
users or other persons, whether or not related to the investigational medical 
device.  
NOTE 1: This includes events related to the investigational medical device or 
comparator. 
NOTE 2: This definition includes events related to the procedures involved 
(any procedure in the clinical investigation plan). 
NOTE 3: For users or other persons, this definition is restricted to events 
related to the investigational medical device 
Adverse Device Effect (ADE) 
 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3 
Adverse event related to the use of an investigational medical device 
NOTE 1: This definition includes any adverse event resulting from 
insufficient or inadequate instructions for use, the deployment, the 
implantation, the installation, the operation, or any malfunction of the 
investigational medical device. 
• NOTE 2: This definition includes any event resulting from use error or from 
intentional misuse of the investigational medical device. 
Serious Adverse Event (SAE) 
 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3 
Note: This definition meets the reporting objectives  and  requirements  of  ISO 
14155  and  MEDDEV 2.7/3. 
Adverse event that: 
• Led to death, 
• Led to  serious deterioration in the health of the subject, as defined by either: 
o a life-threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o in-patient  or prolonged hospitalization of existing hospitalization, or 
o medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body function 
• Led to fetal distress, fetal death, or a congenital abnormality or birth defect. 
NOTE 1: Planned hospitalization for a pre-existing condition, or a procedure 
required by the clinical investigational plan, without serious deterioration in 
health, is not considered a serious adverse event. 
Serious Adverse Device Effect 
(SADE) 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3 
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
 
Unanticipated Adverse Device 
Effect (UADE) 
 
Ref: 21 CFR Part 812 
 
 
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.   
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Table 20.1-1: Adverse Event Definitions 
Term 
Definition 
Unanticipated Serious Adverse 
Device Effect (USADE) 
 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3 
Serious adverse device effect which by its nature, incidence, severity, or 
outcome has not been identified in the current version of the risk analysis 
report. 
NOTE 1: Anticipated serious adverse device effect (ASADE) is an effect 
which by its nature, incidence, severity or outcome has been identified in the 
risk analysis report. 
Device Deficiency 
 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3 
A device deficiency is any inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety or performance. 
NOTE 1: Device deficiencies include malfunctions, misuse or use errors, and 
inadequate labeling. 
 
Underlying diseases are not reported as AEs unless there is an increase in severity or frequency 
during the course of the investigation. Death should not be recorded as an AE, but should only be 
reflected as an outcome of a specific SAE (see Table 20.1-1 for AE definitions). Any AE that 
meets protocol reporting criteria experienced by the study subject after the start of the index 
procedure must be captured on the eCRF. 
Refer to Section 19 for the known risks associated with the study device(s). 
Device deficiencies and other device issues should not be reported as AEs. Instead, they should 
be reported on the appropriate eCRF per the study CRF Completion Guidelines. If an AE results 
from a device deficiency or other device issue, the AE should be reported on the appropriate 
eCRF. 
In-patient hospitalization is defined as the subjects being admitted to the hospital, with the 
following exceptions: 
• A hospitalization that is uncomplicated and elective/planned (i.e., planned prior to 
enrollment) does not have to be reported as an SAE. 
• If complications or AEs occur during an elective/planned (i.e., planned prior to enrollment) 
hospitalization after enrollment, the complications and AEs must be reported as AEs or SAEs 
if they meet the protocol-specified definitions. However, the original elective/planned 
hospitalization(s) itself should not be reported as an SAE. 
20.2. Relationship to Study Device(s) 
The Investigator must assess the relationship of the AE to the study device and procedure.  See 
criteria in Table 20.2-1:  
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Table 20.2-1: Criteria for Assessing Relationship of Study Device and Procedure to 
Adverse Event 
Classification 
Description 
Not Related 
Relationship to the device or procedures can be excluded when: 
 
• 
the event is not a known side effect of the product category the device belongs to or 
of similar devices and procedures; 
• 
the event has no temporal relationship with the use of the investigational device or 
the procedures; 
• 
the serious event does not follow a known response pattern to the medical device (if 
the response pattern is previously known) and is biologically implausible; 
• 
the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible – and reintroduction of its use (or 
increase of the level of activation/exposure), do not impact on the serious event; 
• 
the event involves a body-site or an organ not expected to be affected by the device 
or procedure;  
• 
the serious event can be attributed to another cause (e.g. an underlying 
or concurrent illness/ clinical condition, an effect of another device, drug, treatment or 
other risk factors); 
• 
the event does not depend on a false result given by the investigational device used 
for diagnosis, when applicable; harms to the subject are not clearly due to use error; 
 
In order to establish the non-relatedness, not all the criteria listed above might be 
met at the same time, depending on the type of device/procedures and the serious event. 
 
Unlikely Related 
The relationship with the use of the device seems not relevant and/or the event can be 
reasonably explained by another cause, but additional information may be obtained. 
Possibly Related 
The relationship with the use of the investigational device is weak but cannot be ruled 
out completely. Alternative causes are also possible (e.g. an underlying or concurrent 
illness/ clinical condition or/and an effect of another device, drug or treatment). Cases 
were relatedness cannot be assessed or no information has been obtained should also 
be classified as possible. 
Probably Related 
The relationship with the use of the investigational device seems relevant and/or the 
event cannot reasonably explained by another cause, but additional information may 
be obtained. 
Causal Relationship 
The serious event is associated with the investigational device or with procedures 
beyond reasonable doubt when: 
 
• 
the event is a known side effect of the product category the device belongs to or of 
similar devices and procedures; 
• 
the event has a temporal relationship with investigational device use/application or 
procedures; 
• 
the event involves a body-site or organ that 
o the investigational device or procedures are applied to; 
o the investigational device or procedures have an effect on; 
• 
the serious event follows a known response pattern to the medical device (if the 
response pattern is previously known); 
• 
the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 
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Table 20.2-1: Criteria for Assessing Relationship of Study Device and Procedure to 
Adverse Event 
Classification 
Description 
• 
other possible causes (e.g. an underlying or concurrent illness/ clinical condition 
or/and an effect of another device, drug or treatment) have been adequately ruled out; 
• 
harm to the subject is due to error in use; 
• 
the event depends on a false result given by the investigational device used for 
diagnosis, when applicable; 
 
In order to establish the relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event. 
 
 
20.3. Investigator Reporting Requirements 
The communication requirements for reporting to BSC are as shown in Table 20.3-1. 
Table 20.3-1: Investigator Reporting Requirements 
Event Classification 
Communication Method  
Communication Timeline  
Unanticipated Adverse Device 
Effect / Unanticipated Serious 
Adverse Device Effect  
 
