BIOTRONIK - A Prospective Randomized Multicenter Study to Assess the SaFety and Effectiveness of the Orsiro SiroLimus Eluting Coronary Stent System in the Treatment Of Subjects With up to Three De Novo or Restenotic Coronary Artery Lesions - V
Phase: NA
Conditions: Coronary Artery Disease, Atherosclerosis, Coronary, Myocardial Ischemia, Ischemic Heart Disease, Acute Coronary Syndrome, Angina Pectoris
Sponsor: Biotronik, Inc.

 
 
 
 
 
 
 
 
BIOFLOW-V: 
BIOTRONIK – A Prospective Randomized Multicenter Study to 
Assess the SaFety and Effectiveness of the Orsiro SiroLimus 
Eluting Coronary Stent System in the Treatment Of Subjects With 
up to Three De Novo or Restenotic Coronary Artery Lesions – V 
 
 
 
Clinical Investigational Plan 
Final Version 4.0, February 11, 2016 
 
IDE#G140078 
 
 
 
 
 
 
 
 
This document contains confidential information for use only by investigators 
participating in the clinical study.  Therefore, this document should be maintained in a 
secure location and should not be copied or made available for review by any 
unauthorized personnel. 

 
 
 
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Investigational Device 
Orsiro Sirolimus Eluting Coronary Stent System 
Sponsor and 
Manufacturer 
BIOTRONIK, Inc. 
Vascular Intervention Clinical Studies 
6024 Jean Road 
Lake Oswego, Oregon 97035 
United States of America 
BIOTRONIK AG 
Center for Vascular Intervention 
Ackerstrasse 6 
8180 Bülach 
Switzerland 
Sponsor Contact 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Development 
Harvard Clinical Research Institute 
 
 
 
 
 
 

 
 
 
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STUDY PRINCIPAL INVESTIGATORS SIGNATURE PAGE 
 
IDE# G140078 
 
I, the undersigned, have read and understood the Clinical Investigational Plan for 
the study entitled: 
 
 
BIOFLOW-V: 
BIOTRONIK – A Prospective Randomized Multicenter Study to Assess the SaFety and 
Effectiveness of the Orsiro SiroLimus Eluting Coronary Stent System in the Treatment 
Of Subjects With up to Three De Novo or Restenotic Coronary Artery Lesions – V 
 
 
BIOTRONIK, Inc. 
BIOTRONIK AG 
 
And agree with its contents. I declare that I will comply with all the Clinical 
Investigational Plan’s requirements. The Clinical Investigational Plan, the 
Investigator’s Agreement and any additional information provided by BIOTRONIK 
will serve as a basis for cooperation in the clinical investigation 
 
 
US Study Principal 
Investigator 
 
Investigator’s Signature 
 
Date 
 
 
 
OUS Study Principal 
Investigator 
 
Investigator’s Signature 
 
Date 
 
 
 

 
 
 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
IDE# G140078 
 
I have reviewed this protocol for the study entitled: 
 
 
BIOFLOW-V: 
BIOTRONIK – A Prospective Randomized Multicenter Study to Assess the SaFety and 
Effectiveness of the Orsiro SiroLimus Eluting Coronary Stent System in the Treatment 
Of Subjects With up to Three De Novo or Restenotic Coronary Artery Lesions – V 
 
 
BIOTRONIK, Inc. 
BIOTRONIK AG 
 
 
The signature below documents the receipt and review of the BIOFLOW-V clinical 
study protocol and any attachments, and provides the necessary assurances that 
this study will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal 
and regulatory requirements and applicable US Federal Regulations, ISO 14155, 
ICH and GCP guidelines 
 
 
Investigator Name (print or type) 
 
Investigator’s Signature 
 
Date 
 
 
 
 
 

 
 
