EVOLVE 48: A Prospective Multicenter Single Arm Trial to Assess the Safety and Effectiveness of the SYNERGY 48 mm Everolimus-Eluting Platinum Chromium Coronary Stent System for the Treatment of Atherosclerotic Lesion(s)
Phase: PHASE3
Conditions: Coronary Artery Disease
Sponsor: Boston Scientific Corporation

S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 1 of 84 
  
 
 
EVOLVE 48 (S2356) 
 
A Prospective Multicenter Single Arm Trial to Assess the Safety and Effectiveness of the 
SYNERGYTM 48 mm Everolimus-Eluting Platinum Chromium Coronary Stent System 
(SYNERGYTM Stent System) for the Treatment of Subjects with Atherosclerotic Lesion(s)  
 
 
CLINICAL INVESTIGATION PLAN 
 
 
Sponsored By 
Boston Scientific Corporation 
300 Boston Scientific Way 
 
Marlborough, MA 01752, United States 
 
European Authorized Representative 
Boston Scientific International S.A. 
Le Val Saint-Quentin 
2 rue René Caudron, 78960  
Voisins le Bretonneux, France 
 
 
 
 
 
 
 
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. 
 
 
 
 
 
 
 
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 1 of 84 

S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 2 of 84 
  
 
 
Contact Information 
Role 
Contact  
Clinical Contact 
Patricia O’Mara 
Clinical Trial Manager 
Clinical, Interventional Cardiology 
100 Boston Scientific Way    
Marlborough, MA 01752 USA 
 
 
Coordinating Principal 
Investigator 
Dimitri Karmpaliotis, MD, PhD, FACC 
Columbia University Medical Center 
161 Fort Washington Ave. 
New York, New York  10032 
 
Vendors/Labs 
A list of vendors/laboratories involved in the trial is maintained by 
the sponsor. A complete listing of applicable vendors will be 
provided to investigational sites.  
 
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 2 of 84 

S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 3 of 84 
  
 
Original Release: October 16, 2017 
Current Version: October 16, 2017 
 
Revision History 
Revision 
Number 
Release Date 
Template 
number and 
version 
Section 
Change 
Reason for Change 
A 
October 16, 2017 
90702637 
Rev./Ver. AH 
 
 
Initial Release  
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 3 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 4 of 84 
  
2. Protocol Synopsis 
EVOLVE 48 (S2356) 
A Prospective Multicenter Single Arm Trial to Assess the Safety and Effectiveness of the 
SYNERGYTM 48 mm Everolimus-Eluting Platinum Chromium Coronary Stent System 
(SYNERGYTM Stent System) for the Treatment of Subjects with Atherosclerotic Lesion(s) 
Study 
Objective(s) 
To assess the FDA requirement for safety and effectiveness of the 
SYNERGY 48 mm Coronary Stent System for the treatment of subjects 
with atherosclerotic lesion(s) > 34 mm and ≤ 44 mm in length (by visual 
estimate) in native coronary arteries ≥2.5 mm to ≤4.0 mm in diameter 
(by visual estimate). 
Sites outside the United States (US) are being included in this protocol to 
collect additional 48 mm data to support future FDA approval. This is 
also an opportunity to collect EU post-market safety and performance 
data for the current CE Marked 48 mm device. 
Test Device 
SYNERGYTM Everolimus-Eluting Platinum Chromium Coronary Stent 
System (SYNERGY TM Stent System) 
Device Sizes 
The SYNERGY 48 device matrix consists of the following sizes (stent 
diameter and stent length): 
2.50 mm x 48 mm 
2.75 mm x 48 mm* 
3.00 mm x 48 mm 
3.50 mm x 48 mm 
4.00 mm x 48 mm 
*2.75 x 48 mm will not be included in the investigational device matrix in 
the United States (US) 
Study Design 
Prospective, open label, single arm, multi-center  
Planned 
Number of 
Subjects 
Up to 100 subjects 
Planned 
Number of 
Investigational 
Up to 20 sites in the United States, Europe and New Zealand 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 4 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 5 of 84 
  
EVOLVE 48 (S2356) 
A Prospective Multicenter Single Arm Trial to Assess the Safety and Effectiveness of the 
SYNERGYTM 48 mm Everolimus-Eluting Platinum Chromium Coronary Stent System 
(SYNERGYTM Stent System) for the Treatment of Subjects with Atherosclerotic Lesion(s) 
Sites / Countries 
Primary Safety 
and 
Effectiveness 
Endpoint(s) 
The primary endpoint is the 12-month Target Lesion Failure (TLF) rate, 
defined as any ischemia-driven revascularization of the target lesion 
(TLR), myocardial infarction (MI, Q-wave and non–Q-wave) related to 
the target vessel, or cardiac death. 
Additional 
Endpoints 
Clinical endpoints measured in-hospital and at 30 days, 6 months, 
12 months and 2 years. 
• TLR rate, TLF rate (primary endpoint at 12 months), Target 
vessel revascularization (TVR) rate 
• Target vessel failure (TVF) rate 
• MI (Q-wave and non–Q-wave) rate 
• Cardiac death rate, Non-cardiac death rate 
• All death rate 
• Cardiac death or MI rate 
• All death or MI rate 
• All death/MI/TVR rate 
• Stent thrombosis rates (by Academic Research Consortium [ARC] 
definitions) 
  Periprocedural endpoints: 
• Technical success rate 
• Clinical procedural success rate 
Follow-up 
Schedule 
Clinical follow-up: in-hospital, 30 days, 6 months, 12 months and 
2 years after the index procedure. 
The study will be considered complete with regard to the primary 
endpoint after all subjects have completed the 12-month follow-up 
period.  Subjects who are enrolled but who do not receive a study stent 
will be followed through 12 months only. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 5 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 6 of 84 
  
EVOLVE 48 (S2356) 
A Prospective Multicenter Single Arm Trial to Assess the Safety and Effectiveness of the 
SYNERGYTM 48 mm Everolimus-Eluting Platinum Chromium Coronary Stent System 
(SYNERGYTM Stent System) for the Treatment of Subjects with Atherosclerotic Lesion(s) 
Study Duration 
Enrolled subjects who receive a SYNERGY stent will be followed for 2 
years following the index procedure. 
Antiplatelet 
Therapy 
Aspirin:  
• Subjects must be treated with aspirin for the duration of the trial. 
The minimum daily maintenance dose of aspirin should be 
75 mg –100 mg.   
 
P2Y12 inhibitor:  
• Subjects must be treated with one of the following P2Y12 
inhibitors (clopidogrel, prasugrel, or ticagrelor).  The dose and 
duration should be based on current guidelines.   
o In subjects with stable ischemic heart disease (SIHD) 
P2Y12 inhibitor therapy should be given for at least 6 
months post stent implantation. For subjects at high risk of 
bleeding, discontinuation of P2Y12 inhibitor therapy after 
3 months may be reasonable. 
o In subjects with acute coronary syndrome (ACS) P2Y12 
inhibitor therapy should be given for at least 12 months. 
For subjects at high risk of bleeding, discontinuation of 
P2Y12 inhibitory therapy after 6 months may be 
reasonable. 
• 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.   
Safety 
Parameters 
• All serious adverse events (SAE), adverse device effects (ADE), 
death, MI, TVR and stent thrombosis 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 
Clinical 
Inclusion 
Criteria 
CI1. 
Subject must be at least 18 years of age 
CI2. 
Subject (or legal guardian) understands the trial requirements and 
the treatment procedures and provides written informed consent before 
any trial-specific tests or procedures are performed   
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 6 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 7 of 84 
  
EVOLVE 48 (S2356) 
A Prospective Multicenter Single Arm Trial to Assess the Safety and Effectiveness of the 
SYNERGYTM 48 mm Everolimus-Eluting Platinum Chromium Coronary Stent System 
(SYNERGYTM Stent System) for the Treatment of Subjects with Atherosclerotic Lesion(s) 
CI3. 
Subject is eligible for percutaneous coronary intervention (PCI) 
and is an acceptable candidate for coronary artery bypass grafting 
(CABG) 
CI4. 
Subject has either:  
Symptomatic coronary artery disease with one of the following: stenosis   
≥ 70%, abnormal fractional flow reserve (FFR), abnormal stress or 
imaging stress test, or elevated biomarkers prior to the procedure 
 
OR 
 
Documented silent ischemia based on one of the following: abnormal 
fractional flow reserve (FFR), abnormal stress or imaging stress test, or 
elevated biomarkers prior to the procedure 
CI5. 
Subject is willing to comply with all protocol-required follow-up 
evaluation  
Angiographic 
Inclusion 
Criteria 
AI1. 
Target lesion must be located in a native coronary artery with a 
visually estimated reference vessel diameter (RVD) ≥2.5 mm and 
≤4.0 mm 
AI2. 
Target lesion length must be >34 mm and ≤44 mm (by visual 
estimate) 
AI3. 
 Target lesion must have visually estimated stenosis ≥50% and 
<100% with thrombolysis in Myocardial Infarction (TIMI) flow  >1 
AI4. 
Coronary anatomy is likely to allow delivery of a study device to 
the target lesion  
AI5. 
The target lesion must be successfully predilated/pretreated.   If a 
non-target lesion is treated, it should be treated first and should be 
deemed an angiographic success 
Note:  Angiographic success is a mean lesion diameter stenosis 
< 50% (< 30% for stents) in 2 near-orthogonal projections with TIMI 3 
flow, as visually assessed by the physician, without the occurrence of 
prolonged chest pain or ECG changes consistent with MI. 
Note: Successful predilatation/pretreatment refers to dilatation with a 
balloon catheter of appropriate length and diameter, or pretreatment with 
directional or rotational coronary atherectomy, laser or cutting/scoring 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 7 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 8 of 84 
  
EVOLVE 48 (S2356) 
A Prospective Multicenter Single Arm Trial to Assess the Safety and Effectiveness of the 
SYNERGYTM 48 mm Everolimus-Eluting Platinum Chromium Coronary Stent System 
(SYNERGYTM Stent System) for the Treatment of Subjects with Atherosclerotic Lesion(s) 
balloon with no greater than 50% residual stenosis and no dissection 
greater than National Heart, Lung, Blood Institute (NHLBI) type C. 
Clinical 
Exclusion 
Criteria 
CE1. Subject has clinical symptoms and/or electrocardiogram (ECG) 
changes consistent with acute ST elevation MI (STEMI) 
CE2. Subject has cardiogenic shock, hemodynamic instability requiring 
inotropic or mechanical circulatory support, intractable ventricular 
arrhythmias, or ongoing intractable angina  
CE3. Subject has received an organ transplant or is on a waiting list for 
an organ transplant 
CE4. Subject is receiving or scheduled to receive chemotherapy within 
30 days before or after the index procedure 
CE5. Planned PCI (including staged procedures) or CABG after the 
index procedure 
CE6. Subject previously treated at any time with intravascular 
brachytherapy 
CE7. Subject has a known allergy to contrast (that cannot be adequately 
premedicated) and/or the trial stent system or protocol-required 
concomitant medications (e.g., platinum, platinum-chromium alloy, 
stainless steel, everolimus or structurally related compounds, polymer or 
individual components, all P2Y12 inhibitors, or aspirin)  
CE8. Subject has one of the following (as assessed prior to enrollment): 
o Other serious medical illness (e.g., cancer, congestive heart 
failure) with estimated life expectancy of less than 24 months 
o Current problems with substance abuse (e.g., alcohol, cocaine, 
heroin, etc.)  
o Planned procedure that may cause non-compliance with the 
protocol or confound data interpretation 
CE9. Subject is receiving chronic (≥72 hours) anticoagulation therapy 
(i.e., heparin, coumadin) for indications other than acute coronary 
syndrome 
CE10. Subject has a platelet count <100,000 cells/mm3 or >700,000 
cells/mm3 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 8 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 9 of 84 
  
EVOLVE 48 (S2356) 
A Prospective Multicenter Single Arm Trial to Assess the Safety and Effectiveness of the 
SYNERGYTM 48 mm Everolimus-Eluting Platinum Chromium Coronary Stent System 
(SYNERGYTM Stent System) for the Treatment of Subjects with Atherosclerotic Lesion(s) 
CE11. Subject has a white blood cell (WBC) count < 3,000 cells/mm3 
CE12. Subject has documented or suspected liver disease, including 
laboratory evidence of hepatitis 
CE13. Subject is on dialysis or has baseline serum creatinine level 
>2.0 mg/dL (177µmol/L) 
CE14. Subject has a history of bleeding diathesis or coagulopathy or will 
refuse blood transfusions  
CE15. Subject has had a history of  cerebrovascular accident (CVA) or 
transient ischemic attack (TIA) within the past 6 months 
CE16. Subject has an active peptic ulcer or active gastrointestinal (GI) 
bleeding  
CE17. Subject has signs or symptoms of active heart failure (i.e., NYHA 
class IV) at the time of the index procedure 
CE18. Subject is participating in another investigational drug or device 
clinical trial that has not reached its primary endpoint 
CE19. Subject intends to participate in another investigational drug or 
device clinical trial within 12 months after the index procedure 
CE20. Subject with known intention to procreate within 12 months after 
the index procedure (women of child-bearing potential who are sexually 
active must agree to use a reliable method of contraception from the time 
of screening through 12 months after the index procedure) 
CE21. Subject is a woman who is pregnant or nursing  
Angiographic 
Exclusion 
Criteria 
AE1. Subject has more than 1 target lesion, or more than 1 target lesion 
and 1 non-target lesion, which will be treated during the index procedure 
Note: Multiple focal stenoses will be considered as a single lesion if they 
can be completely covered with 1 study stent 
AE2. Treatment of lesions in more than 2 major epicardial vessels  
Note:  1 target lesion in the target vessel and 1 non-target lesion in non-
target vessel is allowed 
AE3. Subject has unprotected left main coronary artery disease (>50% 
diameter stenosis) 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 9 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 10 of 84 
  
EVOLVE 48 (S2356) 
A Prospective Multicenter Single Arm Trial to Assess the Safety and Effectiveness of the 
SYNERGYTM 48 mm Everolimus-Eluting Platinum Chromium Coronary Stent System 
(SYNERGYTM Stent System) for the Treatment of Subjects with Atherosclerotic Lesion(s) 
AE4. Subject has been treated with any type of PCI (i.e., balloon 
angioplasty, stent, cutting balloon atherectomy) within 24 hours prior to 
the index procedure 
AE5. Thrombus, or possible thrombus, present in the target vessel (by 
visual estimate) 
AE6. Target lesion meets any of the following criteria: 
• Treatment of a single lesion with more than 1 stent 
• Left main location 
• Lesion 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 
• Lesion is located within a saphenous vein graft or an arterial graft 
• Lesion will be accessed via a saphenous vein graft or arterial graft 
• Lesion with a TIMI flow 0 (total occlusion) or TIMI flow 1 prior  
to guide wire crossing 
• Lesion treated during the index procedure that involves a complex 
bifurcation (e.g., bifurcation lesion requiring treatment with more 
than 1 stent) 
• Lesion is restenotic from a previous stent implantation or study 
stent would overlap with a previous stent 
AE7. Non-target lesion meets any of the following criteria: 
• Located within the target vessel 
• Left main location 
• Lesion is located within a saphenous vein graft or an arterial graft 
• Lesion with a TIMI flow 0 (total occlusion) or TIMI flow 1 prior  
to guide wire crossing 
• Lesion treated during the index procedure that involves a complex 
bifurcation (e.g., bifurcation lesion requiring treatment with more 
than 1 stent) 
• Requires additional unplanned stents (treatment of the non-target 
lesion with more than one stent is permitted as long as the stents 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 10 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 11 of 84 
  