Complete AE eCRF page with all 
available new and updated information 
• Within 1 business day of first 
becoming aware1 of the event. 
• Reporting required through the 
end of the study 
Provide source documentation 
(unidentified) as requested by the 
Sponsor 
• When documentation is 
available 
Serious Adverse Event 
including Serious Adverse 
Device Effects 
Complete AE eCRF page with all 
available new and updated information 
• Within 2 business days of first 
becoming aware of the event or 
as per local/regional regulations. 
• Reporting required through the 
end of the study 
Provide source documentation 
(unidentified) as requested by the 
Sponsor 
• When documentation is 
available 
Device Deficiencies (including 
but not limited to failures, 
malfunctions, and product 
nonconformities) 
Complete Device Deficiency CRF with 
all available new and updated 
information 
• Within 2 business day of first 
becoming aware of the event and 
as per local/regional regulations 
• Reporting required through the 
end of the study 
Adverse Device Effect (Non-
Serious) 
Complete AE eCRF page, which 
contains such information as date of 
AE, treatment of AE resolution, 
assessment of seriousness and 
relationship to the device 
• In a timely manner (e.g. 
Recommend within 10 business 
days) after becoming aware of 
the information 
1 The “become aware date” for an event that requires reporting per the protocol is the date that study personnel 
listed on the Delegation of Authority Log identify or are notified of the event. 
Abbreviations: AE=adverse event; CRF=case report form; eCRF=electronic case report form; 
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Table 20.3-1: Investigator Reporting Requirements 
Event Classification 
Communication Method  
Communication Timeline  
UADE=unanticipated adverse device effect 
20.4. Boston Scientific Device Deficiencies 
All device deficiencies (including but not limited to failures, malfunctions, use errors, product 
nonconformities, and labeling errors) will be documented and reported to BSC. If possible, the 
device(s) should be returned to BSC for analysis. If it is not possible to return the device, the 
investigator should document why the device was not returned and the final disposition of the 
device. Device failures and malfunctions should also be documented in the subject’s medical 
record. 
Device deficiencies (including but not limited to failures, malfunctions, and product 
nonconformities) are not to be reported as AEs. However, if there is an AE that results from a 
device failure or malfunction, that specific event would be recorded on the appropriate eCRF. 
Device deficiencies that did not lead to an AE but could have led to a SAE if: 
• 
either suitable action had not been taken, 
• 
intervention had not been made, or 
• 
circumstances had been less fortunate, 
should be reported per Table 20.3-1. 
20.5. Reporting to Regulatory Authorities /IRBs /IECs /Investigators 
BSC will notify all participating study sites if SAEs/SADEs occur which imply a possible 
increase in the anticipated risk of the procedure or use of the device or if the occurrence of 
certain SAEs/SADEs demands changes to the protocol or the conduct of the study in order to 
further minimize the unanticipated risks. 
Boston Scientific Corporation is responsible for reporting AE and device deficiencies 
information to all participating investigators, IRBs/ECs, and regulatory authorities as applicable 
according to local reporting requirements. 
Boston Scientific Corporation, Investigator, or Site must notify the IRB/EC of any UADEs, 
USADEs, SADEs, SAEs, device deficiencies, and other CEC events as applicable according to 
local reporting requirements (refer to Section 22.2.1 for information pertaining to the CEC and 
CEC Events). A copy of the Investigator’s reports and other relevant reports (if applicable) to the 
IRB/IEC must be provided to BSC in accordance with local requirements. 
21. 
Informed Consent 
Subject participation in this clinical study is voluntary.  Informed Consent is required from all 
subjects or their legally authorized representative. The Investigator is responsible for ensuring 
that Informed Consent is obtained prior to the use of any study-required procedures and/or 
testing, or data collection. For subjects less than 20 years of age enrolled at a Japanese site, the 
subject and the subject’s legal representative must provide written Informed Consent. 
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The obtaining and documentation of Informed Consent must be in accordance with the principles 
outlined by the ICH/GCP guidelines, the Declaration of Helsinki, ISO 14155, and national 
regulations, and local Ethics Committee and/or Regulatory authority body, as applicable. The 
ICF must be approved by BSC or its delegate (e.g. CRO), the center’s IRB/EC, or central 
IRB/EC, if applicable. 
BSC will provide a study-specific template of the ICF to Investigators participating in this study. 
The ICF template may be modified to meet the requirements of the investigative center’s 
IRB/EC. Any modification requires approval from BSC prior to use of the form. The ICF must 
be in a language understandable to the subject and if needed, BSC will assist the center in 
obtaining a written consent translation. Translated consent forms must also have IRB/EC 
approval prior to their use.  Privacy language shall be included in the body of the form or as a 
separate form as applicable.   
The process of obtaining Informed Consent shall at a minimum include the following steps, as 
well as any other steps required by applicable laws, rules, regulations and guidelines: 
• be conducted by the Principal Investigator or designee authorized to conduct the process,  
• include a description of all aspects of the clinical study that are relevant to the subject’s 
decision to participate throughout the clinical study, 
• avoid any coercion of or undue influence of subjects to participate, 
• not waive or appear to waive subject’s legal rights, 
• use native language that is non-technical and understandable to the subject or his/her legal 
representative, 
• provide ample time for the subject to consider participation and ask questions if necessary, 
• ensure important new information is provided to new and existing subjects throughout the 
clinical study. 
The ICF shall always be signed and personally dated by the subject or legal representative 
competent to sign the ICF under the applicable laws, rules, regulations and guidelines and by the 
Investigator and/or an authorized designee responsible for conducting the informed consent 
process. If a legal representative signs, the subject shall be asked to provide informed consent for 
continued participation as soon as his/her medical condition allows. The original signed ICF will 
be retained by the clinical site and a copy of the signed and dated document and any other 
written information must be given to the person signing the form. In Japan, signature can be 
replaced by printed name and seal of appropriate individuals. 
Failure to obtain subject consent will be reported by BSC to applicable regulatory bodies 
according to their requirements. Any violations of the informed consent process must be reported 
as deviations to BSC and local regulatory authorities (e.g. IRB/EC), as appropriate. 
If new information becomes available that can significantly affect a subject's future health and 
medical care, that information shall be provided to the affected subject(s) in written form via a 
revised ICF or, in some situations, enrolled subjects may be requested to sign and date an 
addendum to the ICF. In addition to new significant information during the course of a study, 
other situations may necessitate revision of the ICF, such as if there are amendments to the 
applicable laws, protocol, a change in Principal Investigator, administrative changes, or 
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following annual review by the IRB/EC. The new version of the ICF must be approved by the 
IRB/EC. Boston Scientific Corporation approval is required if changes to the revised ICF are 
requested by the site’s IRB/EC. The IRB/EC will determine if the subject population is to be re-
consented. 
A Screening Log will be maintained to document select information about candidates who fail to 
meet the enrollment eligibility criteria, including, but not limited to, the reason for screen failure. 
 
22. 
Committees 
22.1. Steering Committee 
A Steering Committee composed of BSC Clinical Management, the Global and Co-Principal 
Coordinating Investigators , and other investigators/physicians experienced in interventional 
cardiology will be convened. Responsibilities may include oversight of the overall conduct of the 
study with regard to protocol development, study progress, subject safety, overall data quality 
and integrity, as well as disseminating any study results through appropriate scientific sessions 
and publications. Steering Committee members may participate in the review and approval of all 
requests for data analysis, abstract and manuscript preparation and submission.  
22.2. Dynamic Safety Monitoring Committee 
To promote early detection of safety issues, BSC processes will provide accelerated evaluation 
of AEs. Success of this program requires dynamic collection of unmonitored data as soon as the 
event is reported. This is expedited through BSC’s Global Safety Office, which is responsible for 
coordinating the collection of information for the subject dossier from the sites. During regularly 
scheduled monitoring visits, the clinical research monitors will support the dynamic reporting 
process through their review of source document information.  
22.2.1. Clinical Events Committee 
The Clinical Events Committee (CEC) is an independent group of individuals with pertinent 
expertise who review and adjudicate endpoint events reported by study Investigators. 
The CEC will review a safety event dossier, which may include copies of subject source 
documents provided by study sites, for all reported cases of death, MI, stent thrombosis, 
bleeding, stroke, and target vessel revascularization.  
Committee membership will include practitioners of cardiology and cardiovascular 
interventional therapy, as well as other experts with the necessary therapeutic and subject matter 
expertise to adjudicate the event categories outlined above. Responsibilities, qualifications, 
membership, and committee procedures are outlined in the CEC Charter. Contact information for 
the CEC is included in the study Manual of Operations for Japanese sites. 
22.2.2. Data Monitoring Committee 
The Data Monitoring Committee (DMC) is responsible for the oversight review of safety events. 
The DMC will include leading experts in cardiovascular interventional therapy, cardiovascular 
surgery, and biostatistics who are not participating in the study and who have no affiliation with 
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BSC. During the course of the study, the DMC will review accumulating safety data to monitor 
the incidence of CEC events and other trends that would warrant modification or termination of 
the study. Responsibilities, qualifications, membership, and committee procedures are outlined in 
the DMC Charter. 
23. 
Suspension or Termination 
23.1 Premature Termination of the Study 
Boston Scientific Corporation reserves the right to terminate the study at any stage but intends to 
exercise this right only for valid scientific or administrative reasons and reasons related to 
protection of subjects. Investigators, associated IRBs/ECs, and regulatory authorities, as 
applicable, will be notified in writing in the event of study termination. 
23.1.1 Criteria for Premature Termination of the Study 
Possible reasons for premature study termination include, but are not limited to, the following. 
• Significant new information (e.g. safety or product performance) which affects the decision 
to continue the study 
• Withdrawal of FDA or other regulatory authority approval to conduct the clinical study 
• A decision on the part of BSC to suspend or discontinue development of the device. 
23.2 Termination of Study Participation by the Investigator or Withdrawal of IRB/EC 
Approval 
Any Investigator or IRB/EC in the EVOLVE Short DAPT Study may discontinue participation 
in the study or withdraw approval of the study, respectively, with suitable written notice to BSC. 
Investigators, associated IRBs/ECs, and regulatory authorities, as applicable, will be notified in 
writing in the event of these occurrences. 
23.3 Requirements for Documentation and Subject Follow-up 
In the event of premature study termination a written statement as to why the premature 
termination has occurred will be provided to all participating centers by BSC. The IRB/EC and 
regulatory authorities, as applicable, will be notified. Detailed information on how enrolled 
subjects will be managed thereafter will be provided.  
In the event an IRB or EC terminates participation in the study, participating Investigators, 
associated IRBs/ECs, and regulatory authorities, as applicable, will be notified in writing. 
Detailed information on how enrolled subjects will be managed thereafter will be provided by 
BSC. 
In the event an Investigator terminates participation in the study, study responsibility will be 
transferred to a co-Investigator, if possible. In the event there are no opportunities to transfer 
Investigator responsibility; detailed information on how enrolled subjects will be managed 
thereafter will be provided by BSC. 
The Investigator must return all documents to BSC, unless this action would jeopardize the 
rights, safety, or welfare of the subjects. 
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23.4 Criteria for Suspending/Terminating a Study Center 
Boston Scientific Corporation reserves the right to stop the inclusion of subjects at a study site at 
any time after the study initiation visit if no subjects have been enrolled, if enrollment is 
significantly slower than expected, or if the center has multiple or severe protocol violations 
without justification and/or fails to follow remedial actions. The Principal Investigator at the site 
must make a provision for the continued medical monitoring of subjects that were enrolled in the 
study. 
24. 
Publication Policy 
In accordance with the Corporate Policy on the Conduct of Human Subject Research, BSC 
requires disclosure of its involvement as a sponsor or financial supporter in any publication or 
presentation relating to a BSC study or its results. In accordance with the Corporate Policy for 
the Conduct of Human Subject Research, BSC will submit study results for publication 
(regardless of study outcome) following the conclusion or termination of the study. Boston 
Scientific Corporation adheres to the contributorship criteria set forth in the Uniform 
Requirements of the International Committee of Medical Journal Editors (ICMJE; 
http://www.icmje.org). In order to ensure the public disclosure of study results in a timely 
manner, while maintaining an unbiased presentation of study outcomes, BSC personnel may 
assist authors and Investigators in publication preparation provided the following guidelines are 
followed. 
• All authorship and contributorship requirements as described above must be followed. 
• BSC involvement in the publication preparation and the BSC Publication Policy should be 
discussed with the Global and Co-Principal Coordinating Investigators and/or Steering 
Committee at the onset of the project. 
• The First and Senior authors are the primary drivers of decisions regarding publication 
content, review, approval, and submission.  
 