 
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Table of Contents 
 
1. 
Protocol Synopsis ................................................................................................ 10 
2. 
Study Administration ........................................................................................... 17 
3. 
Introduction .......................................................................................................... 20 
3.1. 
Investigational Device Description ............................................................... 21 
3.1.1. 
PRO-Kinetic Energy Stent ....................................................................... 21 
3.1.2. 
Sirolimus .................................................................................................. 23 
3.1.3. 
Poly-L-Lactic Acid .................................................................................... 24 
3.1.4. 
Delivery System ....................................................................................... 25 
3.1.5. 
Investigational Device Matrix ................................................................... 25 
3.2. 
Control Device Description .......................................................................... 26 
3.2.1. 
Control Device Matrix............................................................................... 26 
3.3. 
Indications for Use ....................................................................................... 26 
3.4. 
Contraindications ......................................................................................... 27 
3.5. 
Orsiro Clinical Data Summary ..................................................................... 27 
4. 
Study Objectives and Endpoints ........................................................................ 32 
4.1. 
Study Objectives ......................................................................................... 32 
4.2. 
Primary Endpoint ......................................................................................... 32 
4.3. 
Secondary Endpoints .................................................................................. 32 
5. 
Study Design ........................................................................................................ 33 
5.1. 
Clinical Sites ................................................................................................ 34 
5.2. 
Number of Subjects ..................................................................................... 34 
5.3. 
Study Participation Status ........................................................................... 34 
5.3.1. 
Status Definitions ..................................................................................... 34 
5.3.2. 
Subject Study Exit .................................................................................... 35 
5.3.2.1. 
Subject Lost to Follow-up ................................................................. 36 
6. 
Subject Selection ................................................................................................. 38 
6.1. 
Eligibility Criteria .......................................................................................... 38 
6.1.1. 
Clinical Inclusion Criteria .......................................................................... 38 
6.1.2. 
Angiographic Inclusion Criteria ................................................................ 38 
6.1.3. 
Clinical Exclusion Criteria ........................................................................ 39 
6.1.4. 
Angiographic Exclusion Criteria ............................................................... 40 

 
 
 
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7. 
Trial Procedures and Assessments ................................................................... 42 
7.1. 
Schedule of Events ..................................................................................... 42 
7.2. 
Screening and Baseline Procedures ........................................................... 44 
7.3. 
Concomitant Medications ............................................................................ 45 
7.4. 
Index Procedure .......................................................................................... 47 
7.4.1. 
Subject Preparation and Baseline Angiography ....................................... 47 
7.4.1. 
Randomization ......................................................................................... 47 
7.4.2. 
Target Lesion(s) Pre-Dilatation ................................................................ 47 
7.4.3. 
Stenting .................................................................................................... 48 
7.4.4. 
End of Procedure ..................................................................................... 48 
7.4.5. 
Bailout Procedures .................................................................................. 49 
7.4.6. 
Bailout-Staged Procedure ........................................................................ 49 
7.5. 
Post-Procedure to Hospital Discharge ........................................................ 49 
7.5.1. 
Immediately Post-Procedure .................................................................... 49 
7.5.2. 
Clinical and Laboratory Assessments ...................................................... 49 
7.6. 
Antiplatelet/Anticoagulation Regimen .......................................................... 50 
7.7. 
Follow-Up Assessments .............................................................................. 50 
7.7.1. 
One (1) Month Clinical Follow-Up (30 ± 7 Days) ...................................... 51 
7.7.2. 
Six (6) Month Clinical Follow-Up (180 ± 14 Days) ................................... 51 
7.7.3. 
Twelve (12) Month Clinic Visit (360 ± 30 Days) ....................................... 51 
7.7.4. 
Long-Term Clinical Follow-Up at 2, 3, 4 and 5 Years Post-Procedure 
(Annually ± 60 Days) .............................................................................................. 52 
7.8. 
Unscheduled Study Visit.............................................................................. 52 
7.9. 
Angiographic Core Laboratory ..................................................................... 52 
8. 
Statistical Considerations and Analysis Plan .................................................... 53 
8.1. 
Prior Data .................................................................................................... 53 
8.2. 
Bayesian Analysis ....................................................................................... 55 
8.3. 
Software ...................................................................................................... 55 
8.4. 
Criteria for Success ..................................................................................... 56 
8.5. 
Sample Size Determination ......................................................................... 56 
8.6. 
Statistical Analysis Sets............................................................................... 60 
8.6.1. 
Intent-to-Treat Analysis Population .......................................................... 60 

 
 