EVOLVE 48 (S2356) 
A Prospective Multicenter Single Arm Trial to Assess the Safety and Effectiveness of the 
SYNERGYTM 48 mm Everolimus-Eluting Platinum Chromium Coronary Stent System 
(SYNERGYTM Stent System) for the Treatment of Subjects with Atherosclerotic Lesion(s) 
are initially planned) 
• Treatment not deemed an angiographic success 
Note:  Angiographic success is a mean lesion diameter stenosis < 50% 
(<  30% for stents) in 2 near-orthogonal projections with TIMI 3 flow, as 
visually assessed by the physician, without the occurrence of prolonged 
chest pain or ECG changes consistent with MI. 
Multiple 
Interventions 
During Index 
Procedure 
Up to 2 native coronary artery lesions in 2 major epicardial vessels may 
be treated.   Subjects may have 1 target lesion, or 1 target lesion and 1 
non-target lesion treated.   
• One lesion must meet the angiographic criteria for a target lesion 
as described above, and is appropriate to be treated with a 
SYNERGY 48 mm coronary stent.  
• A maximum of 1 non-target lesion in 1 non-target vessel may be 
treated with a commercial treatment (e.g., stent, balloon 
angioplasty, excluding brachytherapy) during the index procedure. 
If stenting is appropriate for the treatment of a non-target lesion, 
an everolimus-eluting stent should be used.  The non-target vessel 
should be treated during the index procedure prior to the treatment 
of the target lesion and deemed an angiographic success.  
Statistical Methods  
Primary 
Statistical 
Hypothesis 
The 12-month TLF rate for SYNERGY subjects is less than the 
performance goal (PG). 
H0: PSYNERGY ≥ PG 
H1: PSYNERGY < PG 
where PSYNERGY is the 12-month TLF rate for subjects with 48 mm 
SYNERGY stent and PG is a performance goal. 
Statistical Test 
Method 
A one-group Clopper-Pearson exact test will be used to test whether the 
12-month TLF rate for SYNERGY is less than a PG. 
Success Criteria 
for the Primary 
If the P value from the one-sided Clopper-Pearson test is <0.05, the 
48 mm SYNERGY stent is concluded to meet the PG with respect to the 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 11 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 12 of 84 
  
EVOLVE 48 (S2356) 
A Prospective Multicenter Single Arm Trial to Assess the Safety and Effectiveness of the 
SYNERGYTM 48 mm Everolimus-Eluting Platinum Chromium Coronary Stent System 
(SYNERGYTM Stent System) for the Treatment of Subjects with Atherosclerotic Lesion(s) 
Statistical 
Hypothesis Test 
12-month TLF rate. This corresponds to the one-sided 95% upper 
confidence bound on the observed 12-month TLF rate from SYNERGY 
being less than the PG. 
Sample Size 
Parameters 
• 
Expected 12-month TLF rate for SYNERGY = 9.2% 
• 
PG = 19.5% (expected control rate of 13% + delta of 6.5%) 
• 
Test significance level (α) = 0.05 (1-sided) 
• 
Power (1−β) ≥ 0.80 
• 
N = 95 evaluable patients 
• 
Expected attrition rate = 5% 
• 
N=100 enrolled patients 
 
3. Table of Contents 
1. 
TITLE PAGE  ........................................................................................................................ 1 
2. 
PROTOCOL SYNOPSIS .......................................................................................................... 4 
3. 
TABLE OF CONTENTS ........................................................................................................ 12 
 Table of Figures ...................................................................................................... 16 
3.1.
 Table of Tables ....................................................................................................... 16 
3.2.
4. 
INTRODUCTION ................................................................................................................. 18 
 Clinical Development Program for SYNERGY .................................................. 19 
4.1.
 
EVOLVE First Human Use (FHU) Clinical Trial ..................................... 19 
4.1.1.
 
EVOLVE II Clinical Program ................................................................... 20 
4.1.2.
 
Summary .................................................................................................... 21 
4.1.3.
5. 
DEVICE DESCRIPTION ....................................................................................................... 22 
 SYNERGY Device .................................................................................................. 22 
5.1.
 
Drug/Polymer Component Description ..................................................... 22 
5.1.1.
5.1.1.1. 
Everolimus ................................................................................ 22 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 12 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 13 of 84 
  
5.1.1.2. 
Polymer Carrier ......................................................................... 22 
 Device Labeling ...................................................................................................... 22 
5.2.
 
Region – United States .............................................................................. 22 
5.2.1.
 
Region – Europe ........................................................................................ 23 
5.2.2.
6. 
STUDY OBJECTIVES .......................................................................................................... 23 
7. 
STUDY ENDPOINTS ............................................................................................................ 23 
 Primary Endpoint .................................................................................................. 24 
7.1.
 Additional Endpoints ............................................................................................. 24 
7.2.
8. 
STUDY DESIGN .................................................................................................................. 24 
 Scale and Duration ................................................................................................. 24 
8.1.
 Treatment Assignment........................................................................................... 25 
8.2.
 
Target and Non-target Lesions .................................................................. 25 
8.2.1.
 Justification for the Study Design ......................................................................... 26 
8.3.
9. 
SUBJECT SELECTION ......................................................................................................... 27 
 Study Population and Eligibility ........................................................................... 27 
9.1.
 Inclusion Criteria ................................................................................................... 27 
9.2.
 Exclusion Criteria .................................................................................................. 28 
9.3.
10. SUBJECT ACCOUNTABILITY .............................................................................................. 31 
 Point of Enrollment ................................................................................................ 31 
10.1.
 Withdrawal ............................................................................................................. 31 
10.2.
 Enrollment Controls .............................................................................................. 32 
10.3.
11. STUDY METHODS .............................................................................................................. 32 
 Data Collection ....................................................................................................... 32 
11.1.
 Study Candidate Screening ................................................................................... 33 
11.2.
 Informed Consent .................................................................................................. 33 
11.3.
 Baseline/ Procedure / Discharge ........................................................................... 34 
11.4.
 Required Concomitant Medications ..................................................................... 34 
11.5.
 Loading Dose (P2Y12 inhibitor) ............................................................... 34 
11.5.1.
 Loading Dose (Aspirin) ............................................................................. 35 
11.5.2.
 In the Cardiac Catheterization Laboratory ................................................ 35 
11.5.3.
 Postprocedure ............................................................................................ 35 
11.5.4.
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 13 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 14 of 84 
  
11.5.4.1. P2Y12 inhibitor .......................................................................... 35 
11.5.4.2. Aspirin....................................................................................... 36 
11.5.4.3. Optimal medical therapy ........................................................... 36 
 Cardiac Catheterization ........................................................................................ 36 
11.6.
 Index Procedure ......................................................................................... 36 
11.6.1.
11.6.1.1. Stent Placement ......................................................................... 37 
 Post Stent Deployment Procedures ............................................................ 37 
11.6.2.
 End of the Index Procedure .................................................................................. 37 
11.7.
 Postprocedure/Prehospital Discharge .................................................................. 38 
11.8.
 Angiography ........................................................................................................... 38 
11.9.
 
Follow-Up ................................................................................................. 38 
11.10.
 30-Day Follow-up (30±7 Days) ................................................................. 39 
11.10.1.
 6-Month Follow-up (180±30 Days) ........................................................... 39 
11.10.2.
 12-Month Follow-up (365±30 Days) ......................................................... 40 
11.10.3.
 2-Year Follow-up (730±30 Days) ............................................................. 40 
11.10.4.
 Additional Interim Follow-up .................................................................... 40 
11.10.5.
 Missed or Late Visits ................................................................................. 40 
11.10.6.
 
Study Completion .................................................................................... 40 
11.11.
12. STATISTICAL CONSIDERATIONS ....................................................................................... 41 
 Endpoints ................................................................................................................ 41 
12.1.
 Primary Endpoint ....................................................................................... 41 
12.1.1.
12.1.1.1. Hypotheses ................................................................................ 41 
12.1.1.2. Sample Size ............................................................................... 41 
12.1.1.3. Statistical Methods .................................................................... 41 
 General Statistical Methods .................................................................................. 42 
12.2.
 Analysis Sets .............................................................................................. 42 
12.2.1.
 Control of Systematic Error/Bias ............................................................... 42 
12.2.2.
 Number of Subjects per Investigative Site ................................................ 42 
12.2.3.
 Data Analyses ......................................................................................................... 42 
12.3.
 Other Endpoints/Measurements ................................................................. 43 
12.3.1.
 Interim Analyses ........................................................................................ 43 
12.3.2.
 Subgroup Analyses .................................................................................... 43 
12.3.3.
 Justification of Pooling .............................................................................. 43 
12.3.4.
 Multivariable Analyses .............................................................................. 43 
12.3.5.
 Other Analyses ........................................................................................... 44 
12.3.6.
 Changes to Planned Analyses .................................................................... 44 
12.3.7.
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 14 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 15 of 84 
  
13. DATA MANAGEMENT ........................................................................................................ 44 
 Data Collection, Processing, and Review ............................................................. 44 
13.1.
 Data Retention ........................................................................................................ 44 
13.2.
 Core Laboratories .................................................................................................. 45 
13.3.
14. AMENDMENTS ................................................................................................................... 45 
15. DEVIATIONS ...................................................................................................................... 45 
16. DEVICE ACCOUNTABILITY ............................................................................................... 46 
 Region – United States ........................................................................................... 46 
16.1.
 Region – Europe ..................................................................................................... 46 
16.2.
17. COMPLIANCE ..................................................................................................................... 47 
 Statement of Compliance ....................................................................................... 47 
17.1.
 Investigator Responsibilities ................................................................................. 47 
17.2.
 Delegation of Responsibility ..................................................................... 49 
17.2.1.
 Institutional Review Board/ Ethics Committee ................................................... 49 
17.3.
 Sponsor Responsibilities ........................................................................................ 49 
17.4.
 Insurance ................................................................................................................. 49 
17.5.
18. MONITORING ..................................................................................................................... 50 
19. POTENTIAL RISKS AND BENEFITS .................................................................................... 50 
 Risks Associated with the Implantation of Coronary Stents ............................. 50 
19.1.
 Risks Associated with Everolimus ........................................................................ 51 
19.2.
 Anticipated Adverse Device Effects ...................................................................... 53 
19.3.
 Risks Associated with the Study Device(s) ........................................................... 53 
19.4.
 Sex-Specific Risks Associated with the Study Device(s) ..................................... 54 
19.5.
 Risks Associated with Participation in the Clinical Study ................................. 54 
19.6.
 Possible Interactions with Concomitant Medical Treatments ........................... 54 
19.7.
 Risk Minimization Actions .................................................................................... 55 
19.8.
 Anticipated Benefits ............................................................................................... 55 
19.9.
 
Risk to Benefit Rationale ......................................................................... 55 
19.10.
20. SAFETY REPORTING .......................................................................................................... 56 
 Reportable Events by investigational site to Boston Scientific .......................... 56 
20.1.
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 15 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 16 of 84 
  
 Definitions and Classification ............................................................................... 56 
20.2.
 Relationship to Study Device(s) ............................................................................ 58 
20.3.
 Investigator Reporting Requirements .................................................................. 59 
20.4.
 Boston Scientific Device Deficiencies .................................................................... 61 
20.5.
 Reporting to Regulatory Authorities / IRBs / ECs / Investigators .................... 61 
20.6.
21. INFORMED CONSENT......................................................................................................... 62 
22. COMMITTEES .................................................................................................................... 63 
 Safety Monitoring Process ..................................................................................... 63 
22.1.
 Clinical Events Committee .................................................................................... 64 
22.2.
23. SUSPENSION OR TERMINATION ........................................................................................ 64 
 23.1 Premature Termination of the Study ........................................................... 64 
23.1.
 Criteria for Premature Termination of the Study ....................................... 64 
23.1.1.
 23.2 Termination of Study Participation by the Investigator or Withdrawal of 
23.2.
IRB/ EC Approval .................................................................................................. 64 
 23.3 Requirements for Documentation and Subject Follow-up ......................... 64 
23.3.
 23.4 Criteria for Suspending/Terminating a Study Site ..................................... 65 
23.4.
24. PUBLICATION POLICY ....................................................................................................... 65 
25. BIBLIOGRAPHY .................................................................................................................. 66 
26. ABBREVIATIONS AND DEFINITIONS .................................................................................. 68 
 Abbreviations ......................................................................................................... 68 
26.1.
 Definitions ............................................................................................................... 70 
26.2.
 
 
 
Table of Figures 
3.1.
Figure 8.1-1: EVOLVE 48 Study Design ............................................................................... 24 
 
 
Table of Tables 
3.2.
Table 4.1-1:  Summary of the EVOLVE II Global Clinical Program .................................... 21 
Table 9.2-1: Inclusion Criteria ................................................................................................ 27 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 16 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 17 of 84 
  
Table 9.3-1: Exclusion Criteria ............................................................................................... 28 
Table 11.1-1: Data Collection Schedule ................................................................................. 32 
Table 20.2-1: Safety Definitions ............................................................................................. 57 
Table 20.3-1: Criteria for Assessing Relationship of Study Device or Procedure to Adverse 
Event .................................................................................................................... 58 
Table 20.4-1: Investigator Reporting Requirements ............................................................... 60 
Table 26.1-1: Abbreviations ................................................................................................... 68 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 17 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 18 of 84 
  
4. Introduction 
The EVOLVE 48 trial is designed to assess the FDA requirement for safety and effectiveness 
of the SYNERGY 48 mm Coronary Stent System for the treatment of subjects with 
atherosclerotic lesion(s) > 34 mm and ≤ 44 mm in length (by visual estimate) in native 
coronary arteries ≥2.5 mm to ≤4.0 mm in diameter (by visual estimate).  Sites outside the 
United States are being included in this protocol to collect additional 48 mm data to support 
future FDA approval. This is also an opportunity to collect EU post-market safety and 
performance data for the current CE Marked 48 mm device. 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.  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 antiplatelet therapy. First, the 
polymer coating 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 (1).  
The SYNERGY stent system is approved and commercially available in the following sizes 
(stent diameter and length) as shown in the following device matrix.  In addition, the 48 mm 
length stent is CE marked.   
 