25. 
Reimbursement and Compensation for Subjects (Japan Only) 
25.1. Subject Reimbursement 
Travel and other expenses incurred by subjects as a result of participation in the study will be 
reimbursed in accordance with pertinent country laws and regulations and per the study site’s 
regulations.  
25.2. Compensation for Subject’s Health Injury 
In the event of clinical study-related health injury to a subject, Boston Scientific Japan (BSJ) will 
respond based on the clinical study agreement with the investigational site and BSJ work 
instruction 
 
 
 
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26. 
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Byrne RA, Joner M, Kastrati A. Polymer coatings and delayed arterial healing following 
drug-eluting stent implantation. Minerva Cardioangiologica 2009;57:567-84. 
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Levine GN, Bates ER, Bittl JA et al. 2016 ACC/AHA Guideline Focused Update on 
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28. 
Mauri L, Kereiakes DJ, Yeh RW et al. Twelve or 30 Months of Dual Antiplatelet 
Therapy after Drug-Eluting Stents. New Engl J Med 2014;371:2155-2166. 
29. 
Abo-salem E, Alsidawi S, Jamali H, Effat M, Helmy T. Optimal duration of dual 
antiplatelet therapy after drug eluting stents: Meta-analysis of randomized trials. 
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Cassese S, Byrne RA, Ndrepepa G, Schunkert H, Fusaro M, Kastrati A. Prolonged dual 
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31. 
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Eluting Stent Implantation: A Systematic Review and Meta-Analysis of Randomized 
Controlled Trials. Journal of the American College of Cardiology 2015;65:1298-1310. 
32. 
Navarese EP, Andreotti F, Schulze V et al. Optimal duration of dual antiplatelet therapy 
after percutaneous coronary intervention with drug eluting stents: meta-analysis of 
randomised controlled trials. BMJ 2015;350:h1618-h1618. 
33. 
Palmerini T, Benedetto U, Bacchi-Reggiani L et al. Mortality in patients treated with 
extended duration dual antiplatelet therapy after drug-eluting stent implantation: a 
pairwise and Bayesian network meta-analysis of randomised trials. The Lancet 
2015;385:2371-2382. 
34. 
Meredith IT, Verheye S, Dubois CL et al. Primary endpoint results of the EVOLVE trial: 
A randomized evaluation of a novel bioabsorbable polymer-coated, everolimus-eluting 
coronary stent. J Am Coll Cardiol 2012;59:1362-1370. 
35. 
Wilson GJ, Marks A, Berg KJ et al. The SYNERGY biodegradable polymer everolimus 
eluting coronary stent: Porcine vascular compatibility and polymer safety study. Catheter 
Cardiovasc Interv 2015:[Epub ahead of print]. 
36. 
Meredith IT, Whitbourn R, Scott D et al. PLATINUM QCA: a prospective, multicentre 
study assessing clinical, angiographic, and intravascular ultrasound outcomes with the 
novel platinum chromium thin-strut PROMUS Element everolimus-eluting stent in de 
novo coronary stenoses. EuroIntervention 2011;7:84-90. 
37. 
Stone GW, Teirstein PS, Meredith IT et al. A prospective, randomized evaluation of a 
novel everolimus-eluting coronary stent: The PLATINUM Trial. J Am Coll Cardiol 
2011; 57:1700-1708. 
38. 
Kereiakes D. Four-year results of the PLATINUM randomized trial: Can stent metal 
alloy composition and design affect late clinical outcomes? . 'Presented at:' ACC 2014; 
Washington, D.C. 
39. 
Meredith IT, Teirstein PS, Bouchard A et al. Three-year results comparing platinum-
chromium PROMUS Element and cobalt-chromium XIENCE V everolimus-eluting 
stents in de novo coronary artery narrowing (from the PLATINUM Trial). Am J Cardiol 
2014;doi: 10.1016/j.amjcard.2013.12.011. 
40. 
Meredith IT, Teirstein PS, Stone GW et al. Two-year results of the PLATINUM SV 
Trial:  Evaluation of a 2.25mm platinum chromium everolimus-eluting stent in de novo 
coronary artery lesions. 'Presented at:' Euro PCR 2012; Paris. 
41. 
Meredith IT, Teirstein PS, Stone GW et al. The PLATINUM Small Vessel trial: 
Evaluation of the novel thin-strut platinum-chromium PROMUS Element small vessel 
everolimus-eluting stent. 'Presented at:' EuroPCR 2011; Paris. 
42. 
Stone GW. Two-year results of the PLATINUM randomized trial comparing platinum 
chromium PROMUS Element and cobalt chromium PROMUS/XIENCE V everolimus-
eluting stents in de novo coronary artery lesions. 'Presented at:' ACC 2012; Chicago, IL, 
USA. 
43. 
Stone GW. Final Five-Year Results of the PLATINUM Randomized Trial Comparing 
Platinum Chromium PROMUS Element and Cobalt Chromium PROMUS/XIENCE V 
Everolimus-Eluting Stents in Workhorse Lesions. 'Presented at:' ACC 2015; Chicago, IL. 
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44. 
Teirstein P. Two-year outcomes following implantation of 32mm and 38mm platinum 
chromium everolimus-eluting element stents in long coronary lesions. 'Presented at:' TCT 
2012; Miami, FL. 
45. 
Teirstein PS. Three-year results of the PLATINUM Small Vessel and Long Lesion trials 
evaluating the platinum chromium everolimus-eluting stent in de novo coronary artery 
lesions. 'Presented at:' TCT 2013; San Francisco, CA, USA. 
46. 
Teirstein PS. Four-Year Outcomes Following Implantation of the Promus Element® 
Platinum Chromium Everolimus-Eluting Stent in De Novo Coronary Artery Lesions in 
Small Vessels and Long Lesions: Results of the PLATINUM Small Vessel and Long 
Lesion Trials. 'Presented at:' TCT 2014; Washington, DC. 
47. 
Teirstein PS, Meredith IT, Feldman RL et al. Two-year safety and effectiveness of the 
platinum chromium everolimus-eluting stent for the treatment of small vessels and longer 
lesions. Catheterization and Cardiovascular Interventions 2015;85:207-215. 
48. 
Teirstein PS, Stone GW, Meredith IT et al. Platinum Chromium Everolimus-Eluting 
Stent in Long Coronary Lesions. 'Presented at:' TCT 2011; San Francisco. 
49. 
Saito S, Iwabuchi M, Muramatsu T et al. Two-Year Outcomes Following Platinum 
Chromium Everolimus-Eluting Stent Implantation in Small Vessel Lesions in Japan. 
'Presented at:' Cardiovascular Revascularization Therapeutics;2013; 2013. 
50. 
Saito S, Iwabuchi M, Muramatsu T et al. PLATINUM Japan SV: Platinum Chromium 
Everolimus-Eluting Stent in Small Vessels. 'Presented at:' Cardiovascular 
Revascularization Therapeutics 2012. 
51. 
Gao R, Han Y, Yang Y et al. PLATINUM China: A prospective, randomized 
investigation of the platinum chromium everolimus-eluting stent in de novo coronary 
artery lesions. Catheterization and Cardiovascular Interventions 2015;85:716-723. 
52. 
Meredith IT, Verheye S, Weissman NJ et al. Six-month IVUS and two-year clinical 
outcomes in the EVOLVE FHU trial: a randomised evaluation of a novel bioabsorbable 
polymer-coated, everolimus-eluting stent. EuroIntervention 2013;9:308-15. 
53. 
Verheye S. Six-Month IVUS and 12-Month Clinical Outcomes in the EVOLVE FHU 
Trial: A Randomized Evaluation of a Novel Bioabsorbable Polymer-Coated, Everolimus-
Eluting Stent. 'Presented at:' EuroPCR 2012; Paris, France. 
54. 
Meredith IT. Four-year clinical outcomes in the EVOLVE trial: A randomised evaluation 
of a novel bioabsorbable polymer-coated, everolimus-eluting stent. 'Presented at:' 
EuroPCR 2015; Paris, France. 
55. 
Meredith IT. Three-year clinical outcomes in the EVOLVE FHU trial: A randomised 
evaluation of a novel bioabsorbable polymer-coated, everolimus-eluting stent. 'Presented 
at:' EuroPCR 2014; Paris, France. 
56. 
Kereiakes DJ, Meredith IT, Windecker S et al. Efficacy and safety of a novel 
bioabsorbable polymer-coated, everolimus-eluting coronary stent: the EVOLVE II 
Randomized Trial. Circ Cardiovasc Interv 2015;8:e002372. 
57. 
Windecker S. Primary Clinical Outcomes of the EVOLVE II Diabetes Substudy 
Evaluating a Novel Bioabsorbable Polymer-Coated, Everolimus-Eluting Coronary Stent 
in Diabetic Patients. 'Presented at:' EuroPCR 2015; Paris, France. 
58. 
Meredith IT. Nine-month Primary Endpoint Results of the EVOLVE II QCA Study: A 
Prospective, Multicenter Trial Assessing Clinical, Angiographic, and IVUS Outcomes 
with the Novel Platinum-Chromium Abluminally-coated Bioabsorbable Polymer 
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SYNERGY Everolimus-Eluting Stent in De Novo Coronary Stenoses. 'Presented at:' 
ACC 2015; Chicago, IL. 
59. 
Mehran R, Rao SV, Bhatt DL et al. Standardized Bleeding Definitions for Cardiovascular 
Clinical Trials: A Consensus Report From the Bleeding Academic Research Consortium. 
Circulation 2011;123:2736-2747. 
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GUSTO Investigators. An international randomized trial comparing four thrombolytic 
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1993;329:673-82. 
61. 
Rao AK, Pratt C, Berke A et al. 37th Annual Scientific SessionThrombolysis in 
myocardial infarction (TIMI) trial—Phase I: Hemorrhagic manifestations and changes in 
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plasminogen activator and streptokinase. Journal of the American College of Cardiology 
1988;11:1-11. 
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Yeh RW, Secemsky EA, Kereiakes DJ, et al. Development and validation of a prediction 
rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous 
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63. 
Directions for Use, SYNERGY™ Everolimus-Eluting Platinum Chromium Coronary 
Stent System. 
64. 
Dani S, Kukreja N, Parikh P et al. Biodegradable-polymer-based, sirolimus-eluting 
Supralimus stent: 6-month angiographic and 30-month clinical follow-up results from the 
series I prospective study. EuroIntervention 2008;4:59-63. 
65. 
Ormiston JA, Abizaid A, Spertus J et al. Six-month results of the NEVO Res-Elution I 
(NEVO RES-I) trial: a randomized, multicenter comparison of the NEVO sirolimus-
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coronary artery lesions. Circ Cardiovasc Interv 2010;3:556-64. 
66. 
Vedat A, Selcuk G, Refik E et al. Treatment of patients with coronary artery disease with 
biodegradable polymer based paclitaxel-eluting Infinnium coronary stent system: results 
of 1-year clinical follow-up a single center experience. Indian Heart J 2009;61:254-7. 
 