 
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8.6.2. 
Per-Protocol Population ........................................................................... 60 
8.7. 
Endpoint Analyses and Reporting of Results .............................................. 60 
8.8. 
Analysis of Primary Endpoint ....................................................................... 60 
8.9. 
Handling of Missing Data in the Analysis of Primary Endpoint .................... 62 
8.10. Analysis of Secondary Endpoints ................................................................ 63 
8.11. Analysis of Baseline Demographics and Procedural Characteristics .......... 64 
8.12. Subgroup Analysis ...................................................................................... 64 
9. 
Adverse Events .................................................................................................... 65 
9.1. 
Definitions .................................................................................................... 65 
9.1.1. 
Adverse Events ........................................................................................ 65 
9.1.2. 
Adverse Device Effect.............................................................................. 65 
9.1.3. 
Serious Adverse Event ............................................................................ 66 
9.1.4. 
Serious Adverse Device Effect ................................................................ 66 
9.1.5. 
Anticipated Adverse Event ....................................................................... 66 
9.1.6. 
Unanticipated Adverse Device Effect or Unanticipated Serious Adverse 
Device Effect .......................................................................................................... 67 
9.1.7. 
Device Failures, Malfunctions and Misuse ............................................... 67 
9.2. 
Documentation ............................................................................................ 67 
9.3. 
Relatedness ................................................................................................ 68 
9.4. 
Reporting of Serious Adverse Events .......................................................... 68 
9.5. 
Reporting of Adverse Events ....................................................................... 69 
9.5.1. 
Reporting Adverse Device Effects ........................................................... 70 
9.5.2. 
Reporting of Unanticipated Adverse Device Effects or Unanticipated 
Serious Adverse Device Effects ............................................................................. 70 
9.6. 
Reporting of Study Endpoint Adverse Events .............................................. 71 
9.7. 
Reporting Responsibilities ........................................................................... 72 
10. 
Data Handling and Record Keeping ................................................................ 74 
10.1. Electronic Data Capture .............................................................................. 74 
10.2. Electronic Case Report Form Completion ................................................... 74 
10.3. Investigator Records ................................................................................... 74 
10.4. Sponsor Records ......................................................................................... 75 
11. 
Study Committees ............................................................................................ 75 
11.1. Steering Committee ..................................................................................... 75 

 
 
 
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11.2. Data Monitoring Committee ......................................................................... 76 
11.3. Clinical Events Committee ........................................................................... 76 
12. 
Ethical and Regulatory Considerations .......................................................... 77 
12.1. Role of the Study Sponsor ........................................................................... 77 
12.2. General Duties ............................................................................................ 77 
12.3. Subject Confidentiality ................................................................................. 77 
12.4. Informed Consent and Institutional Review Board or Ethics Committee ..... 78 
12.5. Monitoring .................................................................................................... 78 
12.5.1. Visits ........................................................................................................ 78 
12.6. Protocol Compliance ................................................................................... 79 
12.6.1. Protocol Violations ................................................................................... 79 
12.6.2. Protocol Deviations .................................................................................. 80 
12.7. Device Accountability and Storage .............................................................. 80 
12.7.1. Labeling ................................................................................................... 80 
12.8. Supplemental Applications .......................................................................... 81 
12.9. Other Institutions and Physicians ................................................................ 81 
12.10. 
Subject Insurance .................................................................................... 81 
13. 
Risk Analysis .................................................................................................... 82 
13.1. Potential Risks ............................................................................................. 82 
13.2. Potential Benefits ........................................................................................ 83 
13.3. Risk Mitigation ............................................................................................. 83 
13.4. Sex and Gender in Coronary Heart Disease ............................................... 84 
14. 
Use of Information and Publication ................................................................ 85 
15. 
Premature Termination of the Study ............................................................... 86 
16. 
Appendix A: Abbreviations and Acronyms .................................................... 87 
17. 
Appendix B: Definitions ................................................................................... 90 
18. 
References ...................................................................................................... 108 
 
 
 

 
 
 
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List of Tables 
 
Table 3-1. Orsiro Stent System – Device Matrix for the BIOFLOW-V Study ................. 25 
Table 3-2. Xience Family of Stent Systems – Devices Matrix for the BIOFLOW-V Study
 ...................................................................................................................................... 26 
Table 3-3. Orsiro Clinical Trials Summary ..................................................................... 28 
Table 7-1. Schedule of Events ...................................................................................... 42 
Table 7-2. Concomitant Medication Regimen Recommendations ................................. 46 
Table 8-1. Subjects’ Poolability ..................................................................................... 55 
Table 8-2. TVF/MACE Rates at 9 or 12 Months, DES vs. BMS .................................... 58 
Table 9-1. Adverse Events Reporting ............................................................................ 69 
Table 9-2. Investigator Reporting Responsibilities ........................................................ 72 
Table 9-3. Sponsor Reporting Responsibilities ............................................................. 73 
 
List of Figures 
 
Figure 3-1. Image of Orsiro/PRO-Kinetic Energy Stent ................................................. 22 
Figure 3-2. Metal Ion Release with PROBIO® Coating .................................................. 23 
Figure 3-3: Structural Formula of Sirolimus ................................................................... 23 
Figure 3-4. Orsiro Sirolimus Eluting Stent System ........................................................ 25 
Figure 5-1. Trial Design of the BIOFLOW-V Trial .......................................................... 34 
Figure 6-1. Clinical Study Design Flowchart .................................................................. 41 
 