 
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 
 
The availability of a 48 mm SYNERGY stent would reduce the need for overlapping stents.   
When long lesions were treated with 1 long stent instead of 2 shorter, overlapping stents, 
intervention time was less, the need for a contrast agent had a tendency to be lower, and 
procedural costs were significantly less (2).  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 18 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 19 of 84 
  
 
Clinical Development Program for SYNERGY 
4.1.
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 (3-18). The EVOLVE series of trials including EVOLVE, EVOLVE II, and 
EVOLVE II QCA, have established the safety and effectiveness of the SYNERGY Stent 
System for the treatment of coronary artery lesions. 
 EVOLVE First Human Use (FHU) Clinical Trial 
4.1.1.
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 stent (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) (19).  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 (20,21). The study is 
now considered complete with regard to the primary endpoint and follow-up through 5 years 
is complete.   
The final 5-year results of EVOLVE demonstrate no significant differences between groups 
with respect to TLF, cardiac death or MI. 
• Trend toward lower rates of TLR with SYNERGY vs PROMUS Element  
• No definite/probable stent thrombosis in any group at 5 years 
These results support the safety and efficacy of the novel abluminal bioabsorbable polymer 
SYNERGY everolimus-eluting stent for the treatment of patients with de novo coronary 
artery disease(22). 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 19 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 20 of 84 
  
 EVOLVE II Clinical Program 
4.1.2.
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 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 (24). 
• 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 (25,26).  
• 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, 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 20 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 21 of 84 
  
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 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) (27).   
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  
 
 Summary 
4.1.3.
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 48 trial is designed to assess the safety and effectiveness of the SYNERGY 48 mm 
Coronary Stent System for the treatment of subjects with atherosclerotic lesion(s) > 34 mm 
and ≤ 44 mm in length (by visual estimate) in native coronary arteries ≥2.5 mm to ≤4.0 mm 
in diameter (by visual estimate). 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 21 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 22 of 84 
  
5. Device Description 
 
SYNERGY Device  
5.1.
The SYNERGY Everolimus-Eluting Platinum Chromium Coronary Stent System 
(SYNERGY Stent System), manufactured by BSC, 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).   
The SYNERGY Stent System is approved for use and commercially available in sizes 2.25 
mm - 4.0 mm in diameter and 8 mm - 38 mm in length.  Additionally, it is CE marked in the 
48 mm length.    
Device Component Description 
The SYNERGY Stent System consists of a platinum chromium stent platform with an 
abluminal drug/polymer coating mounted onto a Monorail Delivery System.  The 
SYNERGY 48 device matrix consists of the following sizes (stent diameter and stent length): 
• 2.50 mm x 48 mm 
• 2.75 mm x 48 mm* 
• 3.00 mm x 48 mm 
• 3.50 mm x 48 mm 
• 4.00 mm x 48 mm 
*2.75 x 48 mm will not be included in the investigational device matrix in the US 
 Drug/Polymer Component Description 
5.1.1.
5.1.1.1. Everolimus 
The active pharmaceutical ingredient in the SYNERGY Stent is everolimus.  The everolimus 
chemical name is 40-0-(2-hydroxyethyl)-rapamycin.  Everolimus has been evaluated in 
clinical trials in the 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. 
5.1.1.2. 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.  
 
Device Labeling 
5.2.
 Region – US 
5.2.1.
A copy of the DFU for the SYNERGY stent is included in the EVOLVE 48 study Manual of 
Operations. The study devices are labeled on the front, back, and side of the outer cartons, 
and on the outside foil and inside sterile pouch. Packaging will include peelable, self-
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 22 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 23 of 84 
  
adhesive labels for each unit of product shipped. The labeling will include the following 
information. 
• Product Name 
• Catalog Number and Universal Part Number (UPN)  
• Global Trade Item Number (GTIN) 
• Serial or tracking identification number 
• Lot number 
• Stent dimensions (stent diameter and stent length in mm) 
• Expiration (use by) date 
The following statements appear on the SYNERGY study device product labeling for clinical 
US distribution. 
Caution: Investigational Device.  Limited by United States law to investigational use.  
Exclusively for Clinical Investigations.   
 Region – Outside US   
5.2.2.
In regions where the SYNERGY 48 mm is commercially available it will be labeled per 
approved regulations.  A copy of the DFU for the study stent, SYNERGY 48 mm, is 
contained in each product package.  The devices are labeled on the front, back, and side of 
the outer cartons, and on the outside foil and inside sterile pouch. Packaging will include 
peelable, self-adhesive labels for each unit of product shipped. The labeling will include the 
following information. 
• Product Name  
• Catalog Number and Universal Part Number (UPN)  
• Global Trade Item Number (GTIN) 
• Lot number 
• Stent dimensions (stent diameter and stent length in mm) 
• Expiration (use by) date 
6. Study Objectives 
To assess the FDA requirement for safety and effectiveness of the SYNERGY 48 mm 
Coronary Stent System for the treatment of subjects with atherosclerotic lesion(s) > 34 mm 
and ≤ 44 mm in length (by visual estimate) in native coronary arteries ≥2.5 mm to ≤4.0 mm 
in diameter (by visual estimate). 
Sites outside the United States are being included in this protocol to collect additional 48 mm 
data to support future FDA approval. This is also an opportunity to collect EU post-market 
safety and performance data for the current CE Marked 48 mm device. 
7. Study Endpoints 
The primary and additional endpoints will be evaluated for all subjects who are enrolled in 
the trial, whether or not a study stent is implanted. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 23 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 24 of 84 
  
 
Primary Endpoint 
7.1.
The primary endpoint is the 12-month Target Lesion Failure (TLF) rate, defined as any 
ischemia-driven revascularization of the target lesion (TLR), myocardial infarction (MI, Q-
wave and non–Q-wave) related to the target vessel, or cardiac death.  
 
Additional Endpoints 
7.2.
Clinical endpoints measured in-hospital and at 30 days, 6 months, 12 months and 2 years. 
• TLR rate, TLF rate (primary endpoint at 12 months), Target vessel revascularization 
(TVR) rate 
• Target vessel failure (TVF) rate 
• MI (Q-wave and non–Q-wave) rate 
• Cardiac death rate, Non-cardiac death rate 
• All death rate 
• Cardiac death or MI rate 
• All death or MI rate 
• All death/MI/TVR rate 
• Stent thrombosis rates (by Academic Research Consortium [ARC] definitions) 
Periprocedural endpoints: 
• Technical success rate 
• Clinical procedural success rate 
8. Study Design 
The EVOLVE 48 Study is a prospective, multicenter, open label, single-arm study to assess 
the safety and effectiveness of the SYNERGY 48 mm stent for the treatment of 
atherosclerotic lesion(s). 
 
Scale and Duration 
8.1.
The EVOLVE 48 Study will be conducted at up to 20 sites in the United States, Europe and 
New Zealandwith planned enrollment of 100 subjects.  All subjects will be screened 
according to the protocol inclusion and exclusion criteria. 
Clinical follow-up will be required at the following time points: in hospital, 30 days, 6 
months, 12 months and 2 years post index procedure.  
A schematic of the EVOLVE 48 trial design is shown in Figure 8.1-1   
Figure 8.1-1: EVOLVE 48 Study Design 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 24 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 25 of 84 
  
 
 
 
 
Treatment Assignment 
8.2.
Once the subject has met all clinical inclusion and no clinical exclusion criteria, the subject 
should be considered eligible to be enrolled in the trial.  If the subject is found to meet 
exclusion criteria during the angiographic eligibility assessment, the subject will be 
considered a screen failure. If the subject is found to meet the inclusion criteria during the 
angiographic phase of the procedure, the subject will be considered eligible to be enrolled.  
Subjects in this trial will not be randomized.  Subjects will be considered enrolled after the 
subject has signed the IRB/IEC approved study informed consent form (ICF) and successful 
predilation /pretreatment of the target lesion and insertion of a 48 mm SYNERGY stent into 
the introducer sheath. If a non-target lesion is treated, it should be treated first and should be 
deemed to be an angiographic success. 
Subjects will be treated with The SYNERGY Everolimus-Eluting Platinum Chromium 
Coronary Stent System (SYNERGY Stent System), 48 mm in length; refer to Section 5.0 
(Device Description) for study device product matrix.  
 Target and Non-target Lesions 
8.2.1.
A target lesion is the lesion selected by the Investigator for treatment with the study stent. 
The target lesion includes the arterial segment treated with the study stent plus the arterial 
segment 5 mm proximal and 5 mm distal to the treatment site. The target lesion must meet all 
the angiographic selection criteria.  
Up to 2 native coronary artery lesions in 2 major epicardial vessels may be treated. One 
lesion must meet the angiographic criteria described above, and is appropriate to be treated 
with a SYNERGY 48 mm coronary stent. A maximum of 1 non-target lesion in 1 non-target 
vessel may be treated with a commercial treatment (e.g., stent, balloon angioplasty, 
excluding brachytherapy) during the index procedure. If stenting is appropriate for the 
treatment of a non-target lesion, an everolimus-eluting stent should be used.  The non-target 
lesion should be treated first and should be deemed an angiographic success prior to the 
treatment of the target lesion. 
Note:  Angiographic success is a mean lesion diameter stenosis < 50% (< 30% for stents) in 
2 near-orthogonal projections with TIMI 3 flow, as visually assessed by the physician, 
without the occurrence of prolonged chest pain or ECG changes consistent with MI. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 25 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 26 of 84 
  
Note: Multiple focal stenoses will be considered as a single lesion if they can be completely 
covered with 1 study stent. 
Predilitation/pretreatment of the target lesion is required in this trial. If the target lesion is not 
successfully predilated/pretreated, the subject should not be enrolled. If a non-target lesion is 
to be treated, it should be treated first and must be deemed an angiographic success.  
Following the successful treatment of the non-target lesion, predilation of the target lesion 
may then be performed.   
Note: Successful predilatation/pretreatment refers to dilatation with a balloon catheter of 
appropriate length and diameter, or pretreatment with directional or rotational coronary 
atherectomy, laser or cutting/scoring balloon with no greater than 50% residual stenosis and 
no dissection greater than National Heart, Lung, Blood Institute (NHLBI) type C 
 
Justification for the Study Design 
8.3.
The EVOLVE 48 trial will evaluate the FDA requirement for safety and effectiveness of the 
SYNERGY stent for the treatment of subjects with atherosclerotic lesion(s) > 34 mm and ≤ 
44 mm in length (by visual estimate) in native coronary arteries ≥2.5 mm to ≤4.0 mm in 
diameter (by visual estimate).  Safety and performance has been demonstrated for this stent 
in the following sizes which have received CE mark and FDA approval and is commercially 
available in other regions.  
 
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 
 
Sites outside the United States are being included in this protocol to collect additional data to 
support future FDA approval of the 48 mm diameter. This is also an opportunity to collect 
EU post-market safety and performance data for the current CE Marked 48 mm device. 
During the trial, P2Y12 inhibitors will be administered based on current guidelines and 
aspirin use will be required for the duration of the trial post index procedure. Ongoing 
dynamic data safety monitoring will be performed throughout the trial to minimize subject 
risk. All enrolled subjects receiving the study stent will be followed for 2 years post index 
procedure.   
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 26 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 27 of 84 
  
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 48 Study.  
9. Subject Selection  
 
Study Population and Eligibility  
9.1.
Clinical and angiographic inclusion and exclusion criteria for the EVOLVE 48 trial are 
included in Table 9.2-1 and Table 9.3-1 respectively. Prior to enrollment in the trial, a 
subject should meet all of the clinical and angiographic inclusion criteria and none of the 
clinical or angiographic exclusion criteria 
 
Inclusion Criteria 
9.2.
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 criterion (see Table 9.3-1) 
is met.  
Table 9.2-1: Inclusion Criteria 
Clinical 
Inclusion 
Criteria 
CI1. 
Subject must be at least 18 years of age 
CI2. 
Subject (or legal guardian) understands the trial requirements and the 
treatment procedures and provides written informed consent before any 
trial-specific tests or procedures are performed   
CI3. 
Subject is eligible for percutaneous coronary intervention (PCI) and 
is an acceptable candidate for coronary artery bypass grafting (CABG) 
CI4. 
Subject has either:  
Symptomatic coronary artery disease with one of the following: stenosis   
≥ 70%, abnormal fractional flow reserve (FFR), abnormal stress or imaging 
stress test, or elevated biomarkers prior to the procedure 
 
OR 
 
Documented silent ischemia based on one of the following: abnormal 
fractional flow reserve (FFR), abnormal stress or imaging stress test, or 
elevated biomarkers prior to the procedure 
CI5. 
Subject is willing to comply with all protocol-required follow-up 
evaluation 
Angiographic 
Inclusion 
Criteria 
(visual 
AI1. 
Target lesion must be located in a native coronary artery with a 
visually estimated reference vessel diameter (RVD) ≥2.5 mm and ≤4.0 mm 
AI2. 
Target lesion length must be >34 mm and ≤44 mm (by visual 
estimate) 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 27 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 28 of 84 
  
estimate) 
AI3. 
 Target lesion must have visually estimated stenosis ≥50% and 
<100% with thrombolysis in Myocardial Infarction (TIMI) flow  >1 
AI4. 
Coronary anatomy is likely to allow delivery of a study device to the 
target lesion  
AI5. 
The target lesion must be successfully predilated/pretreated.   If a 
non-target lesion is treated, it should be treated first and should be deemed 
an angiographic success 
Note:  Angiographic success is a mean lesion diameter stenosis 
< 50% (< 30% for stents) in 2 near-orthogonal projections with TIMI 3 
flow, as visually assessed by the physician, without the occurrence of 
prolonged chest pain or ECG changes consistent with MI. 
Note: Successful predilatation/pretreatment refers to dilatation with a 
balloon catheter of appropriate length and diameter, or pretreatment with 
directional or rotational coronary atherectomy, laser or cutting/scoring 
balloon with no greater than 50% residual stenosis and no dissection greater 
than National Heart, Lung, Blood Institute (NHLBI) type C. 
 
Exclusion Criteria 
9.3.
Subjects who meet any one of the following criteria (Table 9.3-1) will be excluded from this 
clinical study. 
 