 
 
 
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27. 
Abbreviations and Definitions  
27.1. Abbreviations 
Abbreviations are shown in Table 27.1-1.   
Table 27.1-1: Abbreviations 
Abbreviation/Acronym 
Term 
 
 
ACC 
American College of Cardiology 
ADE 
adverse device effect 
AE 
adverse event 
AHA 
American Heart Association 
ARC 
BARC 
Academic Research Consortium 
Bleeding Academic Research Consortium 
BSC 
Boston Scientific Corporation 
BMS 
bare metal stent 
CABG 
coronary artery bypass graft 
CEC 
Clinical Events Committee 
CK 
creatine kinase 
CK-MB 
creatine kinase-myoglobin band, a fraction of creatine kinase 
CRO 
Contract research organization 
eCRF 
electronic case report form 
CVA 
cerebrovascular accident 
DES 
drug-eluting stent 
DFU 
Directions for Use 
DMC 
EC 
Data Monitoring Committee 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
FHU 
First Human Use 
GCP 
Good Clinical Practices 
GUSTO 
Global Strategies for Opening Occluded Coronary Arteries 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
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Table 27.1-1: Abbreviations 
Abbreviation/Acronym 
Term 
ISO 
International Standards Organization 
ITT 
IVUS 
intention to treat 
intravascular ultrasound 
LAD 
left anterior descending coronary artery 
LBBB 
left bundle branch block 
LCX 
left circumflex coronary artery 
LL 
LVEF 
long lesion 
left ventricular ejection fraction 
MACE 
MACCE 
major adverse cardiac event 
major adverse cardiac and cerebrovascular event 
MI 
myocardial infarction 
NHLBI 
NSTEMI 
National Heart, Lung, and Blood Institute 
Non ST elevation myocardial infarction 
PCI 
percutaneous coronary intervention 
PG 
Performance Goal 
PK 
Pharmacokinetics 
PLGA 
poly(DL-lactide-co-glycolide) 
POBA 
Plain Old Balloon Angioplasty 
QCA 
quantitative coronary angiography 
RCA 
right coronary artery 
RVD 
reference vessel diameter 
SADE 
serious adverse device effect 
SAE 
serious adverse event 
SCAI 
ST 
Society for Cardiovascular Angiography and Interventions 
Stent thrombosis 
STEMI 
ST elevation myocardial infarction 
SV 
Small vessel 
TIA 
transient ischemic attack 
TIMI 
Thrombolysis in Myocardial Infarction 
TLF 
target lesion failure 
TLR 
target lesion revascularization 
TVF 
target vessel failure 
TVR 
target vessel revascularization 
UADE 
USADE 
unanticipated adverse device effect 
uanticipated serious adverse device effect 
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Table 27.1-1: Abbreviations 
Abbreviation/Acronym 
Term 
ULN 
upper limit of normal 
URL 
upper reference limit 
US 
United States 
WH 
Workhorse 
 
 
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27.2. Definitions 
ADVERSE DEVICE EFFECT (Ref: ISO 14155-2011, MEDDEV 2.7/3 Revision 3, 5/2015) 
Adverse event related to the use of an investigational medical device. 
Note: This definition includes AEs resulting from insufficient or inadequate instructions for use, 
the deployment, the implantation, the installation, the operation, or any malfunction of the 
investigational medical device.  
Note: This definition includes any event resulting from use error or from intentional misuse of 
the investigational medical device.  
 
ADVERSE EVENT (Ref: ISO 14155-2011, MEDDEV 2.7/3 Revision 3, 5/2015) 
Any untoward medical occurrence, unintended disease or injury, or any untoward clinical signs 
(including abnormal laboratory finding) in subjects, users or other persons, whether or not 
related to the investigational medical device. This includes events related to: 
• The investigational medical device or comparator 
• The procedures involved (study-required) 
Note: For users/other persons, this definition is restricted to events related to the investigational 
medical device 
 
 
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ADVERSE EVENT RELATIONSHIP TERMS 
Not Related: Relationship to the device or procedures can be excluded when: 
• the event is not a known side effect of the product category the device belongs to or of 
similar devices and procedures; 
• the event has no temporal relationship with the use of the investigational device or the 
procedures; 
• the serious event does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible; 
• the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible – and reintroduction of its use (or increase 
of the level of activation/exposure), do not impact on the serious event; 
• the event involves a body-site or an organ not expected to be affected by the device or 
procedure; the serious event can be attributed to another cause (e.g. an underlying or 
concurrent illness/ clinical condition, an effect of another device, drug, treatment or other 
risk factors); 
• the event does not depend on a false result given by the investigational device used for 
diagnosis, when applicable; harms to the subject are not clearly due to use error; 
• In order to establish the non-relatedness, not all the criteria listed above might be met at 
the same time, depending on the type of device/procedures and the serious event. 
 
Unlikely Related: The relationship with the use of the device seems not relevant and/or the event 
can be reasonably explained by another cause, but additional information may be obtained. 
 