 
 

 
 
 
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1. PROTOCOL SYNOPSIS 
STUDY TITLE 
BIOFLOW-V: 
BIOTRONIK 
– 
A 
Prospective 
Randomized 
Multicenter Study to Assess the SaFety and Effectiveness of the 
Orsiro SiroLimus Eluting Coronary Stent System in the Treatment 
Of Subjects With up to Three De Novo or Restenotic Coronary 
Artery Lesions – V. 
INVESTIGATIONAL 
DEVICE 
BIOTRONIK Orsiro Sirolimus Eluting Coronary Stent System. 
OBJECTIVES 
To assess the safety and efficacy of the Orsiro Sirolimus Eluting 
Coronary Stent System in the treatment of subjects with up to 
three native de novo or restenotic (standard PTCA only) coronary 
artery lesions compared to the Xience coronary stent system. 
STUDY DESIGN 
BIOFLOW-V is a prospective, multicenter, randomized, controlled 
trial combining data on the randomized subjects with data from two 
historical studies by employing a Bayesian approach. 
Subjects with coronary artery disease (CAD) that qualify for 
percutaneous coronary intervention (PCI) with stenting will be 
screened per the protocol inclusion and exclusion criteria to 
achieve a total of up to 1,400 randomized subjects.  Eligible 
subjects will be randomized in a 2:1 ratio to undergo percutaneous 
coronary revascularization with either the Orsiro Sirolimus Eluting 
Stent System (treatment group) or the Xience Everolimus Eluting 
Stent System (control group). 
BIOFLOW-V randomized subjects will be combined with historical 
Orsiro, Xience Prime™ and Xience Xpedition™ randomized 
subjects from the BIOFLOW-II and BIOFLOW-IV trials by 
employing a Bayesian statistical approach.  Only subjects that 
meet all clinical and angiographic eligibility criteria of the 
BIOFLOW-V trial will be included in the analysis. 
SUBJECT 
POPULATIONS 
Subjects with CAD due to de novo lesions or restenotic lesions 
from percutaneous transluminal coronary angioplasty (PTCA) in 
native coronary arteries with a reference vessel diameter of 2.25–
4.0 mm and lesion length of ≤ 36 mm. 
NUMBER OF 
SUBJECTS 
Sufficient number of subjects will be provisionally enrolled in the 
trial to achieve a total of up to 1,400 randomized subjects (933 
Orsiro: 467 Xience).  It is expected that approximately 50% will be 
enrolled in the United States. 
NUMBER OF 
CLINICAL SITES 
Up to 100 clinical sites in the United States and 50 clinical sites 
outside of the United States. 
 
 

 
 
 
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CLINICAL 
INCLUSION 
CRITERIA 
Subjects must meet all of the following criteria to participate in the 
trial: 
1. Subject is ≥18 years or the minimum age required for legal 
adult consent in the country of enrollment. 
2. Subject is an acceptable candidate for PCI. 
3. Subject is an acceptable candidate for CABG. 
4. Subject has clinical evidence of ischemic heart disease, 
stable or unstable angina pectoris or documented silent 
ischemia. 
5. Subject is eligible for dual anti-platelet therapy treatment 
with aspirin plus either, clopidogrel, prasugrel, ticagrelor or 
ticlopidine. 
6. Subject has provided written informed consent. 
7. Subject 
is 
willing 
to 
comply 
with 
study 
follow-up 
requirements. 
ANGIOGRAPHIC 
INCLUSION 
CRITERIA 
Each target lesion/vessel must meet all of the following 
angiographic criteria for the subject to be eligible for the trial: 
1. Subject has up to three target lesions in up to two separate 
target vessels (two target lesions in one vessel and one 
target lesion in a separate vessel). 
2. Target lesion must be de novo or restenotic lesion in native 
coronary artery; restenotic lesion must have been treated 
with a standard PTCA only. 
3. Target lesion must be in major coronary artery or branch 
(target vessel). 
4. Target lesion must have angiographic evidence of ≥ 50% 
and < 100% stenosis (by operator visual estimate).
If the target lesion is < 70% stenosed, there should be 
clinical evidence of ischemia such as a positive functional 
study (e.g. exercise treadmill test, thallium stress test, 
SPECT, or stress echo), cardiac computed tomography 
(CT), electrocardiography, fractional flow reserve, or post 
infarct angina. 
5. Target vessel must have a Thrombolysis In Myocardial 
Infarction (TIMI) flow > 1. 
6. Target lesion must be ≤ 36 mm in length by operator visual 
estimate. 
7. Target vessel must have a reference vessel diameter of 