Table 9.3-1: Exclusion Criteria 
Clinical 
Exclusion 
Criteria 
CE1. Subject has clinical symptoms and/or electrocardiogram (ECG) 
changes consistent with acute ST elevation MI (STEMI) 
CE2. Subject has cardiogenic shock, hemodynamic instability requiring 
inotropic or mechanical circulatory support, intractable ventricular 
arrhythmias, or ongoing intractable angina  
CE3. Subject has received an organ transplant or is on a waiting list for an 
organ transplant 
CE4. Subject is receiving or scheduled to receive chemotherapy within 30 
days before or after the index procedure 
CE5. Planned PCI (including staged procedures) or CABG after the index 
procedure 
CE6. Subject previously treated at any time with intravascular 
brachytherapy 
CE7. Subject has a known allergy to contrast (that cannot be adequately 
premedicated) and/or the trial stent system or protocol-required concomitant 
medications (e.g., platinum, platinum-chromium alloy, stainless steel, 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 28 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 29 of 84 
  
everolimus or structurally related compounds, polymer or individual 
components, all P2Y12 inhibitors, or aspirin)  
CE8. Subject has one of the following (as assessed prior to enrollment): 
o Other serious medical illness (e.g., cancer, congestive heart failure) 
with estimated life expectancy of less than 24 months 
o Current problems with substance abuse (e.g., alcohol, cocaine, 
heroin, etc.)  
o Planned procedure that may cause non-compliance with the protocol 
or confound data interpretation 
CE9. Subject is receiving chronic (≥72 hours) anticoagulation therapy 
(i.e., heparin, coumadin) for indications other than acute coronary syndrome 
CE10. Subject has a platelet count <100,000 cells/mm3 or >700,000 
cells/mm3 
CE11. Subject has a white blood cell (WBC) count < 3,000 cells/mm3 
CE12. Subject has documented or suspected liver disease, including 
laboratory evidence of hepatitis 
CE13. Subject is on dialysis or has baseline serum creatinine level 
>2.0 mg/dL (177µmol/L) 
CE14. Subject has a history of bleeding diathesis or coagulopathy or will 
refuse blood transfusions  
CE15. Subject has had a history of  cerebrovascular accident (CVA) or 
transient ischemic attack (TIA) within the past 6 months 
CE16. Subject has an active peptic ulcer or active gastrointestinal (GI) 
bleeding  
CE17. Subject has signs or symptoms of active heart failure (i.e., NYHA 
class IV) at the time of the index procedure 
CE18. Subject is participating in another investigational drug or device 
clinical trial that has not reached its primary endpoint 
CE19. Subject intends to participate in another investigational drug or 
device clinical trial within 12 months after the index procedure 
CE20. Subject with known intention to procreate within 12 months after the 
index procedure (women of child-bearing potential who are sexually active 
must agree to use a reliable method of contraception from the time of 
screening through 12 months after the index procedure) 
CE21. Subject is a woman who is pregnant or nursing 
Angiographic 
Exclusion 
AE1. Subject has more than 1 target lesion, or more than 1 target lesion 
and 1 non-target lesion, which will be treated during the index procedure 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 29 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 30 of 84 
  
Criteria 
(visual 
estimate) 
Note: Multiple focal stenoses will be considered as a single lesion if they 
can be completely covered with 1 study stent 
AE2. Treatment of lesions in more than 2 major epicardial vessels  
Note:  1 target lesion in the target vessel and 1 non-target lesion in non-
target vessel is allowed 
AE3. Subject has unprotected left main coronary artery disease (>50% 
diameter stenosis) 
AE4. Subject has been treated with any type of PCI (i.e., balloon 
angioplasty, stent, cutting balloon atherectomy) within 24 hours prior to the 
index procedure 
AE5. Thrombus, or possible thrombus, present in the target vessel (by 
visual estimate) 
AE6. Target lesion meets any of the following criteria: 
• Treatment of a single lesion with more than 1 stent 
• Left main location 
• Lesion 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 
• Lesion is located within a saphenous vein graft or an arterial graft 
• Lesion will be accessed via a saphenous vein graft or arterial graft 
• Lesion with a TIMI flow 0 (total occlusion) or TIMI flow 1 prior  to 
guide wire crossing 
• Lesion treated during the index procedure that involves a complex 
bifurcation (e.g., bifurcation lesion requiring treatment with more 
than 1 stent) 
• Lesion is restenotic from a previous stent implantation or study stent 
would overlap with a previous stent 
AE7. Non-target lesion meets any of the following criteria: 
• Located within the target vessel 
• Left main location 
• Lesion is located within a saphenous vein graft or an arterial graft 
• Lesion with a TIMI flow 0 (total occlusion) or TIMI flow 1 prior  to 
guide wire crossing 
• Lesion treated during the index procedure that involves a complex 
bifurcation (e.g., bifurcation lesion requiring treatment with more 
than 1 stent) 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 30 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 31 of 84 
  
• Requires additional unplanned stents (treatment of the non-target 
lesion with more than one stent is permitted as long as the stents are 
initially planned) 
• Treatment not deemed an angiographic success 
Note:  Angiographic success is a mean lesion diameter stenosis < 50% 
(<  30% for stents) in 2 near-orthogonal projections with TIMI 3 flow, as 
visually assessed by the physician, without the occurrence of prolonged 
chest pain or ECG changes consistent with MI. 
10. Subject Accountability 
   Point of Enrollment 
10.1.
Once the subject has met all clinical inclusion and no clinical exclusion criteria, the subject 
should be considered eligible to be enrolled in the trial. If the subject is found to meet 
exclusion criteria during the angiographic eligibility assessment, the subject will be 
considered a screen failure.  If the subject is found to meet the inclusion criteria during the 
angiographic phase of the procedure the subject will be considered eligible to be enrolled.  
Subjects will be considered enrolled after the subject has signed the IRB/IEC approved study 
informed consent form (ICF) and successful predilation /pretreatment of the target lesion and 
insertion of the stent in the introducer sheath.  If a non-target lesion is treated, it should be 
treated first and should be deemed an angiographic success. 
   Withdrawal 
10.2.
All subjects enrolled in the clinical study (including those withdrawn from the clinical study 
or lost to follow-up) shall be accounted for and documented. If a subject withdraws from the 
clinical investigation, the reason(s) shall be reported. If such withdrawal is due to problems 
related to investigational device safety or performance, the investigator shall ask for the 
subject’s permission to follow his/her status/condition outside of the clinical study.   
 
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. The Investigator may discontinue a subject 
from participation in the trial if the Investigator feels that the subject can no longer fully 
comply with the requirements of the trial or if any of the trial procedures are deemed 
potentially harmful to the subject. Data that have already been collected on withdrawn 
subjects will be retained and used for analysis but no new data will be collected after 
withdrawal. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 31 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 32 of 84 
  
   Enrollment Controls 
10.3.
The EVOLVE 48 trial will implement a formal Enrollment Communication Plan. The plan 
will outline the specific activities and responsibilities of BSC employees and representatives, 
and nature and timing of communications to Investigators as enrollment draws to a close. 
The objective of the plan is to minimize the risk of enrollment beyond the protocol-specified 
enrollment cap of 100 subjects.  
11. Study Methods 
   Data Collection 
11.1.
The data collection schedule for the SYNERGY 48 mm trial is summarized in Table 11.1-1. 
Table 11.1-1: Data Collection Schedule 
 
Baseline/ 
Procedure/ 
Discharge 
Follow-up Visits 
30 Days  
(±7 Days)b 
 
6 Months  
(±30 Days)b 
 
12 Months  
(±30 Days)b 
 
2 Years  
(±30 Days)b 
 
Informed consent form, 
including informed consent 
signature datea 
X 
 
 
 
 
Demographics, including 
age, gender, and race and 
ethnicity (unless restricted by 
local laws)   
X 
 
 
 
 
Medical history, including 
diabetes mellitus statusc 
 
X 
 
 
 
 
Angina assessment 
X 
X 
X 
X 
X 
Cardiac enzymesd,e,f 
X 
 
 
 
 
Antithrombotic medications 
X 
 
 
 
 
Antiplatelet medications 
X 
X 
X 
X 
X 
Most recent previous PCI 
procedure information 
X 
 
 
 
 
Procedural, target lesion, 
non-target lesion (if 
applicable) predilatation, 
postdilatation (if applicable), 
and study stent information 
X 
 
 
 
 
Angiography 
X 
 
 
 
 
ADE, SAE, SADE, UADE, 
USADE, all CEC events 
inclusive of death, MI, TVR 
and stent thrombosis and 
device deficiency 
assessmentg 
X 
X 
X 
X 
X 
a: If the study Informed Consent Form is modified during the course of the trial, study subjects will be re-
consented, if necessary 
b: All follow-up dates will be calculated from the date of the index procedure. The protocol-required 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 32 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 33 of 84 
  
Table 11.1-1: Data Collection Schedule 
 
Baseline/ 
Procedure/ 
Discharge 
Follow-up Visits 
30 Days  
(±7 Days)b 
 
6 Months  
(±30 Days)b 
 
12 Months  
(±30 Days)b 
 
2 Years  
(±30 Days)b 
 
follow-ups may be performed via telephone interview or an office visit within the applicable follow-up 
window. Beyond the 12-month follow-up, follow-up will be limited to the Safety Population (e.g., those 
study subjects who received a study stent). Subjects who are enrolled but who do not receive a study stent 
will be followed for 12 months only.  
c:  Height and weight should be documented in the eCRF if available in the subject medical record  
d: Preprocedure cardiac enzymes can be drawn from the sheath at the time of sheath insertion.  If cardiac 
enzymes are drawn preprocedure, the two results drawn closest to the procedure time should be recorded 
in the eCRF.   
e: In subjects with Non-STEMI, 2 cardiac enzyme draws (as per standard of care)  should be obtained prior 
to the index procedure if possible 
f: Two cardiac enzyme draws must be obtained at intervals per standard of care within 24 hours after the 
index procedure. The first draw should be performed 6-12 hours postprocedure and the second draw 
should be performed 18-24 hours postprocedure.  If the subject is discharged prior to 18 hours 
postprocedure, the second draw should be obtained at the time of discharge (it is recommended that in 
these cases the second draw occur no earlier than 16 hours postprocedure). 
g: ADEs, SAEs, SADEs, UADEs, USADEs, CEC events, and device deficiencies will be monitored and 
reported to BSC from the time of enrollment through the 12-month follow-up for all subjects enrolled 
(regardless of whether a study stent was received) and beyond the 12-month follow-up through the 2-year 
follow-up for the Safety Population (e.g., those study subjects who received a study stent). 
Abbreviations: ADE=adverse device effect; BSC=Boston Scientific Corporation; PCI=percutaneous 
coronary 
intervention; 
SADE=serious 
adverse 
device 
effect; 
SAE=serious 
adverse 
events; 
UADE=unanticipated adverse device effect; USADE=unanticipated serious adverse device effect 
   Study Candidate Screening 
11.2.
A Screening Log will be maintained to document selected information about subjects who 
fail to meet the EVOLVE 48 trial eligibility criteria, including the reason for screen failure. 
   Informed Consent 
11.3.
Before any study specific tests or procedures are performed, subjects who meet eligibility 
criteria will be asked to sign the IRB/IEC-approved study ICF.  Subjects must be given 
ample time to review the ICF and have questions answered before signing. 
In the US, subjects must sign the ICF prior to the procedure. Study personnel should explain 
to the subject that even if the subject agrees to participate in the trial and signs the ICF, 
cardiac catheterization may demonstrate that the subject is not a suitable candidate for the 
trial.  
In Europe and New Zealand, the subject must sign the ICF within 12 hours post procedure.    
 
Refer to section 10.1 for definition of point of enrollment. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 33 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 34 of 84 
  
   Baseline/ Procedure / Discharge 
11.4.
The following data must be collected:  
• Confirmation of clinical eligibility criteria 
• Demographics including  age, gender, and race and ethnicity (unless restricted by local 
laws) 
• Medical history (general medical, cardiac, neurological, renal and peripheral history), 
including but not limited to, the following 
o Diabetes mellitus status 
o Current angina status  
o Height and Weight  
• Current antiplatelet medications 
• For the most recent previous PCI procedure, vessel treated, site treated, and type of 
procedure performed 
• Pre-procedure cardiac enzymes should be recorded if drawn based on the standard of 
care.  The one or two (if two enzyme draws are performed) results drawn  closest to the 
start of the procedure should be recorded in the eCRF  
 
Note: Preprocedure cardiac enzymes can be drawn from the sheath at the time of sheath 
insertion. 
Note: It is recommended that the data listed above are obtained within 14 days prior to the 
procedure.  
Note: In subjects with Non-STEMI, 2 cardiac enzyme draws (as per standard of care) should 
be obtained prior to the index procedure if possible. 
Note: While Troponin is the preferred cardiac enzyme, it is recommended that the same type 
of cardiac enzymes be analyzed prior to the index procedure and postprocedure for a given 
index hospitalization (i.e., not switching from CK-MB to troponin or vice versa). 
   Required Concomitant Medications 
11.5.
Protocol-required concomitant medications must be reported in the electronic case report 
form (eCRF) from the time of baseline through the 2-year follow-up. Information pertaining 
to the use of antiplatelet medications including dose changes, medication interruptions, and 
medication cessation, must be documented. Additional concomitant medications may be 
prescribed at the discretion of the treating physician according to standard of care. 
  Loading Dose (P2Y12 inhibitor) 
11.5.1.
• 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 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 34 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 35 of 84 
  
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. 
  Loading Dose (Aspirin) 
11.5.2.
• 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. 
  In the Cardiac Catheterization Laboratory 
11.5.3.
The subject must be treated with heparin or an alternative antithrombotic (such as bivalirudin 
or enoxaparin) during the interventional portion of the procedure. If heparin is used, 
maintenance of an activated clotting time (ACT) >250 seconds throughout the interventional 
portion of the procedure is recommended. If enoxaparin or bivalirudin is used for procedural 
anticoagulation, monitoring of the anticoagulation level should be performed according to 
local laboratory practice. 
Note: Abciximab, eptifibatide, and tirofiban may be used at the discretion of the Investigator. 
To eliminate coronary artery spasm that would interfere with accurate measurement of lumen 
obstruction due to plaque alone, intracoronary nitroglycerin (NTG) or isosorbide dinitrate 
(ISDN) should be administered prior to the baseline angiogram. A dose of 100-200 µg of 
NTG is preferred; however, a 50 µg dose of NTG may be administered at the Investigator’s 
discretion when deemed clinically necessary. Alternatively, if ISDN is administered, a dose 
of 2-3 mg is recommended. 
  Postprocedure 
11.5.4.
The treatment described in this section is applicable to subjects who receive a study stent in a 
target vessel. Subjects who are enrolled but who do not receive a study stent should be 
treated per standard of care and followed per protocol. 
Based on the ACC/AHA/SCAI and ESC guidelines, dual antiplatelet therapy with aspirin and 
a P2Y12 inhibitor must be prescribed as follows to reduce the risk of thrombosis. 
11.5.4.1.  P2Y12 inhibitor 
Subjects must be treated with one of the following P2Y12 inhibitors (clopidogrel, prasugrel, 
or ticagrelor).  The dose and duration should be based on current guidelines.   
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 35 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 36 of 84 
  
• In subjects with stable ischemic heart disease (SIHD) P2Y12 inhibitor therapy should 
be given for at least 6 months post stent implantation. For subjects at high risk of 
bleeding, discontinuation of P2Y12 inhibitor therapy after 3 months may be 
reasonable. 
• In subjects with acute coronary syndrome (ACS) P2Y12 inhibitor therapy should be 
given for at least 12 months. For subjects at high risk of bleeding, discontinuation of 
P2Y12 inhibitory therapy after 6 months may be reasonable. 
11.5.4.2.  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.  
 