Possibly Related: The relationship with the use of the investigational device is weak but cannot 
be ruled out completely. Alternative causes are also possible (e.g. an underlying or concurrent 
illness/ clinical condition or/and an effect of another device, drug or treatment). Cases were 
relatedness cannot be assessed or no information has been obtained should also be classified as 
possible. 
 
Probably Related: The relationship with the use of the investigational device seems relevant 
and/or the event cannot reasonably explained by another cause, but additional information may 
be obtained. 
 
Causal Relationship: The serious event is associated with the investigational device or with 
procedures beyond reasonable doubt when: 
• the event is a known side effect of the product category the device belongs to or of 
similar devices and procedures; 
• the event has a temporal relationship with investigational device use/application or 
• procedures; 
• the event involves a body-site or organ that 
o the investigational device or procedures are applied to; 
o the investigational device or procedures have an effect on; 
• the serious event follows a known response pattern to the medical device (if the response 
pattern is previously known); 
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• the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 
• other possible causes (e.g. an underlying or concurrent illness/ clinical condition or/and 
an effect of another device, drug or treatment) have been adequately ruled out; 
• harm to the subject is due to error in use; 
• the event depends on a false result given by the investigational device used for diagnosis, 
when applicable; 
• In order to establish the relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event. 
 
ANTICIPATED EVENT 
Event that is previously identified in the protocol, ICF, or DFU 
BIFURCATION LESION 
A bifurcation lesion is a lesion associated with the area where a branch vessel ≥2.0 mm in 
diameter by visual estimate originates. 
BLEEDING CLASSIFICATIONS-GUSTO (60) 
Major Bleeding will be defined by the GUSTO classification of “Severe/life-threatening” or 
“Moderate” below: 
• 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 
• Mild: Bleeding that does not meet criteria for either severe or moderate bleeding 
Bleeding events that are medically important, but that do not meet the severe/moderate levels 
(e.g., require laboratory testing, evaluation by a physician, ER visit, or cessation of either study 
medication or other antithrombotic therapies) will be collected. 
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BLEEDING CLASSIFICATIONS-Bleeding Academic Research Consortium (BARC) (59) 
• Type 0: No Bleeding 
• Type 1: Bleeding that is not actionable and does not cause the patient to seek treatment 
• Type 2: Any clinically overt sign of hemorrhage that “is actionable” and requires 
diagnostic studies, hospitalization, or treatment by a health care professional 
• Type 3a: Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL (provided hemoglobin 
drop is related to bleed); transfusion with overt bleeding 
• Type 3b: Overt bleeding plus hemoglobin drop ≥5 g/dL (provided hemoglobin drop is 
related to bleed); cardiac tamponade; bleeding requiring surgical intervention for control; 
bleeding requiring IV vasoactive agents 
• Type 3c: Intracranial hemorrhage confirmed by autopsy, imaging, or lumbar puncture; 
intraocular bleed compromising vision 
• Type 4: CABG-related bleeding within 48 hours 
• Type 5a: Probable fatal bleeding 
• Type 5b: Definite fatal bleeding 
 
BARC types 2, 3a, 3b, 3c, 4, 5a and 5b will be collected in the study. 
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BLEEDING CLASSIFICATIONS-TIMI (61) 
Non-CABG related bleeding 
Major 
• Any intracranial bleeding (excluding microhemorrhages 10 mm evident only on gradient-
echo MRI) 
• Clinically overt signs of hemorrhage associated with a drop in hemoglobin of 5 g/dL 
• Fatal bleeding (bleeding that directly results in death within 7 d) 
Minor 
• Clinically overt (including imaging), resulting in hemoglobin drop of 3 to 5 g/dL 
• Requiring medical attention 
• Any overt sign of hemorrhage that meets one of the following criteria and does not meet 
criteria for a major or minor bleeding event, as defined above 
• Requiring intervention (medical practitioner-guided medical or surgical treatment to stop 
or treat bleeding, including temporarily or permanently discontinuing or changing the 
dose of a medication or study drug) 
• Leading to or prolonging hospitalization 
• Prompting evaluation (leading to an unscheduled visit to a healthcare professional and 
diagnostic testing, either laboratory or imaging) 
Minimal 
• Any overt bleeding event that does not meet the criteria above 
Bleeding in the setting of CABG 
• Fatal bleeding (bleeding that directly results in death) 
• Perioperative intracranial bleeding 
• Reoperation after closure of the sternotomy incision for the purpose of controlling 
bleeding 
• Transfusion of 5 U PRBCs or whole blood within a 48-h period; cell saver transfusion 
will not be counted in calculations of blood products. 
• Chest tube output 2 L within a 24-h period 
 
All TIMI bleeding events (with the exception of minimal) will be collected in this study. 
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BRAUNWALD CLASSIFICATION OF UNSTABLE ANGINA 
Severity 
• Class I: New onset, severe or accelerated angina. Subjects with angina of less than 2 months 
duration, severe or occurring 3 or more times per day, or angina that is distinctly more 
frequent and precipitated by distinctly less exertion; no pain at rest in the last 2 months. 
• Class II: Angina at rest, subacute.  Subjects with 1 or more episodes of angina at rest during 
the preceding month, but not within the preceding 48 hours. 
• Class III: Angina at rest, acute. Subjects with 1 or more episodes of angina at rest within the 
preceding 48 hours. 
Clinical Circumstances 
• Class A: Secondary unstable angina. A clearly identified condition extrinsic to the coronary 
vascular bed that has intensified myocardial ischemia (e.g., anemia, fever, infection, 
hypotension, tachyarrhythmia, thyrotoxicosis, and hypoxemia secondary to respiratory 
failure). 
• Class B: Primary unstable angina. 
• Class C: Postinfarction unstable angina (within 2 weeks of documented MI). 
 
CANADIAN CARDIOVASCULAR SOCIETY CLASSIFICATION 
• Class 1: Ordinary physical activity does not cause angina, such as walking and climbing 
stairs. Angina with strenuous or rapid or prolonged exertion at work or recreation. 
• Class 2: Slight limitation of ordinary activity. Walking or climbing stairs rapidly, walking 
uphill, walking or stair climbing after meals, or in cold, or in wind, or under emotional stress, 
or any only during the first hours after awakening. Walking more than 2 blocks on the level 
and climbing more than 1 flight of ordinary stairs at a normal pace and in normal conditions. 
• Class 3: Marked limitations of ordinary physical activity. Walking 1 to 2 blocks on the level 
and climbing 1 flight of stairs in normal conditions and at a normal pace. 
• Class 4: Inability to carry on any physical activity without discomfort; angina syndrome may 
be present at rest. 
CLINICAL EVENTS COMMITTEE 
A CEC is an independent group of individuals with pertinent expertise that review and adjudicate 
important endpoints and relevant AEs reported by study investigators. 
 
 
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DEATH 
All deaths are considered cardiac unless an unequivocal non-cardiac cause can be established. 
Specifically, any unexpected death even in subjects with coexisting potentially fatal non-cardiac 
disease (e.g. cancer, infection) should be classified as cardiac. 
• 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. This includes all procedure related deaths including those related to 
concomitant treatment. 
• Vascular death: Death due to cerebrovascular disease, pulmonary embolism, ruptured 
aortic aneurysm, dissecting aneurysm, or other vascular cause. 
• Non-cardiac death: Any death not covered by the above definitions, including death due 
to infection, sepsis, pulmonary causes, accident, suicide or trauma. 
 
DEVICE DEFICIENCY (Ref: ISO 14155-2011, MEDDEV 2.7/3 Revision 3, 5/2015) 
A device deficiency is any inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance. 
Note: Device deficiencies include malfunctions, use errors, and inadequate labeling. 
 
DISSECTION, NHLBI CLASSIFICATION 
• Type A: Small radiolucent area within the lumen of the vessel disappearing with the passage 
of the contrast material 
• Type B: Appearance of contrast medium parallel to the lumen of the vessel disappearing 
within a few cardiac cycles 
• Type C: Dissection protruding outside the lumen of the vessel persisting after passage of the 
contrast material 
• Type D: Spiral shaped filling defect with or without delayed run-off of the contrast material 
in the antegrade flow 
• Type E: Persistent luminal filling defect with delayed run-off of the contrast material in the 
distal lumen 
• Type F: Filling defect accompanied by total coronary occlusion 
 
DIABETES MELLITUS 
Subjects will be categorized as having diabetes mellitus if medical treatment (oral or injection) is 
required for control of blood glucose levels. 
EPICARDIAL VESSEL 
Epicardial vessels include the LAD and its branches, the LCX and its branches, and the RCA and 
its branches. 
 
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HYPERTENSION 
Hypertension is persistently high arterial blood pressure. Various criteria for its threshold have 
been suggested, ranging from 140 mmHg systolic and 90 mmHg diastolic to as high as 
220 mmHg systolic and 110 mmHg diastolic. Hypertension may have no known cause or be 
associated with other primary diseases. 
 