 
 
 
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2.25–4.0 mm by operator visual estimate. 
ANGIOGRAPHIC 
INCLUSION 
CRITERIA (CONT.) 
8. Target lesion must be amenable to treatment with a 
maximum of two overlapping stents. 
CLINICAL 
EXCLUSION 
CRITERIA 
Subjects will be excluded from the trial if any of the following 
criteria are met: 
1. Subject has clinical symptoms and/or electrocardiogram 
(ECG) changes consistent with acute ST elevation 
myocardial infarction (STEMI) within 72 hours prior to the 
index procedure. 
Note:  Hemodynamically stable non-STEMI (NSTEMI) subjects 
are eligible for study enrollment.  
2. Subject is hemodynamically unstable. 
3. Subject is pregnant and/or breastfeeding or intends to 
become pregnant during the duration of the study. 
4. Subject has a known allergy to contrast medium that cannot 
be adequately pre-medicated, or any known allergy to 
thienopyridine, aspirin, both heparin and bivalirudin, L-605 
cobalt-chromium (Co-Cr) alloy or one of its major elements 
(cobalt, 
chromium, 
tungsten 
and 
nickel), 
acrylic, 
fluoropolymers, 
silicon 
carbide, 
PLLA, 
sirolimus 
or 
everolimus. 
5. Revascularization of any target vessel within 9 months prior 
to the index procedure or previous PCI of any non-target 
vessel within 30 days prior to the index procedure. 
6. Planned treatment of a lesion not meeting angiographic 
inclusion and exclusion criteria during the index procedure 
or after the index procedure. 
7. Planned surgery within 6 months of index procedure unless 
dual antiplatelet therapy can be maintained throughout the 
peri-surgical period. 
8. History of a stroke or transient ischemic attack (TIA) within 6 
months prior to the index procedure. 
9. Subjects 
with 
active 
bleeding 
disorders, 
active 
coagulopathy, or any other reason, who are ineligible for 
DAPT. 
10. Subject will refuse blood transfusions. 
11. Subject has documented left ventricular ejection fraction 
(LVEF) 
< 
30% 
as 
evaluated 
by 
angiography, 

 
 
 
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echocardiogram, radionuclide ventriculography or any non-
invasive imaging method within 90 days prior to the index 
procedure. 
CLINICAL 
EXCLUSION 
CRITERIA (CONT.) 
12. Subject is dialysis-dependent. 
13. Subject has impaired renal function (i.e., blood creatinine > 
2.5 mg/dL or 221 μmol/L determined within 7 days prior to 
the index procedure). 
14. Subject has leukopenia (i.e. < 3,000 white blood cells/mm3), 
thrombocytopenia 
(i.e. 
< 
100,000 
platelets/mm3) 
or 
thrombocytosis (i.e. > 700,000 platelet/mm3). 
15. Subject is receiving oral or intravenous immunosuppressive 
therapy (inhaled steroids are permitted), or has known life-
limiting immunosuppressive or autoimmune disease (e.g., 
human 
immunodeficiency 
virus, 
systemic 
lupus 
erythematosus; diabetes mellitus is permitted). 
16. Subject is receiving chronic anticoagulation (e.g. coumadin, 
dabigatran, apixaban, rivaroxaban or any other agent). 
17. Subject has life expectancy of < 1 year. 
18. Subject is participating in another investigational (medical 
device or drug) clinical study.  Subjects may be concurrently 
enrolled in a post-market study, as long as the post-market 
study device, drug or protocol does not interfere with the 
investigational treatment or protocol of this study. 
19. In the investigator’s opinion, subject will not be able to 
comply with the follow-up requirements. 
ANGIOGRAPHIC 
EXCLUSION 
CRITERIA 
Subjects will be excluded from the trial if any of the target 
lesions/vessels meets any of the following angiographic criteria: 
1. Target lesion is located within a saphenous vein graft or arterial 
graft. 
2. Target lesion is a restenotic lesion that was previously treated 
with a bare metal or drug eluting stent (in-stent restenosis). 
3. Target lesion has any of the following characteristics: 
a. Lesion location is within the left main coronary artery, or 
within 3 mm of the origin of the left anterior descending 
(LAD) or left circumflex (LCX). 
b. Involves a side branch of > 2.0 mm in diameter.  
Note: Lesions within 3 mm of the origin of the right coronary 
artery may be treated. 