11.5.4.3.  Optimal medical therapy 
In addition to dual antiplatelet therapy, it is recommended that subjects be treated with 
optimal medical therapy (including statins and beta blockers) in order to improve outcomes. 
   Cardiac Catheterization 
11.6.
  Index Procedure 
11.6.1.
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.  
During cardiac catheterization, the following procedures and assessments must be completed.  
• Angiography should be performed according to the Angiographic Core Laboratory 
procedure guidelines. 
• Confirm angiographic eligibility criteria of lesion(s). 
• Pre-dilate/pretreat the target lesion and non-target lesion (if applicable) 
Note: Balloon catheter predilatation/pretreatment is required for the target lesion and non-
target lesion (if applicable). The target lesion must be successfully predilated/pretreated in 
order for the subject to be eligible for enrollment. Unsuccessful predilatation/pretreatment of 
the target lesion excludes the subject from enrollment in this trial. The subject should be 
treated per local standard of care, but must not be enrolled or receive a study stent 
If a non-target lesion is to be treated, it should be treated prior to the target lesion and should 
be deemed an angiographic success.  Following the successful treatment of the non-target 
lesion, predilation of the target lesion may then be performed. 
Note: Successful predilatation/pretreatment refers to dilatation with a balloon catheter of 
appropriate length and diameter, or pretreatment with directional or rotational coronary 
atherectomy, laser or cutting/scoring balloon with no greater than 50% residual stenosis and 
no dissection greater than NHLBI type C.  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 36 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 37 of 84 
  
Note: Per AE6 (Table 9.3-1), the planned treatment should not result in overlap of the study 
stent with a previously placed stent. 
• If stenting is required in a bailout situation within the target vessel, it is recommended the 
stent be a SYNERGY stent or another everolimus eluting stent.   
o Bailout typically refers to a peri-stent dissection but can also include a vessel 
complication at the ostium or along the course of the major coronary artery used to 
access the target lesion. 
o The decision of whether to treat in a bailout situation is at the discretion of the 
Interventionalist. 
o In cases of bailout, the stent used should be documented in the eCRF.    
11.6.1.1. Stent Placement 
Refer to the DFU for detailed instructions about preparation and placement of the 
SYNERGY stent. 
  Post Stent Deployment Procedures 
11.6.2.
After stent placement, the Investigator should ensure that the stent is in full contact with the 
arterial wall. In order to achieve full contact, postdilatation may be performed at the 
discretion of the Investigator using the stent delivery system balloon or other balloon 
catheter. 
Peri-stent dissections should be treated conservatively, with low pressure prolonged balloon 
inflation, or with additional stent implantation per standard practice. Haziness, lucency, or 
filling defects within or adjacent to the stent, and angiographic complications such as distal 
thromboemboli or no reflow, should also be treated per standard practice. All angiographic 
complications that occur should be documented by angiography and submitted to the 
Angiographic Core Laboratory for analysis. 
To eliminate coronary artery spasm that would interfere with accurate measurement of lumen 
obstruction due to plaque alone, NTG or ISDN should be administered prior to the final 
angiogram. A dose of at least 100 µg of NTG is preferred; however, a 50 µg dose of NTG 
may be administered at the Investigator’s discretion when deemed clinically necessary. 
Alternatively, if ISDN is administered, a dose of 2-3 mg is recommended.  
  End of the Index Procedure 
11.7.
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 procedural, target lesion, non-target lesion (if applicable), pre-dilatation, post-
dilatation (if applicable), and study stent information on the appropriate eCRFs. 
• Record antithrombotic medications 
• Complete AE assessment and collect source documents as described in Section 20 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 37 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 38 of 84 
  
• Finalize angiographic procedure film and related required documentation to submit to the 
Core Laboratory per instructions set in the Manual of Operations 
  Postprocedure/Prehospital Discharge 
11.8.
The subject may be discharged from the hospital when clinically stable at the Investigator’s 
discretion but preferably not less than 18 hours after the index procedure. The following 
assessments must be completed post index procedure.  
• Angina assessment 
• Cardiac enzymes  
Two cardiac enzyme draws must be obtained at intervals per standard of care within 
24 hours after the index procedure. The first draw should be performed 6-12 hours 
postprocedure and the second draw should be performed 18-24 hours postprocedure. 
Note: If the subject is discharged prior to 18 hours postprocedure, the second draw 
should be obtained at the time of discharge (it is recommended that in these cases the 
second draw occur no earlier than 16 hours postprocedure). 
• Record antiplatelet medications 
• 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 for follow-up assessments 
according to the trial event schedule in  
Table 11.1-1. Study staff should establish a date for the follow-up telephone call with the 
subject and if possible, schedule the visit at the time of hospital discharge. 
 Angiography 
11.9.
All subjects will undergo angiographic assessment during the index procedure per standard 
of care. Subjects requiring reintervention for the target vessel during the 2-year follow-up 
period will undergo angiographic assessment at the time of reintervention as standard of care. 
Angiographic data and images collected during the index procedure and during any 
reinterventions of a target vessel during the 2-year follow-up period must be forwarded to the 
Angiographic Core Laboratory for analysis. Angiograms performed at outside institutions 
should also be sent to the Core Laboratory.  
Angiograms will be centrally assessed by the Angiographic Core Laboratory, for qualitative 
and quantitative analysis including longitudinal stent deformation. 
 Follow-Up 
11.10.
All enrolled subjects who receive a study stent will be evaluated through hospital discharge 
and at 30 days, 6 months, 12 months and 2 years after the index procedure. Subjects who are 
enrolled but who do not receive a study stent will be followed for 12 months only.  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 38 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 39 of 84 
  
All protocol-required follow-up assessments must be conducted with direct contact with the 
subjects either in person or by telephone interview.  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. In the absence of cardiac 
symptoms, routine follow-up, cardiac procedures, and tests are left to the discretion of the 
Investigator.  
During the 2 year follow-up period, if the subject experiences an event, it must be assessed 
and documented as described in Section 20. If the subject experiences new or recurrent 
cardiac symptoms during the trial, a more detailed evaluation (including repeat angiography) 
may be performed at the discretion of the Investigator and treating physicians. 
If the subject undergoes repeat catheterization, the circumstances and outcome of the event 
must be assessed and documented as described in Section 20.  If the repeat catheterization 
results in reintervention of the target vessel(s), angiographic data and images must be sent to 
the Angiographic Core Laboratory. 
Subjects requiring reintervention should be treated according to the Investigator’s discretion 
and standard of care. These subjects should receive an approved, commercially available 
treatment (if appropriate) and must not receive an investigational study stent for retreatment. 
Prior to initiating an angiogram, the results of the subjects’ clinical status and functional 
testing should be documented. Prior to conducting the angiogram, indication(s) for the 
angiogram must be documented. 
  30-Day Follow-up (30±7 Days) 
11.10.1.
All enrolled subjects must be evaluated 30 days after the index procedure. The follow-up 
assessment may be performed via telephone interview with the subject or during an office 
visit. During the 30 day follow-up, the following assessments must be completed.  
• Angina assessment 
• AE assessment and source document collection as described in Section 20 
• Current antiplatelet medications (P2Y12 inhibitor and aspirin). Information pertaining to 
dose changes, medication interruptions, and medication cessation must be documented. 
  6-Month Follow-up (180±30 Days) 
11.10.2.
All enrolled subjects must be evaluated 6 months after the index procedure. 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.  
• Angina assessment 
• AE assessment and source document collection as described in Section 20 
• Current antiplatelet medications (P2Y12 inhibitor and aspirin). Information pertaining to 
dose changes, medication interruptions, and medication cessation must be documented. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 39 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 40 of 84 
  
  12-Month Follow-up (365±30 Days) 
11.10.3.
All enrolled subjects must be evaluated 12 months after the index procedure. 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.  
• Angina assessment 
• AE assessment and source document collection as described in Section 20 
• Current antiplatelet medications (P2Y12 inhibitor and aspirin). Information pertaining to 
dose changes, medication interruptions, and medication cessation must be documented. 
 2-Year Follow-up (730±30 Days) 
11.10.4.
All enrolled subjects who receive a study stent must be at evaluated 2 years after the index 
procedure. The follow-up assessment may be performed via telephone interview with the 
subject or during an office visit. During the 2 year follow-up, the following assessments must 
be completed.  
• Angina assessment 
• AE assessment and source document collection as described in Section 20 
• Current antiplatelet medications (P2Y12 inhibitor and aspirin). Information pertaining to 
dose changes, medication interruptions, and medication cessation must be documented. 
  Additional Interim Follow-up 
11.10.5.
Additional interim follow-up visits may be conducted at the Investigator’s discretion. 
Clinical study-specific medical care will terminate upon completion or termination of the 
subject’s participation in the study. 
  Missed or Late Visits 
11.10.6.
A subject will be considered lost to follow-up after the subject misses the first (12 m) and 
final (2 year) follow-up visit. A minimum of 3 attempts (i.e., 2 phone calls followed by a 
certified letter, or other traceable letter, if necessary) should be made to contact the subject 
for each missed follow-up visit and this information documented in the source. 
Missed or late visits will be recorded as Protocol Deviations. 
   Study Completion 
11.11.
Enrolled subjects that received a SYNERGY 48 mm stent will be followed for 2 years after 
the index procedure.   
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 40 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 41 of 84 
  
12. Statistical Considerations 
 Endpoints 
12.1.
 Primary Endpoint 
12.1.1.
The primary endpoint is the 12 month (365 days) TLF expressed as the proportion of subjects 
who experience TLF within 365 days after the index procedure among all subjects who either 
experience TLF within 365 days after the index procedure or are followed for at least 335 
days after the index procedure.  
12.1.1.1. Hypotheses 
The 12-month TLF rate for SYNERGY subjects with 48 mm is less than the performance 
goal (PG) of 19.5%. 
12.1.1.2. Sample Size  
• The expected 12-month TLF rate for SYNERGY = 9.2%; estimated by the observed rate 
(6.6%) for SYNERGY in EVOLVE II RCT and a 40% relative increase for TLF due to 
longer lesion length (assuming a relative 20% increase in rates for every 10 mm increase 
in mean lesion length) with an expected mean lesion length of 20 mm longer than the one 
observed in EVOLVE II RCT (mean lesion length of 16 mm for SYNERGY arm), i.e. 
6.6% * (1 + 20%* 2) = 9.2% 
• The Performance Goal = 19.5%; based on EVOLVE II-like patients with lesion length 
greater than 34 mm and less than or equal to 44 mm from PROMUS Element Plus US 
Post-Approval Study and PE-Prove Study. The pooled historical 12 month TVF rate 
related to study stent from these 2 studies (6.7% (3/45) and 0% (0/12), respectively) is 
5.3% (3/57) with the corresponding exact binominal one-sided 95% upper CI of 13%. 
The expected control rate for these long lesion patients is chosen to be the exact binomial 
one-sided 95% upper CI of 13% of the pooled historical rate accounting for the lack of 
systematic post-procedural enzyme collection in the Post-Approval studies, small sample 
size and the event rate variability between studies. The PG is set to be 19.5% (expected 
control rate 13% + delta, where delta is chosen to be relative 50% of the expected control 
rate of 13% = 6.5%) 
• Test significance level (α) = 0.05 (1-sided) 
• Power (1−β) ≥ 0.80  
• N = 95 evaluable patients 
• Expected attrition rate = 5% 
• N=100 enrolled patients 
• The worst observed rate allowable for meeting the PG of 19.5% is 12% (12/100) 
12.1.1.3. Statistical Methods 
A one-group Clopper-Pearson exact test will be used to test whether the 12‑month TLF rate 
for SYNERGY is less than the PG. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 41 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 42 of 84 
  
 General Statistical Methods 
12.2.
 Analysis Sets 
12.2.1.
The primary endpoint will be analyzed on an ITT basis and on a per-protocol basis. For the 
ITT analysis, all subjects who sign the written ICF and are enrolled in the study will be 
included in the analysis sample, regardless of whether the study stent was implanted. For the 
per-protocol analysis, only enrolled subjects who received a 48 mm SYNERGY stent in the 
target lesion will be included in the analysis sample.  
A conclusion of the 48 mm SYNERGY stent meeting the PG with respect to the 12-month 
TLF rate is tested successfully if the P value from the one-sided Clopper-Pearson test is 
<0.05 in both the per-protocol and ITT populations. This corresponds to the one-sided 95% 
upper confidence bound on the observed 12-month TLF rate from SYNERGY being less 
than the PG. 
 Control of Systematic Error/Bias 
12.2.2.
Selection of subjects will be made from the Investigator's usual subject load. All subjects 
meeting the inclusion/exclusion criteria and having signed the ICF will be eligible to enroll in 
the trial. Consecutively eligible subjects should be enrolled into the study to minimize 
selection bias. In determining subject eligibility for the study, the investigator’s assessment 
of angiographic parameters before stent placement will be used. However, the Angiographic 
Core Laboratory will independently analyze the angiograms and the data obtained from the 
core lab will be used for analyses in order to control for inter-observer variability. An 
independent CEC composed of expert cardiologists will adjudicate all reported events of 
death, MI, TVR, and stent thrombosis. 
 Number of Subjects per Investigative Site 
12.2.3.
Investigative sites are recommended to enroll preferably a minimum of 6 subjects but no 
more than 20 subjects (20% of the total number of subjects) in the trial. 
 Data Analyses 
12.3.
Baseline data will be summarized, 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, and n, minimum, maximum) and frequency tables or proportions for discrete 
variables.  Estimates of primary and other endpoints will be reported and their 95% 
confidence intervals will be presented.  No formal statistical testing will be done for other 
endpoints. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 42 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 43 of 84 
  
 Other Endpoints/Measurements  
12.3.1.
Clinical event rates will be summarized using proportions while continuous data will be 
summarized by presenting means, standard deviations, sample sizes, minimums, and 
maximums.  
Kaplan-Meier time-to-event plots will be constructed for clinical events. The analysis of stent 
thrombosis will focus on all events in the “possible”, “probable”, “definite”, and “definite or 
probable” categories, according to ARC definitions. Rates of serious adverse events (SAEs) 
and AEs will be reported. 
 
 
No formal tests of hypotheses are proposed for additional endpoints. 
 Interim Analyses  
12.3.2.
No formal interim analyses are planned for the purpose of stopping this study early for 
declaring effectiveness or for futility. 
 Subgroup Analyses 
12.3.3.
Primary endpoint of 12 month TLF and its clinical components will be summarized by 
gender (male and female).  Given limited sample size, no other subgroup analyses will be 
performed.  
 Justification of Pooling 
12.3.4.
In the analysis to justify pooling across centers, the centers with fewer than 6 subjects 
enrolled in the study will be combined into “virtual centers” based on geographic region so 
that “virtual centers” have ≥6 subjects in the study but no more than the largest enrolling 
center. 
 Multivariable Analyses 
12.3.5.
Univariate and multivariate analyses may be performed to assess the effect of potential 
predictors on the primary endpoint of 12 month TLF using Logistic regression. Analyses may 
also be performed for pre-specified clinical endpoints, if feasible; liner regression may be 
used for continuous outcomes and Cox proportional hazards regression may be used to assess 
the effects of possible predictors in a time-to-event manner. 
Variables from the following categories will be considered as possible predictors: 
demographics, medical history, coronary artery disease risk factors, procedural 
characteristics, baseline angiographic measurements, and medication used during study 
procedure. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 43 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 44 of 84 
  