INDEX PROCEDURE START TIME 
Index procedure start time is defined as the time of sheath insertion. If a previously placed sheath 
is used (i.e., from an earlier diagnostic procedure), index procedure start time is defined as the 
time of guide catheter insertion into sheath for the interventional procedure. 
 
INDEX PROCEDURE END TIME 
Index procedure end time is defined as the time the guide catheter is removed after the final 
angiography. 
 
LEFT MAIN DISEASE 
Left main disease is a significant lesion in the left main coronary artery of at least 50% diameter 
stenosis. A protected left main artery means left main with a functioning graft, either venous or 
arterial, placed to any of the branches of the left main. This is usually the LAD or CX, but could 
also include one of the branches of those vessels. Having a stent in the left main coronary artery 
does not in itself constitute a protected left main. 
 
LESION CHARACTERISTICS (ACC/AHA CLASSIFICATION) 
• Type A lesions: Minimally complex, length <10 mm, concentric, readily accessible, 
non-angulated segment (<45°), smooth contour, little or no calcification, less than totally 
occlusive, not ostial in location, no major side branch involvement, and an absence of 
thrombus. 
• Type B lesions: Moderately complex, tubular (length 10 to 20 mm), eccentric, moderate 
tortuosity of proximal segment, moderately angulated segment (>45°, <90°), irregular 
contour, moderate or heavy calcification, total occlusions <3 months old, ostial in location, 
bifurcation lesions requiring double guidewire, and some thrombus present. 
• B1 lesion has one of the above characteristics 
• B2 lesion has two or more of the above characteristics 
• Type C lesions: Severely complex, diffuse (length ≥20 mm), excessive tortuosity of proximal 
segment, extremely angulated segments >90°, total occlusions >3 months old and/or bridging 
collaterals, inability to protect major side branches, and degenerated vein grafts with friable 
lesions. 
 
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LESION LENGTH 
Lesion length is measured as distance from the proximal to the distal shoulder in the view that 
demonstrates the stenosis in its most elongated projection. 
 
LESION LOCATION 
Lesion location is the location of the lesion according to the specific coronary artery (i.e., left 
main, LAD, LCX, or RCA) or bypass graft, and is specified as proximal, mid, or distal. A 
standard map will be provided to be used for location descriptions. 
Note: In the EVOLVE Short DAPT Study, the ramus will be considered to be a branch of the 
LCX for purposes of determining eligibility and for determining TVR. 
 
MULTI-VESSEL DISEASE 
Multi-vessel disease refers to the presence of >50% diameter stenosis in 2 or 3 major epicardial 
coronary vessels or bypassed branches. 
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MYOCARDIAL INFARCTION -3rd Universal Definition (1)  
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 
Percutaneous Coronary Intervention-Related Myocardial Infarction 
Percutaneous coronary intervention (PCI) related MI is arbitrarily defined by elevation of cTn 
value (>5 x 99th percentile URL) in patients with normal baseline values (≤99th percentile URL) 
or a rise of cTn values >20% if the baseline values are elevated and are stable or falling.   
AND 
One of the following: 
• Symptoms suggestion of myocardial ischemia  
• New ischemic ECG changes  
• Angiographic findings consistent with a procedural complication  
• Imaging demonstration of new loss of viable myocardial or new regional wall motion 
abnormality are required. 
Coronary Artery Bypass Grafting-Related Myocardial Infarction 
Coronary artery bypass graft (CABG) related MI is arbitrarily defined by elevation of cardiac 
biomarker values (>10 x 99th percentile URL) in patients with normal baseline cTn values 
(≤99th percentile URL).   
AND 
One of the following: 
• New pathological Q waves or new LBBB  
• Angiographic documented new graft or new native coronary artery occlusion 
• Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality. 
• Cardiac death with symptoms suggestive of myocardial ischemia and presumed new 
ischemic ECG changes or new LBBB, but death occurred before cardiac biomarkers were 
obtained, or before cardiac marker values would be increased.  
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• Stent thrombosis associated with MI when detected by coronary angiography or autopsy 
in the setting of myocardial ischemia and with a rise and/or fall of cardiac biomarker 
values with at least one value above the 99th percentile URL. 
 
RESTENOSED LESION 
A restenosed lesion is a previously treated lesion that again has a stenosis. 
 
RESTENOSIS 
A > 50% reduction in diameter of a previously-treated lesion when compared to the reference 
luminal diameter. 
 
SERIOUS ADVERSE DEVICE EFFECT (Ref: ISO 14155-2011, MEDDEV 2.7/3 Revision 
3, 5/2015) 
Adverse device effect that has resulted in any of the consequences characteristic of a SAE. 
 
SERIOUS ADVERSE EVENT (Ref: ISO 14155-2011, MEDDEV 2.7/3 Revision 3, 5/2015) 
Adverse event that: 
• Led to death 
• Led to a serious deterioration in the health of the subject as defined by either: 
o A life-threatening illness or injury, or 
o A permanent impairment of a body structure or a body function, or 
o In-patient or prolonged hospitalization of existing hospitalization, or 
o Medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to body structure or a body function 
• Led to fetal distress fetal death or a congenital abnormality or birth defect 
 
STENT THROMBOSIS (8) 
Stent thrombosis should be reported as a cumulative value at the different time points and with 
the different separate time points. Time 0 is defined as the time point after the guide catheter has 
been removed and the patient left the catheterization lab. 
Timing: 
• Acute stent thrombosis*: 0-24 hours after stent implantation 
• Subacute stent thrombosis*: >24 hours to 30 days after stent implantation 
• Late stent thrombosis: >30 days to 1 year after stent implantation 
• Very late stent thrombosis: >1 year after stent implantation 
* Acute/subacute can also be replaced by early stent thrombosis. Early stent thrombosis is 0-30 days. 
Stent thrombosis may be defined as: 
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• Confirmed/definite 
• Probable 
• Possible 
Confirmed/Definite (is considered either angiographic confirmed or pathologic confirmed) 
Angiographic confirmed stent thrombosis is considered to have occurred if: 
• TIMI flow is: 
o TIMI flow grade 0 with occlusion originating in the stent or in the segment 5mm 
proximal or distal to the stent region in the presence of thrombus* 
o TIMI flow grade 1, 2 or 3 originating in the stent or in the segment 5mm proximal or 
distal to the stent region in the presence of a thrombus* 
AND at least one of the following criteria, up to 48 hours, has been fulfilled: 
• New onset of ischemic symptoms at rest (typical chest pain with duration >20 minutes) 
• New ischemic ECG changes suggestive of acute ischemia 
• Typical rise and fall in cardiac biomarkers (>2× ULN of CK) 
The incidental angiographic documentation of stent occlusion in the absence of clinical 
syndromes is not considered a confirmed stent thrombosis (silent thrombosis). 
* Intracoronary thrombus 
Non-occlusive thrombus: Spheric, ovoid or irregular non-calcified filling defect or lucency surrounded by contrast 
material (on 3 sides of within a coronary stenosis) seen in multiple projections, or persistence of contrast material 
within the lumen, or a visible embolization of intraluminal material downstream. 
Occlusive thrombus: A TIMI 0 or TIMI 1 intra-stent or proximal to a stent up to the most adjacent proximal side 
branch or main branch (if originating from the side branch). 
Probable 
Clinical definition of probable stent thrombosis is considered to have occurred in the following 
cases: 
• Any unexplained death within the first 30 days 
• Irrespective of the time after the index procedure and MI in the absence of any obvious cause 
which is related to documented acute ischemia in the territory of the implanted stent without 
angiographic confirmation of stent thrombosis 
Possible 
Clinical definition of possible stent thrombosis is considered to have occurred with any 
unexplained death beyond 30 days. 
STROKE  
An acute symptomatic episode of neurological dysfunction attributed to a vascular cause lasting 
more than 24 hours or lasting 24 hours or less with a brain imaging study or autopsy showing 
infarction. 
 
Classification: 
• Ischemic Stroke: An acute symptomatic episode of focal cerebral, spinal, or retinal 
dysfunction caused by an infarction of central nervous system tissue. 
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• Hemorrhagic Stroke: An acute symptomatic episode of focal or global cerebral or spinal 
dysfunction caused by a nontraumatic intraparenchymal, intraventricular, or subarachnoid 
hemorrhage. 
• Undetermined Stroke: A stroke with insufficient information to allow categorization as 
ischemic or hemorrhagic. 
 
An event that lasts < 24 hours may be adjudicated as a stroke if the following treatments were 
used: 
• Pharmacologic, i. e., thrombolytic drug administration, or 
• Non-pharmacologic, i.e., neurointerventional procedure (e.g., intracranial angioplasty) 
 
STAGED PROCEDURE 
Any elective percutaneous intervention using a SYNERGY stent that is not within a target vessel 
or any side branch of a target vessel treated during the index procedure and occurs ≤ 7 days after 
the index procedure. 
TARGET LESION 
Any lesion treated or attempted to be treated with a SYNERGY stent during the index or staged 
procedure(s). The target lesion includes the arterial segment treated with the stent plus the 
arterial segment 5 mm proximal and 5 mm distal to the treatment site. 
 