 
 
 
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4. Target vessel/lesion is excessively tortuous/angulated or is 
severely calcified, that would prevent complete inflation of an 
angioplasty balloon.  This assessment should be based on 
visual estimation. 
ANGIOGRAPHIC 
EXCLUSION 
CRITERIA (CONT.) 
5. Target vessel has angiographic evidence of thrombus. 
6. Target lesion is totally occluded (100% stenosis). 
7. Target vessel was treated with brachytherapy any time prior to 
the index procedure. 
PRIMARY 
ENDPOINT 
Target lesion failure (TLF) rate at 12 months post–index 
procedure.  TLF is defined as all cardiac death, target vessel Q-
wave or non–Q-wave myocardial infarction (MI), or clinically driven 
target lesion revascularization (TLR). 
SECONDARY 
ENDPOINTS  
Secondary endpoints include the following measures: 
1. Device success, defined as attainment of < 30% residual 
stenosis of the target lesion using the assigned study stent 
only. 
Note: Post-dilatation is allowed to achieve device success. 
2. Lesion success, defined as attainment of < 30% residual 
stenosis of the target lesion using any percutaneous 
method. 
3. Procedure success, defined as attainment of < 30% residual 
stenosis of the target lesion using the assigned study stent 
only without occurrence of in-hospital major adverse cardiac 
events (MACE; composite of all-cause death, Q-wave or 
non–Q-wave MI, and any clinically-driven TLR). 
The following secondary clinical endpoints will be evaluated prior 
to discharge, at 1, 6 and 12 months and annually thereafter 
through 5 years follow-up: 
4. Death. 
5. MI. 
6. Cardiac death or MI. 
7. MACE 
and 
individual 
MACE 
components 
(MACE: 
composite of all-cause death, Q-wave or non–Q-wave MI, 
and any clinically-driven TLR). 
8. TLF and individual TLF components (TLF: composite of 
cardiac death, target vessel Q-wave or non–Q-wave MI, and 
any clinically-driven TLR). 
9. Target vessel failure (TVF) and individual TVF components 

 
 
 
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(TVF: composite of cardiac death, target vessel Q-wave or 
non–Q-wave MI, and any clinically-driven TVR). 
SECONDARY 
ENDPOINTS 
(CONT.) 
10. Stent thrombosis (all, definite, definite/probable, probable, 
possible) according to Academic Research Consortium 
(ARC) criteria for acute, subacute, late, very late and 
cumulative stent thrombosis. 
SUBJECTS 
FOLLOW-UP 
Randomized subjects will be followed through 5 years post–index 
procedure, with clinical follow-up at 1 month, 6 months, 12 months 
and annually thereafter through 5-years.  An office visit is required 
for the 12-month follow-up.  All visits except the 12-month visit may 
be performed by telephone interview. 
TREATMENT 
STRATEGY 
 Eligible subjects will be randomized in a 2:1 ratio to receive 
either the Orsiro Sirolimus Eluting Stent or the Xience 
Everolimus Eluting Stent.  Randomization will be stratified 
by study center. 
 Subjects may receive treatment for up to three target 
lesions, one or two target lesions per target vessel, for a 
maximum of two target vessels.  
Note: Concurrent treatment of non-target lesions during the 
index procedure is not allowed. 
 All target lesions are to be treated with the assigned study 
stent per randomization. 
 All target lesions are to be treated during a single index 
procedure. Pre-dilatation of the target lesion(s) must be 
performed.  Direct stenting of the target vessel(s) is not 
allowed.    
 Post-dilatation may be performed at the investigator’s 
discretion. 
 Cardiac biomarkers CK and/or CKMB (CKMB is required [or 
troponin if CKMB is not available]) will be measured at 6–24 
hours post index procedure.   
 Dual antiplatelet therapy (DAPT) is recommended for a 
minimum of 6 months and highly recommended for 12 
months in subjects not at a high risk of bleeding. 
 All subjects will receive a minimum of 150 mg aspirin within 
24 hours prior to the procedure and continued on a 
minimum of 75 mg aspirin daily indefinitely post-procedure. 
 Subjects will receive a loading dose of 600 mg clopidogrel, 
within 24 hours prior to the procedure or immediately post-
procedure (within 30 minutes).  Clopidogrel may be 
substituted with prasugrel at a loading dose of 60 mg or 

 
 