 Other Analyses 
12.3.6.
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, including a tipping-point analysis for the primary endpoint, may be 
conducted to assess the impact of different assumptions about the missing data on 
interpretation of the results. Outlier values will be evaluated for their validity; all data will be 
included unless judged to be invalid. 
 Changes to Planned Analyses 
12.3.7.
Any changes to the planned statistical analyses made prior to performing the primary 
endpoint analysis will be documented in an amended Statistical Analysis Plan approved prior 
to performing the analysis.  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 
 Data Collection, Processing, and Review 
13.1.
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 the sponsor 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 electronic case 
report forms (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 the sponsor 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. 
 Data Retention 
13.2.
The Principal Investigator or his/her designee or Investigational site will maintain, at the 
investigative site, all essential study documents and source documentation that support the 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 44 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 45 of 84 
  
data collected on the study subjects in compliance with ICH/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 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 other country/regional/local regulations.  
The Principal Investigator or his/her designee will take measures to ensure that these 
essential documents are not accidentally damaged or destroyed. If for any reason the 
Principal Investigator or his/her designee 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. Sites are 
required to inform Boston Scientific in writing where paper or electronic files are maintained 
in case files are stored off site and are not readily available. 
 Core Laboratories 
13.3.
The EVOLVE 48 trial will use an Angiographic Core Laboratory for analysis of angiography 
data. Results from the angiographic Core Laboratory will be entered or uploaded into the 
EDC system and will only be available to BSC. 
All subjects will undergo angiographic assessment during the index procedure. Angiographic 
follow-up is not required; however, subjects requiring reintervention for the target vessel 
during the 2-year follow-up period will undergo angiographic assessment at the time of 
reintervention as standard of care. 
Angiographic data, images, and technician’s worksheets collected during the index procedure 
and during reinterventions for the target vessel(s) during the 2-year follow-up period (if 
applicable) must be forwarded to the Angiographic Core Laboratory for analysis. 
Angiographic data and images for reintervention for vessels not treated during the study 
index procedure should not be sent to the Angiographic Core Laboratory. 
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 (e.g., 
IRB/EC/FDA/CA) of the revised protocol must be obtained prior to implementation. 
15. Deviations 
An Investigator must 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 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 45 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 46 of 84 
  
deviations from the investigational plan, 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, IRB/EC/FDA notification, 
site re-training, or site discontinuation/ termination ) will be put into place by the sponsor. 
16. Device Accountability 
 Region – US 
16.1.
The investigational devices shall be securely maintained, controlled, and used only in this 
clinical study.  The sponsor shall keep records to document the physical location of all 
investigational devices from shipment of investigational devices from BSC or designated 
facility to the investigation sites until return or disposal. 
The principal investigator or an authorized designee shall keep records documenting the 
receipt, use, return and disposal of the investigational devices, which shall include the 
following 
• Date of receipt 
• Identification of each investigational device (batch number or unique code) 
• Expiry date, as applicable 
• Date or dates of use 
• Subject identification 
• Date on which the investigational device was returned/explanted from subject, if 
applicable 
• Date of return (and number) of unused, expired, or malfunctioning investigational 
devices, if applicable. 
 Region – Outside US  
16.2.
In regions where the SYNERGY 48 mm is commercially available the devices for subjects 
enrolled in the study will be selected from the sites commercial inventory.  The principal 
investigator or an authorized designee shall keep records documenting the receipt, use, return 
and disposal of the devices, which shall include the following 
• Identification of each device (lot number ) 
• Expiry date, as applicable 
• Date or dates of use 
• Subject identification 
• Date on which the device was returned/explanted from subject, if applicable 
• Date of return of malfunctioning devices, if applicable. 
 
Written procedures may be required by national regulations. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 46 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 47 of 84 
  
17. Compliance 
 Statement of Compliance 
17.1.
This study will be conducted in accordance with ISO 14155:2011 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, and pertinent 
individual country laws and regulations. The study shall not begin until the required 
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.  
 Investigator Responsibilities 
17.2.
The Principal Investigator of an investigational site is responsible for ensuring that the study 
is conducted in accordance with the Clinical Study Agreement, the clinical investigation 
plan/, 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 the Clinical Study Agreement and comply with the 
Investigator responsibilities as described in such Agreement.   
• Prior to beginning the study, the 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 site 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/procedure) every 
adverse event as applicable per the protocol and observed device deficiency. 
• Report to sponsor, per the protocol requirements, all SAEs and device deficiencies that 
could have led to a SADE and potential/USADE or UADE. 
• Report to the IRB/EC and regulatory authorities any SAEs and device deficiencies that 
could have led to a SADE and potential/USADE or UADE, if required by the national 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 47 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 48 of 84 
  
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. 
• Investigators in the US must maintain the device accountability records and control of the 
device, ensuring that the investigational device is used only by authorized/designated 
users and in accordance with this protocol and instructions/directions for use. 
• Allow the sponsor to perform monitoring and auditing activities, and be accessible to the 
clinical research monitor or auditor and respond to questions during monitoring visits or 
audit(s). 
• 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. 
• Provide adequate medical care to a subject during and after a subject’s participation in a 
clinical study in the case of adverse events, as described in the Informed Consent Form 
(ICF). 
• Inform the subject of the nature and possible cause of any adverse events 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, including decoding procedures for blinded/masked clinical investigations, as 
needed. 
• 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 a plan of oversight is documented when multiple locations (satellite sites) are 
overseen by one Principal Investigator. 
• Inform the Sponsor of any site location changes, additions to, or deletions from sites 
where study subjects are seen or treated; inform IRB/EC and update Informed Consent 
Form accordingly. 
• Ensure that maintenance and calibration of the equipment relevant for the assessment of 
the clinical investigation is appropriately performed and documented, where applicable. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 48 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 49 of 84 
  
 Delegation of Responsibility 
17.2.1.
When specific tasks are delegated by an investigator, including but not limited to conducting 
the informed consent process, the Principal 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.  
 Institutional Review Board/ Ethics Committee 
17.3.
Prior to gaining Approval-to-Enroll status, the investigational site will provide to the sponsor 
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.   
A copy of the written IRB/EC and/or competent authority approval of the protocol (or 
permission to conduct the study) and Informed Consent Form, must be received by the 
sponsor before recruitment of subjects into the study and shipment of investigational 
product/equipment (if applicable). Prior approval must also be obtained for other materials 
related to subject recruitment or which will be provided to the subject. 
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.  
 Sponsor Responsibilities 
17.4.
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, but not limited to 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. 
Boston Scientific will keep subjects’ identifiable health information confidential in 
accordance with all applicable laws and regulations.  Boston Scientific 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 names 
will not be placed on any mailing lists or sold to anyone for marketing purposes.  
 Insurance  
17.5.
Where required by local/country regulation, proof and type of insurance coverage, by BSC 
for subjects in the study will be obtained. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 49 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 50 of 84 
  
18. Monitoring 
Monitoring will be performed during the study, according to the Monitoring Plan, to assess 
continued compliance with the current, approved protocol/amendment (s) and applicable 
regulations. In addition, the clinical research 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 Principal 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 and device accountability logs. Data documented in 
the eCRF relevant to device deficiencies, relationship of AE to study device(s), index 
procedure, and antiplatelet medication; and anticipatedness assessment of ADEs, may be 
considered source data for the study.   
A risk-based approach to source data verification will be implemented as described in the 
Monitoring Plan.  The monitoring plan for EVOLVE 48 will include source data verification 
of critical data for a sampling of subjects enrolled and review of 100% of ICFs for all 
subjects.   
The Principal 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 20.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 Principal 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 
 Risks Associated with the Implantation of Coronary Stents 
19.1.
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 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 50 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 51 of 84 
  
• 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 
• Vessel trauma requiring surgical repair or reintervention 
 
  Risks Associated with Everolimus  
19.2.
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, 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 51 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 52 of 84 
  
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 (38) .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 
• 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 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 52 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 53 of 84 
  
• 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. 
  Anticipated Adverse Device Effects  
19.3.
The anticipated adverse device effects (ADE) have been identified and are listed in section 
19.1 and 19.2.   
  Risks Associated with the Study Device(s)  
19.4.
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 and follow up through 3 years 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 (28-30). 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. When considering the incremental risk of using a 48 mm stent versus 
a shorter stent, it is conceivable that it might be more challenging to deliver a 48 mm stent 
than a shorter stent.  If it is not possible to deliver a 48 mm stent – use of two overlapping 
stents is a bailout option. Another consideration is the vessel tapering which could potentially 
be more pronounced in a longer stent. However, vessel tapering is expected to affect the 
post-dilation strategy more than stent selection.  The overexpansion capabilities of 
SYNERGY provide adequate margin for the anticipated variation in vessel size. 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 53 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 54 of 84 
  
  Sex-Specific Risks Associated with the Study Device(s)  
19.5.
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.  
  Risks Associated with Participation in the Clinical Study 
19.6.
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. There may be additional risks linked to the procedure which are 
unforeseen at this time. 
  Possible Interactions with Concomitant Medical Treatments 
19.7.
The following describes known drug interactions for orally administered everolimus at 
significantly higher doses than are present on the PROMUS Element Plus and SYNERGY 
stents. Interactions observed at these higher doses may not be relevant to the PROMUS 
Element Plus and SYNERGY stents. 
When taken orally, everolimus is extensively metabolized by the cytochrome P4503A4 
(CYP3A4) in the gut wall and liver and is a substrate for the countertransporter P 
glycoprotein. Therefore, absorption and subsequent elimination of everolimus may be 
influenced by drugs that affect these pathways. Concurrent treatment with strong CYP3A4 
inhibitors and inducers is not recommended unless the benefits outweigh the risk. Inhibitors 
of P glycoprotein may decrease the efflux of everolimus from intestinal cells and increase 
everolimus blood concentrations. In vitro, everolimus was a competitive inhibitor of 
CYP3A4 and of cytochrome P4502D6 (CYP2D6), potentially increasing the concentrations 
of drugs eliminated by these enzymes. Thus, caution should be exercised when co-
administering everolimus with CYP3A4 and CYP2D6 substrates with a narrow therapeutic 
index (42).  
Everolimus has also been shown to reduce the clearance of some prescription medications 
when it was administered orally along with cyclosporine. Formal drug interaction studies 
have not been performed with the SYNERGY stent. Therefore, due consideration should be 
given to the potential for both systemic and local drug interactions in the vessel wall when 
deciding to place the SYNERGY stent in a subject taking a drug with known interaction with 
everolimus.  
Everolimus, when prescribed as an oral medication, may interact with the following drugs or 
substances.  
• CYP3A4 isozyme inhibitors (ketoconazole, itraconazole, voriconazole, ritonavir, 
erythromycin, clarithromycin, fluconazole, calcium channel blockers [verapamil and 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 54 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 55 of 84 
  
diltiazem), aprepitant, atazanavir, nefazodone, amprenavir, indinavir, nelfinavir, 
delavirdine, fosamprenavir, saquinavir, and telithromycin) 
• Inducers of CYP3A4 isozyme (rifampin, rifabutin, carbamazepine, phenobarbital, 
phenytoin, St. John’s Wort, efavirenz, nevirapine, and dexamethasone) 
• Antibiotics (ciprofloxacin, ofloxacin) 
• Glucocorticoids 
• HMGCoA reductase inhibitors (simvastatin, lovastatin) 
• PgP inhibitors (digoxin, cyclosporine) 
• Cisapride (theoretical potential interaction) 
• Sildenafil (Viagra®) (theoretical potential interaction) 
• Antihistaminics (terfenadine, astemizole) 
• Grapefruit/grapefruit juice 
 
  Risk Minimization Actions 
19.8.
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, 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. 
  Anticipated Benefits 
19.9.
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. Regarding specifically the use of a long stent, 
clinical data form the TAXUS ATLAS Long Lesion trial suggests a benefit of treatment with 
a single long stent versus multiple overlapping stents (31). It is also conceivable that the use 
of one versus two overlapping stents potentially decreases contrast use, exposure to 
irradiation and procedure time. However, given there are no clinical data on the SYNERGY 
48 mm stent these potential benefits may or may not actually be present 
 Risk to Benefit Rationale 
19.10.
The 48 mm SYNERGY stent is expected to be suitable for its intended purpose. There are no 
new patient harms associated with the use of a 48 mm SYNERGY stent versus using a 
shorter SYNERGY stent. There are no unacceptable residual risks/intolerable risks and all 
applicable risks have been addressed through the provision of appropriate Directions for Use. 
Evaluation of the risks and benefits that are expected to be associated with use of the 48 mm 
SYNERGY stent demonstrate that when used under the conditions intended, the benefits 
associated with use of the 48 mm SYNERGY stent should outweigh the risks.  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 55 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 56 of 84 
  
20. Safety Reporting 
  Reportable Events by investigational site to Boston Scientific 
20.1.
It is the responsibility of the investigator to assess and report to BSC any event which occurs 
in any of following categories: 
• All serious adverse events (SAE)  
• All CEC events inclusive of death, MI*, TVR and stent thrombosis  
• All Adverse Device Effects (ADE)  
• All SYNERGY 48 mm Device Deficiencies  
• Unanticipated Adverse Device Effects/Unanticipated Serious Adverse Device Effects 
• New findings/updates in relation to already reported events 
 
* MI should be reported per protocol definition.  If pre-procedure cardiac enzymes were not 
drawn, but the event otherwise meets the protocol definition of MI, the event should be 
reported as an MI for CEC adjudication.   
When possible, the medical diagnosis should be reported as the Event Term instead of 
individual symptoms. 
If it is unclear whether or not an event fits one of the above categories, or if the event cannot 
be isolated from the device or procedure, it should be submitted as an adverse event and/or 
device deficiency. 
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 ONE (1) specific SAE (see Table 20.2-1 for AE 
definitions). 
Refer to Section 19 for the known risks associated with the study device(s). 
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 events occur during an elective/planned (i.e., planned prior to 
enrollment) hospitalization after enrollment, the complications and event AEs must be 
reported if they meet the protocol-specified definitions. However, the original 
elective/planned hospitalization(s) itself should not be reported as an SAE. 
 Definitions and Classification 
20.2.
Adverse event definitions are provided in Table 20.2-1. Administrative edits were made on 
the definition of serious adverse event from ISO 14155 and MEDDEV 2.7/3 for clarification 
purposes. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 56 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 57 of 84 
  
Table 20.2-1: Safety 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. 
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 includes any adverse event resulting from insufficiencies 
or inadequacies in the 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 
intentional abnormal use 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: 
a) Led to death, 
b) Led to  serious deterioration in the health of the subject as defined by 
either: 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function, 
or 
3) in-patient hospitalization or prolongation of existing 
hospitalization , or 
4) medical or surgical intervention to prevent life-threatening 
illness or injury or permanent impairment to a body structure or 
a body function 
c) 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 a 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) 
 
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 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 57 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 58 of 84 
  
Table 20.2-1: Safety Definitions 
Term 
Definition 
Ref: 21 CFR Part 812 
 
 
of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious 
problem associated with a device that relates to the rights, safety, or welfare 
of subjects.   
Unanticipated 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 inadequacy of an investigational medical device related to its identity, 
quality, durability, reliability, safety or performance. This may include 
malfunctions, use error, or inadequacy in the information supplied by the 
manufacturer. 
 
Abbreviations: EC=Ethics Committee; IRB=Institutional Review Board 
 Relationship to Study Device(s) 
20.3.
The Investigator must assess the relationship of the AE to the study device or procedure. See 
criteria in Table 20.3-1:  
Table 20.3-1: Criteria for Assessing Relationship of Study Device or 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; 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 58 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 59 of 84 
  
Table 20.3-1: Criteria for Assessing Relationship of Study Device or Procedure to 
Adverse Event 
Classification 
Description 
- 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 
• 
the investigational device or procedures are applied to; 
• 
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); 
- 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. 
 