TARGET LESION REVASCULARIZATION 
A target vessel revascularization that involves a target lesion. 
TARGET VESSEL 
A target vessel is defined as any vessel containing a target lesion. 
TARGET VESSEL FAILURE  
Target vessel failure is defined as the composite of target vessel revascularization, cardiac death 
or target vessel related myocardial infarction  
For the purposes of this protocol, if it cannot be determined with certainty whether MI was 
related to the target vessel it will be considered TVF. 
TARGET VESSEL REVASCULARIZATION 
Any attempted or successfully completed percutaneous or surgical revascularization of a target 
vessel. 
THROMBOLYSIS IN MYOCARDIAL INFARCTION CLASSIFICATION 
• TIMI 0: No perfusion. 
• TIMI 1: Penetration with minimal perfusion. Contrast fails to opacify the entire bed distal to 
the stenosis of the duration of the cine run. 
• TIMI 2: Partial perfusion. Contrast opacifies the entire coronary bed distal to the stenosis. 
However, the rate of entry and/or clearance is slower in the coronary bed distal to the 
obstruction than in comparable areas not perfused by the dilated vessel. 
• TIMI 3: Complete perfusion. Filling and clearance of contrast equally rapid in the coronary 
bed distal to stenosis as in other coronary beds. 
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TOTAL OCCLUSION 
A total occlusion is a lesion with no flow (i.e., TIMI flow 0). 
TRANSIENT ISCHEMIC ATTACK 
A TIA is a focal ischemic neurological deficit of abrupt onset and of presumed vascular etiology 
that resolves completely within 24 hours of onset. 
UNANTICIPATED ADVERSE DEVICE EFFECT (Ref: 21CFR Part 812) 
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 protocol or application (including a supplementary 
plan or application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects. 
UNANTICIPATED SERIOUS ADVERSE DEVICE EFFECT (Ref: ISO 14155-2011, 
MEDDEV 2.7/3 Revision 3, 5/2015) 
A serious adverse device effect which by its nature, incidence, severity, or outcome has not been 
identified in the current version of the risk analysis report. 
 
 
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28. 
Appendices 
28.1. Clinical Trial Organization (Japan) 
Clinical trial organization in Japan including CRO information, and a list of study sites in Japan 
is provided as an attachment only in Japan to fulfill local requirements 
 