 
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ticagrelor at a loading dose of 180 mg.  No loading dose is 
required for subjects on chronic thienopyridine therapy.   
Following the procedure, subjects will receive treatment with 
the same thienopyridine agent for a minimum of 6 months, 
highly recommended for 12 months for subjects not at high 
risk for bleeding, as follows: 
Clopidogrel: 75 mg daily  
Prasugrel: 10 mg daily; a lower dose of 5 mg daily is 
allowed for subjects < 60 kg.  
Ticagrelor: 90 mg twice daily. 
Ticlopidine: 250 mg twice daily. 
OUS investigators may follow medication administration 
recommendations in accordance with the European Society 
of Cardiology (ESC) guidelines, national guidelines and/or 
hospital standard of care. 
 
 

 
 
 
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2. STUDY ADMINISTRATION 
SPONSOR 
BIOTRONIK, Inc. 
Vascular Intervention Clinical Studies 
6024 Jean Road 
Lake Oswego, Oregon 97035 
United States of America 
 
 
 
 
 
 
BIOTRONIK AG 
Center for Vascular Intervention 
Ackerstrasse 6 
8180 Bülach 
Switzerland 
 
 
 
US STUDY PRINCIPAL 
INVESTIGATOR 
 
 
 
OUS STUDY PRINCIPAL 
INVESTIGATOR 
 
 
 
STEERING COMMITTEE 
CHAIRPERSON 
 
 
ELECTRONIC DATA 
CAPTURE VENDOR 
 
MedNet Solutions, Inc. 
110 Cheshire Lane  
Minnetonka, Minnesota 55305 

 
 
 
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United States of America 
DATA COORDINATING 
CENTER  
 
Harvard Clinical Research Institute 
930 Commonwealth Ave 
Boston, Massachusetts 02215 
United States of America 
 
 
 
 
 
STATISTICAL CENTER 
Harvard Clinical Research Institute 
930 Commonwealth Avenue 
Boston, Massachusetts 02215 
United States of America 
 
DATA MONITORING 
COMMITTEE 
CHAIRPERSON 
 
 
 
  
 
 
 
CLINICAL EVENTS 
COMMITTEE 
 
Harvard Clinical Research Institute 
930 Commonwealth Avenue 
Boston, Massachusetts 02215 
United States of America 
 
 
 
 
 
ANGIOGRAPHIC CORE 
LABORATORY 
 
MedStar Health Research Institute 
CRI Angiographic Core Lab 
Washington Hospital Center 
110 Irving St, NW, Suite 4B-1, 
Washington, District of Columbia 20010, USA 
United States of America 
 
 

 
 
 
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MONITORING 
 
Harvard Clinical Research Institute 
930 Commonwealth Avenue 
Boston, Massachusetts 02215 
United States of America 
 
 
 
 
 
 
 
 
 
   
 
 
 
BIOTRONIK AG 
Center for Vascular Intervention 
Ackerstrasse 6 
8180 Bülach 
Switzerland 
BIOTRONIK, Inc. 
Vascular Intervention Clinical Studies 
6024 Jean Road 
Lake Oswego, Oregon 97035 
United States of America 
 
 

 
 