 
 Investigator Reporting Requirements 
20.4.
The communication requirements for reporting to BSC are as shown in Table 20.4-1. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 59 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 60 of 84 
  
 
Table 20.4-1: 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 aware of 
the event. 
• Terminating at the end of the study 
Serious Adverse 
Event* 
Complete AE eCRF 
page with all available 
new and updated 
information.  
• Within 3 calendar days of first becoming aware 
of the event or as per local/regional regulations.  
• Reporting required through the end of the study 
Provide all relevant 
source documentation 
(unidentified) for 
reported event upon 
request of the sponsor 
• At request of sponsor 
Serious Adverse 
Device Effects 
Complete AE eCRF 
page with all available 
new and updated 
information. 
• Within 3 calendar days of first becoming aware 
of the event or as per local/regional regulations.  
• Reporting required through the end of the study 
Provide all relevant 
source documentation 
(unidentified) for 
reported event 
• When documentation is available 
Device Deficiencies 
(including but not 
limited to failures, 
malfunctions, and 
product 
nonconformities) 
Note:  Any 
Investigational 
Device Deficiency 
that might have led 
to a serious adverse 
event if a) suitable 
action had not been 
taken or b) 
intervention had not 
been made or c) if 
circumstances had 
been less fortunate 
is considered a 
reportable event. 
Complete Device 
Deficiency CRF with all 
available new and 
updated information.  
• Within 3 calendar days of first becoming aware 
of the event.  
• Reporting required through the end of the study 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 60 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 61 of 84 
  
Table 20.4-1: Investigator Reporting Requirements 
Event 
Classification 
Communication 
Method  
Communication Timeline  
 
Adverse Device 
Effects  
Complete AE eCRF 
page, which contains 
such information as date 
of AE, treatment of AE 
resolution, assessment 
of seriousness and 
relationship to the 
device.  
• Within 10 business days after becoming aware 
of the information 
• ADEs reporting required through end of study 
 
* All CEC events must be reported using the timeframe for SAE, regardless of whether they meet 
serious criteria 
Abbreviations: AE=adverse event; CRF=case report form; IDE=Investigational Device 
Exemption; UADE=unanticipated adverse device effect 
 
  Boston Scientific Device Deficiencies 
20.5.
All SYNERGY 48 mm device deficiencies (including but not limited to failures, 
malfunctions, use errors, product nonconformities, and inadequacy in the information 
supplied by the manufacturer) will be documented and reported to BSC. If possible, the 
device(s) should be returned to BSC for analysis. Instructions for returning the 
investigational device(s) will be provided in the MOP. 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 adverse events; they should be reported on the appropriate eCRF 
per the study CRF Completion Guidelines.  If an adverse event results from a device failure 
or malfunction, the AE should be recorded as an adverse event on the appropriate eCRF if it 
meets the protocol-specified definition of a reportable event. 
Any Device Deficiency that might have led to a serious adverse event if a) suitable action 
had not been taken or b) intervention had not been made or c) if circumstances had been less 
fortunate is considered a reportable event.  
  Reporting to Regulatory Authorities / IRBs / ECs / Investigators 
20.6.
BSC is responsible for reporting adverse event information to all participating Principal 
Investigators and regulatory authorities, as applicable.  
Boston Scientific Corporation will notify all participating study centers 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 Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 61 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 62 of 84 
  
Boston Scientific Corporation is responsible for reporting AE and device deficiencies 
information to all participating investigators, IRBs/IECs, and regulatory authorities as 
applicable according to local reporting requirements. 
Boston Scientific Corporation, Investigator, or Site must notify the IRB/IEC of any UADEs, 
USADEs, SADEs, SAEs, device deficiencies, and other CEC events as applicable according 
to local reporting requirements (refer to Section 22 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. 
The Principal Investigator is responsible for informing the IRB/EC, and regulatory 
authorities of UADE and SAE as required by local/regional regulations. 
21. Informed Consent 
Subject participation in this clinical study is voluntary.  Informed Consent is required from 
each subject or his/her legally authorized representative. The Investigator is responsible for 
ensuring that Informed Consent is obtained prior to the use of any investigational devices, 
study-required procedures and/or testing, or data collection.  
The obtaining and documentation of Informed Consent must be in accordance with the 
principles of the Declaration of Helsinki, ISO 14155, any applicable national regulations, and 
local Ethics Committee and/or Regulatory authority body, as applicable. The ICF must be 
accepted by BSC or its delegate (e.g. CRO), and approved by the site’s IRB/EC, or central 
IRB, if applicable. 
Boston Scientific 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 site’s IRB/EC.  Any modification requires acceptance 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 site 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.  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 62 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 63 of 84 
  
 
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 site and a copy of the signed and dated document and any 
other written information must be given to the person signing the form.  
Failure to obtain subject consent will be reported by BSC to the applicable regulatory body 
according to their requirements (e.g., FDA requirement is within 5 working days of learning 
of such an event). Any violations of the informed consent process must be reported as 
deviations to the sponsor 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, 
the presence of, addition, or deletion of satellite sites or following annual review by the 
IRB/EC. The new version of the ICF must be approved by the IRB/EC. Acceptance by 
Boston Scientific is required if changes to the revised ICF are requested by the site’s 
IRB/EC. The IRB/EC will determine the subject population to be re-consented. 
Study personnel should explain to the subject that even if the subject agrees to participate in 
the trial and signs the ICF, cardiac catheterization may demonstrate that the subject is not a 
suitable candidate for the trial. A Screening Log will be maintained to document select 
information about candidates who fail to meet the EVOLVE 48trial eligibility criteria, 
including, but not limited to, the reason for screen failure. 
22. Committees 
  Safety Monitoring Process 
22.1.
To promote early detection of safety issues, BSC processes will provide accelerated 
evaluation of safety events. 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 and Angiographic Core Laboratory.  During regularly scheduled 
monitoring visits, the clinical research monitors will support the dynamic reporting process 
through their review of source document information.  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 63 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 64 of 84 
  
  Clinical Events Committee 
22.2.
The Clinical Events Committee (CEC) is an independent group of individuals with pertinent 
expertise who review and adjudicate important clinical endpoints and relevant AEs 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 stent thrombosis, TVR, MI (Q-
wave and non–Q-wave), and death.  
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.  
23. Suspension or Termination 
 Premature Termination of the Study 
23.1.
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. 
 Criteria for Premature Termination of the Study 
23.1.1.
Possible reasons for premature study termination include, but are not limited to, the 
following. 
• The occurrence of unanticipated adverse device effects that present a significant or 
unreasonable risk to subjects enrolled in the study. 
• An enrollment rate far below expectation that prejudices the conclusion of the study.  
• A decision on the part of Boston Scientific to suspend or discontinue development of the 
device. 
 Termination of Study Participation by the Investigator or Withdrawal of 
23.2.
IRB/ EC Approval 
Any investigator, or IRB/ EC in the EVOLVE 48 Study may discontinue participation in the 
study or withdraw approval of the study, respectively, with suitable written notice to Boston 
Scientific. Investigators, associated IRBs/ECs, and regulatory authorities, as applicable, will 
be notified in writing in the event of these occurrences. 
 Requirements for Documentation and Subject Follow-up 
23.3.
In the event of premature study termination a written statement as to why the premature 
termination has occurred will be provided to all participating sites by Boston Scientific. The 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 64 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 65 of 84 
  
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 Boston Scientific. 
In the event a Principal Investigator terminates participation in the study, study responsibility 
will be transferred to another investigator, if possible. In the event there are no opportunities 
to transfer Principal Investigator responsibility; detailed information on how enrolled 
subjects will be managed thereafter will be provided by Boston Scientific. 
The Principal Investigator or his/her designee must return all study-related documents and 
investigational product to Boston Scientific, unless this action would jeopardize the rights, 
safety, or welfare of the subjects. 
 Criteria for Suspending/Terminating a Study Site 
23.4.
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 site has multiple or severe protocol 
violations/noncompliance without justification and/or fails to follow remedial actions. 
In the event of termination of site participation, all study devices and testing equipment, as 
applicable, will be returned to BSC unless this action would jeopardize the rights, safety or 
well-being of the subjects. The IRB/EC and regulatory authorities, as applicable, will be 
notified. All subjects enrolled in the study at the site will continue to be followed per 
protocol as defined in Section 11. The Principal Investigator at the site must make provision 
for these follow-up visits unless BSC notifies the investigational site otherwise. 
24. Publication Policy 
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. 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 Coordinating Principal Investigator(s) and/or Executive/Steering 
Committee at the onset of the project. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 65 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 66 of 84 
  
• The First and Senior authors are the primary drivers of decisions regarding publication 
content, review, approval, and submission.  
25. Bibliography 
1. 
Wilson GJ, Marks A, Berg KJ et al. The SYNERGY biodegradable polymer 
everolimus eluting coronary stent: Porcine vascular compatibility and polymer safety 
study. Catheterization and Cardiovascular Interventions 2015;86:E247-57. 
2. 
Raber L, Juni P, Loffel L et al. Impact of stent overlap on angiographic and long-term 
clinical outcome in patients undergoing drug-eluting stent implantation. J Am Coll 
Cardiol 2010;55:1178-88. 
3. 
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. 
4. 
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. 
5. 
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. 
6. 
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. 
7. 
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. 
8. 
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. 
9. 
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. 
10. 
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; 2015. 
11. 
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. 
12. 
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. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 66 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 67 of 84 
  
13. 
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. 
14. 
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. 
15. 
Teirstein PS, Stone GW, Meredith IT et al. Platinum Chromium Everolimus-Eluting 
Stent in Long Coronary Lesions. Presented at: TCT 2011; San Francisco. 
16. 
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. 
17. 
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. 
18. 
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. 
19. 
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. Journal of the American College of Cardiology 2012;59:1362-
70. 
20. 
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. 
21. 
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. 
22. 
Meredith IM. Final five-year clinical outcomes in the EVOLVE trial: A randomised 
evaluation of a novel bioabsorbable polymer-coated, everolimus-eluting stent. 
Presented at: EuroPCR;May 19th, 2016; Paris, France. 
23. 
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. 
24. 
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. Circulation: Cardiovascular Interventions 2015;8:Article ID 
e002372. 
25. 
Kereiakes DJ, Meredith IT, Masotti M et al. Safety and efficacy of a bioabsorbable 
polymer-coated, everolimus-eluting coronary stent in patients with diabetes: the 
EVOLVE II diabetes substudy. EuroIntervention 2017;12:1987-1994. 
26. 
Windecker S, DJ K, Meredith I et al. Primary clinical outcomes of the EVOLVE II 
diabetes substudy evaluating a novel bioabsorbable polymer-coated, everolimus-
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 67 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 68 of 84 
  
eluting coronary stent in diabetic patients. EuroIntervention 2015;Abstracts EuroPCR 
2015:OP040. 
27. 
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 SYNERGY Everolimus-Eluting Stent in De Novo Coronary Stenoses. 
Presented at: ACC 2015; Chicago, IL. 
28. 
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. 
29. 
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-
eluting coronary stent with the TAXUS Liberte paclitaxel-eluting stent in de novo 
native coronary artery lesions. Circ Cardiovasc Interv 2010;3:556-64. 
30. 
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. 
31. 
Ormiston JA, Charles O, Mann T et al. Final 5-year results of the TAXUS ATLAS, 
TAXUS ATLAS Small Vessel, and TAXUS ATLAS Long Lesion clinical trials of 
the TAXUS Liberte paclitaxel-eluting stent in de-novo coronary artery lesions. Coron 
Artery Dis 2013;24:61-8. 
32. 
Cutlip DE, Windecker S, Mehran R et al. Clinical end points in coronary stent trials: a 
case for standardized definitions. Circulation 2007;115:2344-51. 
Abbreviations and Definitions  
 Abbreviations 
25.1.
Table 26.1-1: Abbreviations 
Abbreviation/Acronym 
Term 
 
 
ACC 
American College of Cardiology 
ACT 
activated clotting time 
ADE 
adverse device effect 
AE 
adverse event 
AHA 
American Heart Association 
ARC 
Academic Research Consortium 
BSC 
Boston Scientific Corporation 
BMS 
bare metal stent 
CABG 
coronary artery bypass graft 
CBC 
complete blood count 
CEC 
Clinical Events Committee 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 68 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 69 of 84 
  
Table 26.1-1: Abbreviations 
Abbreviation/Acronym 
Term 
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 
Data Monitoring Committee 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ESC 
European Society of Cardiology 
FDA 
Food and Drug Administration 
FHU 
First Human Use 
FFR 
fractional flow reserve 
GCP 
Good Clinical Practices 
GI 
gastrointestinal 
GUSTO 
Global Strategies for Opening Occluded Coronary Arteries 
IABP 
intra-aortic balloon pump 
IC 
Intercontinental 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDE 
Investigational Device Exemption 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISDN 
isosorbide dinitrate 
ISO 
International Standards Organization 
ITT 
intention to treat 
IVRS 
interactive voice response system 
IWRS 
Interactive web response system 
LAD 
left anterior descending coronary artery 
LBBB 
left bundle branch block 
LCX 
left circumflex coronary artery 
LL 
long lesion 
MACE 
major adverse cardiac event 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 69 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 70 of 84 
  
Table 26.1-1: Abbreviations 
Abbreviation/Acronym 
Term 
MI 
myocardial infarction 
MLD 
minimum lumen diameter 
NHLBI 
National Heart, Lung, and Blood Institute 
NTG 
Nitroglycerin 
OUS 
Outside the United States 
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 
Society for Cardiovascular Angiography and Interventions 
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 
unanticipated adverse device effect 
ULN 
upper limit of normal 
URL 
upper reference limit 
US 
United States 
WBC 
white blood cell 
WH 
Workhorse 
 
 
  Definitions 
25.2.
Terms are defined below.  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 70 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 71 of 84 
  
ABRUPT CLOSURE 
Abrupt closure is the occurrence of new severely reduced flow (TIMI grade 0 or 1) within the 
target vessel that persists and requires bailout, including emergency surgery, or results in MI 
or death. Abrupt closure requires proven association with a mechanical dissection of the 
treatment site or instrumented vessel, coronary thrombus, or severe spasm. Abrupt closure 
does not connote “no reflow” due to microvascular flow limitation in which the epicardial 
artery is patent but has reduced flow. Abrupt closure also does not connote transient closure 
with reduced flow in which the assigned treatment reversed the closure. 
Sub-abrupt closure is an abrupt closure that occurs after the target procedure is completed 
and the subject has left the catheterization laboratory and before hospital discharge. 
Threatened abrupt closure is a grade B dissection and ≥50% diameter stenosis or any 
dissection of grade C or higher. 
ADVERSE DEVICE EFFECT (Ref: ISO 14155 and MEDDEV 2.7/3)   
Adverse event related to the use of an investigational medical device 
NOTE 1: This includes any adverse event resulting from insufficiencies or 
inadequacies in the 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 intentional 
abnormal use of the investigational medical device.  
ADVERSE EVENT (Ref: ISO 14155 and 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. 
NOTE 3: For users or other persons, this definition is restricted to events related to the 
investigational medical device. 
ADVERSE EVENT RELATIONSHIP TERMS 
Adverse Event Relationship terms are detailed in section 20.3-1.   
ANGIOGRAPHIC SUCCESS 
Angiographic success is a mean lesion diameter stenosis < 50% (< 30% for stents) in 2 near-
orthogonal projections with TIMI 3flow, as visually assessed by the physician, without the 
occurrence of prolonged chest pain or ECG changes consistent with MI 
ANNUAL FOLLOW-UPS 
Annual follow-ups are those that occur annually through 2 years after the index procedure. 
The timing of annual follow-ups is calculated based on one calendar year equaling 365 days. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 71 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 72 of 84 
  
The follow-up window is 30 days. Therefore, the 1-year and 2-year follow-ups should occur 
365±30 days and 730±30 days after the index procedure, respectively. 
ANTICIPATED EVENT 
Event that is previously identified in the Protocol, ICF, or DFU. 
ARRHYTHMIA 
An arrhythmia is any variation from the normal rhythm of the heart, including sinus 
arrhythmia, premature beats, heart block, atrial or ventricular fibrillation, atrial or ventricular 
flutter, and atrial or ventricular tachycardia. 
ARTERIOVENOUS FISTULA 
An arteriovenous fistula is an abnormal passage or communication between an artery and a 
vein. It may result from injury or it may occur as a congenital abnormality. 
BAILOUT 
• Bailout typically refers to a peristent dissection but can also include a vessel complication 
at the ostium or along the course of the major coronary artery used to access the target 
lesion. 
• The decision of whether to treat in a bailout situation is at the discretion of the 
interventionalist. 
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. 
BINARY RESTENOSIS 
Binary restenosis is a diameter stenosis >50% at the previously treated lesion site, including 
the original treated area and the adjacent proximal and distal QCA analysis segment. 
BLEEDING CLASSIFICATIONS (Ref: GUSTO) 
• 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 
 
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. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 72 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 73 of 84 
  
• 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. 
 