 
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28.2. Revision History 
Revision History 
Revision 
Number 
Release Date 
Section 
Change 
Reason for Change 
AA to AB 
November 
13, 2015 
Synopsis, 
Section 7, 
12 
Revision to include 
the rate of ARC Stent 
Thrombosis as a co-
primary endpoint, 
rather than a 
secondary endpoint 
FDA 
recommendation 
AA to AB 
November 
13, 2015 
Synopsis, 
Section 9.2 
Revision to inclusion 
criteria defining 
subjects at high risk 
for bleeding 
FDA 
recommendation 
AA to AB 
November 
13, 2015 
Synopsis, 
Section 9.3 
Revision to exclusion 
criterion for NSTEMI 
FDA 
recommendation 
AA to AB 
November 
13, 2015 
Synopsis, 
Section 
11.10.1.2 
Clarification of 
method to be used to 
assess DAPT 
compliance 
FDA 
recommendation 
AA to AB 
November 
13, 2015 
Section 
12.2.1 
Revision to the 
analysis set definition 
to “enrolled subjects 
who are eligible for 
P2Y12 inhibitor 
discontinuation and 
discontinue the 
P2Y12 inhibitor at 
the 3 month 
assessment visit” 
FDA 
recommendation 
AA to AB 
November 
13, 2015 
Synopsis, 
Section 7.3 
Inclusion of rate of 
target lesion 
revascularization as 
an additional 
endpoint 
Endpoint of interest 
AA to AB 
November 
13, 2015 
Table 12.1 1 Revision to 
propensity score 
covariates 
FDA 
recommendation 
AA to AB 
November 
13, 2015 
N/A 
Additional minor 
corrections/clarificati
ons 
Improve clarity of 
document 
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Revision History 
Revision 
Number 
Release Date 
Section 
Change 
Reason for Change 
AB to AC 
November 
17, 2015 
Synopsis, 
Section 7.3 
Additional Endpoint 
added “Rate of MI 
(Q-wave and non Q-
wave, ST-related and 
not ST-related)” 
Endpoint of interest 
AB to AC 
November 
17, 2015 
Section 
11.4.1 
Revision to 
recommended peri-
procedural loading 
dose of clopidogrel 
from 600mg to 
≥300mg  
Lower recommended 
loading dose, as 
enrolled subjects are 
at higher risk for 
bleeding 
AB to AC 
November 
17, 2015 
Section 24 
Addition of “Global 
and Co-Principal” to 
“BSC involvement in 
the publication 
preparation and the 
BSC Publication 
Policy should be 
discussed with the 
Global and Co-
Principal 
Coordinating 
Investigator(s) and/or 
Executive/Steering 
Committee at the 
onset of the project.” 
Clarification of role 
of Global and Co-
Principal 
Coordinating 
Investigators in the 
Publication Process 
AC to AD  
June 20,  
2016 
Synopsis, 
Section 8.1 
Update in planned # 
sites from “up to 
110” to “up to 120” 
Option of additional 
sites in protocol 
allows opportunity 
for enrollment 
projection, as needed 
AC to AD 
June 20, 
2016 
Synopsis, 
Section 7.2, 
Section 
12.1.2 
Secondary Endpoint 
of “Rate of major 
bleeding (GUSTO 
severe/life-
threatening + 
moderate) between 3 
and 15 month ” 
revised to “Rate of 
bleeding, based upon 
Modification to 
bleeding secondary 
endpoint to use the 
BARC classification 
and to remove 
subjects on chronic 
anticoagulants 
(higher risk for 
bleeding and not 
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Revision History 
Revision 
Number 
Release Date 
Section 
Change 
Reason for Change 
the Bleeding 
Academic Research 
Consortium (BARC) 
classification (types 
2, 3 and 5) between 3 
and 15 months  in 
subjects not taking 
chronic 
anticoagulation. 
represented in the 
DAPT Study control 
population). 
AC to AD 
June 20, 
2016 
Synopsis, 
Section 
11.10 
Update to calculation 
for follow-up 
windows after 3-
months. Windows for 
6, 12 and 15 month 
follow-ups based 
upon the date of the 
3-month visit 
(representing the date 
of DAPT 
discontinuation). 
Revisions to allow 
full year of follow-up 
in analysis dataset, 
following the 3-
month DAPT 
discontinuation. 
Removal of earlier 
half of 15-month visit 
ensures full year of 
follow-up after 3-
month visit date. 
AC to AD 
June 20, 
2016 
Synopsis, 
Section 11.8 
Addition of  
“• Enrolled subjects 
with a need for 
chronic or lifelong 
anticoagulation must 
be treated with a 
P2Y12 inhibitor 
(clopidogrel, 
prasugrel, or 
ticagrelor) for 3 
months following the 
index procedure, but 
are not required to 
take aspirin in 
addition to the P2Y12 
inhibitor between 0-3 
months. These 
subjects may be 
treated with aspirin 
between 0-3 months, 
in addition to the 
Clarification of 
antiplatelet 
requirements for 
subjects who are also 
taking chronic 
anticoagulants 
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Revision History 
Revision 
Number 
Release Date 
Section 
Change 
Reason for Change 
P2Y12 inhibitor and 
anticoagulant at the 
discretion of the 
treating physician, 
but this is not 
required.   
• Enrolled subjects 
who are not on 
chronic 
anticoagulation must 
take both aspirin and 
a P2Y12 inhibitor 
(clopidogrel, 
prasugrel, or 
ticagrelor) for 3 
months following the 
index procedure. 
• Enrolled subjects 
will be evaluated at 3 
months to confirm 
that discontinuation 
of P2Y12 inhibitor 
remains appropriate. 
• Subjects who are 
eligible for 
discontinuation of 
P2Y12 inhibitor 
therapy at 3 months, 
regardless of whether 
they are taking 
chronic 
anticoagulation, are 
required to take 
aspirin starting at 3 
months and 
continuing for the 
duration of the 
study.” 
AC to AD 
June 20, 
2016 
Synopsis, 
Section 9.2 
Revision to Inclusion 
from “Subject must 
be able to take study 
Inclusion criterion 
revised to 
accommodate revised 
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Revision History 
Revision 
Number 
Release Date 
Section 
Change 
Reason for Change 
required dual 
antiplatelet therapy (3 
months of P2Y12 
inhibitor, 15 months 
of aspirin)” to 
“Subject must be able 
to take study required 
dual antiplatelet 
therapy (as required 
per protocol).” 
antiplatelet 
requirements for 
subjects taking 
chronic 
anticoagulants 
AC to AD 
June 20, 
2016 
Synopsis, 
Section 9.3, 
Section 
12.2.1 
Revision of exclusion 
criterion from 
“Planned treatment of 
more than 2 lesions” 
to “Planned treatment 
of more than 3 
lesions.” 
Revision to align 
exclusion criterion 
with pivotal study for 
SYNERGY  
AC to AD 
June 20, 
2016 
Synopsis, 
Section 9.3, 
Section 
12.2.1 
Addition of exclusion 
criterion “Planned 
treatment of lesions 
in more than 2 major 
epicardial vessels” 
Revision to align 
exclusion criterion 
with pivotal study for 
SYNERGY  
AC to AD 
June 20, 
2016 
Synopsis, 
Section 9.3 
Revision of  two 
exclusion criteria 
“Target lesion(s) 
treated during the 
index procedure that 
involves a side 
branch ≥ 2.0 mm in 
diameter by visual 
estimate” and “Target 
lesion(s) treated 
during the index 
procedure that 
involves a clinically 
significant side 
branch < 2.0 mm in 
diameter by visual 
estimate that has a 
clinically significant 
stenosis at the 
Revision to align 
exclusion criterion 
with pivotal study for 
SYNERGY 
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Revision History 
Revision 
Number 
Release Date 
Section 
Change 
Reason for Change 
ostium,” to “Target 
lesion(s) treated that 
involves a complex 
bifurcation (i.e. 
bifurcation lesion 
requiring treatment 
with more than one 
stent).” 
AC to AD 
June 20, 
2016 
Synopsis, 
Section 11.9 
Additional language 
regarding staged 
procedures:  
“• A staged 
procedure is only 
permitted when all 
enrollment inclusion 
criteria and no 
enrollment exclusion 
criteria are met for all 
lesions treated during 
both the initial 
procedure and the 
subsequent staged 
procedure.  
• The total number of 
lesions treated during 
the index and staged 
procedures combined 
must not exceed 3. 
• The total number of 
epicardial vessels 
treated during the 
index and staged 
procedures combined 
must not exceed 2.  
• In the case of a 
staged procedure 
meeting these 
criteria, the subject 
should return for the 
3-month visit (i.e. 
assessment for 
Clarification of 
staged procedure 
requirements 
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Revision History 
Revision 
Number 
Release Date 
Section 
Change 
Reason for Change 
eligibility to 
discontinue P2Y12 
inhibitor) 90 days 
following the staged 
procedure + 30 days 
or - 7 days.” 
AC to AD 
June 20, 
2016 
Synopsis, 
Section 
11.10 
Addition of the 
following note: 
“(Note: Subjects 
taking chronic 
anticoagulation 
between 0-3 months 
are not eligible if 
they were not taking 
P2Y12 inhibitor or 
P2Y12 
inhibitor/aspirin 
between 0-3 
months).” 
Clarification of 
eligibility of subjects 
on chronic 
anticoagulants for 
discontinuation of 
P2Y12 inhibitor at 3-
months 
AC to AD 
June 20, 
2016 
Synopsis, 
Section 
11.4, 
Section 
11.10 
Significant 
interruption of 
P2Y12 inhibitor or 
aspirin defined as 3 
days or greater. 
Clarification of 
reporting 
requirements for 
antiplatelet 
interruption. 
AC to AD 
June 20, 
2016 
Section 4 
DAPT Guideline 
reference updated to 
“The American 
College of 
Cardiology/American 
Heart 
Association/Society 
for Cardiovascular 
Angiographic 
Intervention 
recommends that, 
following DES 
implantation, patients 
with stable ischemic 
heart disease should 
receive clopidogrel 
(or an alternative 
Revision to align 
with “ACC/AHA 
Guideline Focused 
Update on Duration 
of Dual Antiplatelet 
Therapy in Patients 
With Coronary 
Artery Disease” 
(revised 2016). 
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Revision History 
Revision 
Number 
Release Date 
Section 
Change 
Reason for Change 
P2Y12 inhibitor) in 
addition to aspirin for 
a minimum of 6 
months, unless there 
is a high bleeding 
risk. Following DES 
implantation, patients 
with stable ischemic 
heart disease who 
develop a high risk of 
bleeding (e.g., 
treatment with oral 
anticoagulant 
therapy), are at high 
risk of severe 
bleeding 
complication (e.g., 
major intracranial 
surgery), or develop 
significant overt 
bleeding, 
discontinuation of 
P2Y12 inhibitor 
therapy after 3 
months may be 
reasonable.” 
AC to AD 
June 20, 
2016 
Section 10.1 Addition of 
“Enrollment should 
occur within 3 
calendar days of the 
index procedure 
date.” 
Clarification of 
timeline for 
enrollment 
AC to AD 
June 20, 
2016 
Section 18 
Removal of “and 
source data 
verification of all 
endpoint events 
(death, myocardial 
infarction, target 
vessel 
revascularization, 
stent thrombosis, 
Detailed review of 
CEC events against 
source data will be 
performed by the 
Safety Function, 
rather than the on-site 
Clinical Research 
Associate. 
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Revision History 
Revision 
Number 
Release Date 
Section 
Change 
Reason for Change 
stroke, and major 
bleeding).” 
AC to AD 
June 20, 
2016 
Section 
20.1, 
Definitions 
References to 
MEDDEV updated 
Update to align with 
recent revision 
(MEDDEV 2.7/3 
Revision 3, 5/2015) 
AC to AD 
June 20, 
2016 
Section 
20.1, 
Definitions 
Serious Adverse 
Event definition: 
replaced “Led to 
serious deterioration 
in the health of the 
subject, that either 
resulted in…” with 
“Led to serious 
deterioration in the 
health of the subject, 
as defined by 
either…” 
Clarification of 
definition 
AC to AD 
June 20, 
2016 
Section 20.2 Update of Criteria for 
Assessing 
Relationship of Study 
Device and 
Procedure to Adverse 
Event from 
“Unrelated and 
Related” to “Not 
Related, Unlikely 
Related, Possibly 
Related, Probably 
Related and Causal 
Relationship.”  
Update to align with 
recent revision 
(MEDDEV 2.7/3 
Revision 3, 5/2015) 
AC to AD 
June 20, 
2016 
Section 22.1 Addition of “A 
Steering Committee 
composed of BSC 
Clinical 
Management, the 
Study Coordinating 
Principal 
Investigators, and 
other 
Steering Committee 
has been convened 
for this study 
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Revision History 
Revision 
Number 
Release Date 
Section 
Change 
Reason for Change 
investigators/physicia
ns experienced in 
interventional 
cardiology will be 
convened. 
Responsibilities may 
include oversight of 
the overall conduct of 
the study with regard 
to protocol 
development, study 
progress, subject 
safety, overall data 
quality and integrity, 
as well as 
disseminating any 
study results through 
appropriate scientific 
sessions and 
publications. Steering 
Committee members 
may participate in the 
review and approval 
of all requests for 
data analysis, abstract 
and manuscript 
preparation and 
submission.” 
AD to AE 
April 4, 2017 Synopsis, 
Section 8.1, 
Section 12 
# Subjects: Changed 
“approximately 2,000 
subjects” to “up to 
2,250 subjects.” 
 
Addition of the 
following text: 
“Enrollment may be 
continued beyond 
2,000 subjects (up to 
a maximum of 2,250 
subjects) if the 
observed dropout rate 
Increase maximum 
enrollment from 
“approximately 2,000 
subjects” to “up to 
2,250 subjects,” to 
account for a slightly 
higher attrition rate of 
subjects not 
discontinuing from 
P2Y12 inhibitor at 3-
months. 
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Revision History 
Revision 
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Section 
Change 
Reason for Change 
in 0 to 3 months is 
projected to be 
>15%.” 
AD to AE 
April 4, 2017 Synopsis, 
Section 9.2 
& 9.3 
Removal of the 
following from 
Inclusion Criterion 
#1: “Need for chronic 
or lifelong 
anticoagulation 
therapy.” 
 
Addition of the 
following Exclusion 
Criterion: “Subject 
who is taking (or is 
planning to take) 
chronic or lifelong 
anticoagulation 
within 15 months 
following index 
procedure.” 
 
In addition, text 
throughout the 
protocol regarding 
antiplatelet 
requirements was 
removed/edited, 
given the new 
exclusion of this 
population. 
This change will cap 
subset enrollment 
(subjects on 
anticoagulation) by 
removing from 
inclusion criterion 
(high risk bleeding 
qualifier) and adding 
it to the exclusion 
criteria. There has 
been a higher 
enrollment of patients 
on anticoagulation 
than expected and a 
cap is necessary to 
ensure comparability 
to the control 
population. 
 
 
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