CARDIAC TAMPONADE 
Cardiac tamponade is an acute compression of the heart due to effusion of the fluid into the 
pericardium, or the collection of blood in the pericardium, from rupture of the heart or 
penetrating trauma. 
CARDIOGENIC SHOCK 
Cardiogenic shock is a clinical state of hypoperfusion characterized by a systolic blood 
pressure <80 mmHg and/or a central filling pressure >20 mmHg, or a cardiac index 
<1.8 liters/min/m2 where there is evidence of insufficient end organ profusion. Shock is also 
considered present if intravenous inotropes and/or intra-aortic balloon pump (IABP) are 
needed to maintain a systolic blood pressure >80 mmHg and a cardiac index 
>1.8 liters/minute/m2. 
CREATINE KINASE-MYOGLOBIN BAND 
Creatine kinase-myoglobin band (CK-MB) is an isoenzyme of creatine kinase (CK) with a 
distinct molecular structure specific as an indicator of myocardial cell injury. It is used to 
evaluate possible causes of chest pain, to detect and diagnose acute MI and re-infarction, and 
to monitor the severity of myocardial ischemia. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 73 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 74 of 84 
  
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. 
CLINICAL EVENTS COMMITTEE EVENT 
The CEC will adjudicate all reported cases of stent thrombosis, TVR, MI (Q-wave and non–
Q-wave), and death (to ensure appropriate classification of death as cardiac or non-cardiac). 
A case adjudicated by the CEC is considered to be a CEC event. 
CLINICAL PROCEDURAL SUCCESS (VISUAL ESTIMATE) 
Clinical procedural success is postprocedure diameter stenosis <30% in 2 near-orthogonal 
projections with TIMI 3 flow in the target lesion, as visually assessed by the physician, 
without the occurrence of in-hospital MI, TVR, or cardiac death. 
COMPLICATION (ANGIOGRAPHIC OR CLINICAL) 
A complication (angiographic or clinical) is an undesirable clinical event that results in death, 
injury, or invasive intervention. Complications may include, but are not limited to, 
perforation, occlusion, intimal flap, dissection, loss of side branch, distal embolization, non-
fatal MI, elevated CK Total, prolonged angina, hypotension, hematoma, arrhythmias, etc. 
Complications may or may not be related to the investigational device. 
CONGESTIVE HEART FAILURE 
Congestive heart failure is an inadequacy of the heart such that it fails to maintain adequate 
circulation of blood, so that congestion and edema develop in the tissues. Clinical syndrome 
is characterized by shortness of breath, non-pitting edema, enlargement of the liver, engorged 
neck veins, and pulmonary rales. 
CORONARY ANEURYSM 
A coronary aneurysm is a pathologic dilatation of a segment of a blood vessel involving all 
three layers of the vessel wall ≥1.5× the RVD. 
CORONARY ARTERY SPASM 
Coronary artery spasm, or coronary vasospasm, is a spasm of a coronary artery, resulting in a 
decrease in lumen diameter. It may occur distal to the treatment site and is generally reversed 
with intracoronary administration of NTG or with adjunct balloon dilatation. 
DEATH 
Death is categorized as cardiac or non-cardiac. 
Cardiac death is defined as death due to any of the following. 
• Acute MI 
• Cardiac perforation/pericardial tamponade 
• Arrhythmia or conduction abnormality 
• CVA through hospital discharge or CVA suspected of being related to the procedure 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 74 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 75 of 84 
  
• Death due to complication of the procedure, including bleeding, vascular repair, 
transfusion reaction, or bypass surgery 
• Any death in which a cardiac cause cannot be excluded 
Non-cardiac death is defined as a death not due to cardiac causes as defined above. 
DEVICE DEFICIENCY (Ref: ISO 14155 and MEDDEV 2.7/3) 
A inadequacy of an investigational medical device related to its identity, quality, durability, 
reliability, safety or performance. This may include malfunctions, use error, or inadequacy in 
the information supplied by the manufacturer. 
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. 
DISTAL EMBOLIZATION 
Distal embolization is migration of a filling defect or thrombus to distally occlude the target 
vessel or one of its branches. 
EMERGENCY BYPASS SURGERY 
Emergency bypass surgery is CABG surgery performed on an urgent or emergent basis for 
severe vessel dissection or closure, or treatment failure resulting in new ischemia. 
EPICARDIAL VESSEL 
Epicardial vessels include the LAD and its branches, the LCX and its branches, and the RCA 
and its branches. 
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. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 75 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 76 of 84 
  
HYPOTENSION 
Sustained hypotension is a systolic blood pressure less than 80 mmHg lasting more than 
30 minutes or requiring intervention (e.g., pacing, IABP, intravenous vasopressors, to sustain 
systolic blood pressure). This excludes transient hypotension or vagal reactions, which are 
self-limited or readily reversible. 
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. 
INTIMAL FLAP 
An intimal flap is an extension of the vessel wall into the arterial lumen. 
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. 
• 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. 
 
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 length is classified as 
discrete (<10 mm), tubular (10-20 mm), or diffuse (>20 mm). 
LESION LOCATION 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 76 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 77 of 84 
  
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 48 trial, the ramus will be considered to be a branch of the LCX for 
purposes of determining eligibility and for determining TVR. 
LEUKOPENIA 
Leukopenia is a leukocyte count of <3.0 × 109/liter for more than 3 days. 
MALFUNCTION 
A malfunction is a failure of the device to meet performance specifications or otherwise 
perform as intended. 
MULTI-VESSEL DISEASE 
Multi-vessel disease refers to the presence of >50% diameter stenosis as measured by caliper 
method or QCA on-line in 2 or 3 major epicardial coronary vessels or bypassed branches. 
MYOCARDIAL INFARCTION 
In the EVOLVE 48 trial, MI will be defined according to the 3rd Universal Definition  
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: 
(i) 
Symptoms suggestion of myocardial ischemia 
(ii) 
New ischemic ECG changes 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 77 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 78 of 84 
  
(iii) 
Angiographic findings consistent with a procedural complication 
(iv) 
Imaging demonstration of a 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: 
(i) 
New pathological Q waves or new LBBB 
(ii) 
Angiographic documented new graft or new native coronary artery occlusion 
(iii) 
Imaging evidence of new loss of viable myocardium or new regional wall 
motion abnormality 
Myocardial Infarction resulting in death when biomarker values are unavailable: 
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. 
Stent thrombosis- Related Myocardial Infarction: 
MI associated with stent thrombosis 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. 
NON-TARGET LESION 
A non-target lesion is any lesion treated during the index procedure which is not a target 
lesion. A maximum of 1 non-target lesion in 1 non-target vessel may be treated with a 
commercial treatment (e.g., stent, balloon angioplasty, excluding brachytherapy) during the 
index procedure.  
PERFORATION 
Perforations are classified as follows: 
• Angiographic perforation: Perforation detected by clinical site or Angiographic Core 
Laboratory at any point during the procedure. 
• Clinical perforation: Perforation requiring additional treatment, including efforts to seal 
the perforation or pericardial drainage, or resulting in significant pericardial effusion, 
abrupt closure, MI, or death. 
• Pericardial hemorrhage/tamponade: Perforation causing tamponade. 
 
PROLONGED ANGINA PECTORIS 
Prolonged angina pectoris is angina lasting longer than 1 hour. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 78 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 79 of 84 
  
PSEUDOANEURYSM 
A pseudoaneurysm is an encapsulated hematoma in communication with an artery. It is often 
difficult to distinguish from an expanding hematoma at the site of arterial puncture. It usually 
requires surgical repair. 
REFERENCE DIAMETER OF NORMAL ARTERY SEGMENT 
Reference diameter of the normal artery segment is an angiographic measurement of the 
artery proximal and/or distal to the lesion intended for angioplasty. This is also referred to as 
“reference vessel diameter” (RVD). 
REPEAT INTERVENTION 
Repeat intervention is a PCI or CABG performed after the end of the index procedure. The 
repeat intervention should be performed to improve blood flow. 
RESTENOSED LESION 
A restenosed lesion is a previously treated lesion that again has a stenosis. 
RESTENOSIS 
See Binary Restenosis. 
SERIOUS ADVERSE DEVICE EFFECT (Ref: ISO 14155 and MEDDEV 2.7/3 ) 
Adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event. 
SERIOUS ADVERSE EVENT (Ref: ISO 14155 and MEDDEV 2.7/3) 
Adverse event that: 
a) Led to death, 
• b) Led to  serious deterioration in the health of the subject as defined by either: 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function, or 
3) in-patient hospitalization or prolongation of existing hospitalization , or 
4) medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function 
• 
c) 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 a serious deterioration in health, is not considered a 
serious adverse event.  
 
SOURCE DATA  
All information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a nclinical trial necessary for the reconstruction 
and evaluation of the trial. Source data are contained in the source documents (original 
records or ceritifed copies) (ICH E6 (1.51 and 1.52))   
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 79 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 80 of 84 
  
SOURCE DOCUMENTS 
Original documents, data, and records  (ICH E6 (1.51 and 1.52))   
STENT THROMBOSIS (Ref: Academic Research Consortium Definition) (32) 
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: 
• 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: 
TIMI flow grade 0 with occlusion originating in the stent or in the segment 5 mm proximal 
or distal to the stent region in the presence of thrombus* 
TIMI flow grade 1, 2 or 3 originating in the stent or in the segment 5 mm 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. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 80 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 81 of 84 
  
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/CEREBROVASCULAR ACCIDENT  
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. 
• 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) 
 
SUCCESSFUL PREDILATATION/PRETREATMENT 
Successful predilatation/pretreatment refers to dilatation with a balloon catheter of 
appropriate length and diameter, or pretreatment with directional or rotational coronary 
atherectomy, laser or cutting/scoring balloon with no greater than 50% residual stenosis and 
no dissection greater than NHLBI type C. 
TARGET LESION 
The target lesion is the lesion selected by the Investigator for treatment with a study stent.  
The target lesion includes the arterial segment treated with the study stent plus the arterial 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 81 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 82 of 84 
  
segment 5 mm proximal and 5 mm distal to the treatment site. The target lesion should meet 
the angiographic selection criteria.  
TARGET LESION FAILURE 
Target lesion failure is any ischemia-driven revascularization of the target lesion, MI (Q-
wave and non–Q-wave) related to the target vessel, or (cardiac) death. For the purposes of 
this protocol, if it cannot be determined with certainty whether the MI was related to the 
target vessel, it will be considered a TLF. 
TARGET LESION REVASCULARIZATION 
Target lesion revascularization is any ischemia-driven repeat percutaneous intervention, to 
improve blood flow, of the successfully treated target lesion or bypass surgery of the target 
vessel with a graft distally to the successfully treated target lesion. A TLR will be considered 
as ischemia-driven if the target lesion diameter stenosis is ≥50% by QCA and there is 
presence of clinical or functional ischemia which cannot be explained by other coronary or 
graft lesions. Clinical or functional ischemia is any of the following: 
• The subject has a positive functional study corresponding to the area served by the target 
lesion. 
• The subject has ischemic ECG changes at rest in a distribution consistent with the target 
vessel. 
• The subject has ischemic symptoms referable to the target lesion. 
A TLR will be considered as ischemia-driven if the lesion diameter stenosis is ≥70% by 
QCA even in the absence of clinical or functional ischemia. 
TARGET VESSEL 
The target vessel is any coronary vessel (e.g., left main coronary artery, LAD, LCX, or RCA) 
containing a target lesion. Side branches of a target vessel such as the LAD are also 
considered part of the target vessel. 
Note: In the EVOLVE 48 trial, the ramus will be considered to be a branch of the LCX for 
purposes of determining eligibility and for determining TVR. 
TARGET VESSEL FAILURE 
Target vessel failure is any ischemia-driven revascularization of the target vessel, MI (Q-
wave and non–Q-wave) related to the target vessel or death related to the target vessel. For 
the purposes of this protocol, if it cannot be determined with certainty whether the MI or 
death was related to the target vessel, it will be considered a TVF. 
TARGET VESSEL REVASCULARIZATION 
Target vessel revascularization is defined as a TLR (see definition above) or a TVR remote 
(see definition below). 
TARGET VESSEL REVASCULARIZATION REMOTE 
Target vessel revascularization remote is any ischemia-driven repeat percutaneous 
intervention, to improve blood flow, or bypass surgery of not previously existing lesions 
diameter stenosis ≥50% by QCA in the target vessel, excluding the target lesion. A TVR will 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 82 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 83 of 84 
  
be considered ischemia-driven if the target vessel diameter stenosis is ≥50% by QCA and any 
of the following are present: 
• The subject has a positive functional study corresponding to the area served by the target 
vessel. 
• The subject has ischemic ECG changes at rest in a distribution consistent with the target 
vessel. 
• The subject has ischemic symptoms referable to the target vessel. 
A TVR will also be considered as ischemia-driven if the lesion diameter stenosis is ≥70% 
even in the absence of clinical or functional ischemia. 
TECHNICAL SUCCESS 
Technical success is successful delivery and deployment of the study stent to the target 
vessel, without balloon rupture or stent embolization, and post-procedure diameter stenosis 
of <30% in 2 near-orthogonal projections with TIMI 3 flow in the target lesion, as visually 
assessed by the physician.  
TECHNICIAN WORKSHEET 
A Technician Worksheet is a record for listing the filming sequence and angulations of x-ray 
equipment, details of inflations, and description of lesion(s). 
THROMBUS (ANGIOGRAPHIC) 
Thrombus (angiographic) is discrete, mobile intraluminal filling with defined borders 
with/without associated contrast straining, classified as either absent or present. 
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. 
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 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 83 of 84 

 
S2356  
 
 
 
 
 
  Form/Template 90702637 Rev/Ver AH 
Confidential                     EVOLVE 48 Clinical Investigational Plan, 92149705, Rev/Ver A  
                                                                                                                       Page 84 of 84 
  
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 and 
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. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92149705 A.1
EVOLVE 48 Protocol
Page 84 of 84