 
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3. INTRODUCTION 
Each year, approximately 7.2 million people worldwide die from coronary artery disease 
(CAD),1 with 11.1 million deaths per year projected by 2020.2 Since the first 
percutaneous transluminal coronary angioplasty (PTCA), this procedure has become a 
widely accepted treatment modality for coronary artery disease.  For the majority of 
patients with CAD, treatment with PTCA provides high initial procedural success, 
symptomatic relief, improvement in functional capacity, and survival rates similar to 
those of coronary artery bypass grafting (CABG).  However, all percutaneous 
techniques, regardless of mode of intervention, have relatively high rates of repeat 
interventions at long-term follow-up, a limitation that is attributable to restenosis or 
angiographic re-narrowing of the vessel’s lumen.3 Distinct from atherosclerotic lesions, 
restenosis following conventional angioplasty results from elastic recoil, vessel 
contraction, thrombus formation, smooth muscle cell proliferation and excessive 
production of extracellular matrix.  Depending on the subject population and 
angiographic diagnostic criteria, reported incidence of restenosis after PTCA ranges 
from 30% to 50%.4 Such rates of recurrence have serious economic consequences. 
The first type of stent used in percutaneous coronary intervention (PCI) was a bare 
metal stent (BMS), designed to address restenosis following PTCA.5 BMS reduced the 
angiographic and clinical restenosis rates in de novo lesions compared with PTCA 
alone as well as decreased the need for CABG.  BMS substantially reduced the 
incidence of abrupt artery closure, but restenosis still occurred in about 15% to 30% of 
cases, necessitating repeat procedures.6,7,8,9 
The development of drug eluting stents (DES) significantly improved on the principle of 
BMS by adding an antiproliferative drug that is either directly immobilized on the stent 
surface or released from a polymer matrix, allowing for controlled drug release at the 
site of injury to inhibit neointimal hyperplasia.  The introduction of DES greatly reduced 
incidence of restenosis and resulted in a better safety profile compared with BMS with 
systemic drug administration.  These advantages and lower cost compared with surgical 
interventions made DES an attractive option for treating coronary artery disease.10 
However, despite significant improvement in revascularization rates, certain clinical 
events were reported more frequently for DES compared with BMS,11,12 especially late 
and very late stent thrombosis, a life-threatening complication that relates to occurrence 
of myocardial infarction (MI) and death.13,14 The pathophysiology of very late stent 
thrombosis includes hypersensitivity, inflammatory infiltrates, delayed endothelialization, 
delayed vascular healing, malapposed and uncovered struts, and vessel remodeling 
due to inflammation and neoartherosclerosis, which are more common with DES than 
BMS.15,16,17,18,19 
To address these limitations, newer technologies have been developed, including BMS 
with thinner struts of cobalt-chromium and passive coating, fully absorbable stents, 
second-generation DES with improved stent design and new limus analogues, and DES 
with biodegradable polymers.  Unlike non-biodegradable polymers, which reside on the 
surface of the stent indefinitely, biodegradable polymers dissolve after a certain period 

 
 
 
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of time, leaving only the BMS platform in the vessel wall, which is designed to improve 
late clinical incomes by reducing inflammation burden and improving arterial healing.20 
Several randomized controlled trials have demonstrated better late clinical outcomes 
among subjects receiving DES with biodegradable polymers compared with DES with 
conventional durable polymers.21,22,23 Nine-month follow-up data from the LEADERS 
trial, involving 1,707 subjects randomized to a biolimus eluting stent with a 
biodegradable polymer or to a sirolimus eluting stent with a durable polymer, 
demonstrated no significant difference in the primary endpoint of major adverse cardiac 
events (MACE; includes cardiac death, MI or target-vessel revascularization; 9.2% vs. 
10.5%).24 Furthermore, an optical coherence tomography (OCT) sub-study at 9 months 
demonstrated a statistically significant lower rate of uncovered struts for subjects 
treated with a biolimus eluting stent with biodegradable polymer,25 and 4-year data 
demonstrated superiority of the stent with biodegradable polymer with respect to MACE  
(18.7% vs. 22.6%).26 A marked reduction of stent thrombosis was also observed (80% 
relative risk reduction of very late stent thrombosis), with a statistically significant 
(superiority) difference in definite stent thrombosis between 1 and 4 years (0.4% vs. 
2.0%). 
3.1. Investigational Device Description 
The ORSIRO stent system is a drug eluting balloon expandable stent, mounted on a 
delivery system.  It is a combination product comprised of two regulated components: 
1. The device:   
 Bare Metal Stent:  PRO-Kinetic Energy (PKE) Stent (IDE# G110147) 
 Delivery System:  Fast-exchange with a Polyamide 12 semi-compliant balloon 
2. The drug-polymer coating:  
 A formulation of the drug substance Sirolimus with  
 A bioresorbable Poly-L-lactic acid (PLLA) polymer excipient 
Full details can be found in the Instructions for Use (IFU) that are provided with each 
system. 
3.1.1. PRO-Kinetic Energy Stent 
The backbone of the Orsiro stent system is the PRO-Kinetic Energy stent, the BMS 
platform of which is left in the vessel wall after the biodegradable polymer has 
dissolved.  It is a tubular, balloon-expandable stent sculpted by laser from a single tube 
of L-605 Co-Cr alloy.  As shown in Figure 3-1, the stent consists of circular segments at 
each end, followed by a transition zone and helicoidally arranged struts in the middle.  
Each loop of the helix is connected to the next loop by 3 longitudinal struts.  The stent 
surface is fully coated with a layer of amorphous silicon carbide (PROBIO®). 
 
 

 
 
 
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Figure 3-1. Image of Orsiro/PRO-Kinetic Energy Stent 
 
The PRO-Kinetic ENERGY stent received CE marking in September 2008.  
BIOTRONIK is conducting an investigational device exemption (IDE) study in the United 
States to evaluate the safety and efficacy of the PRO-Kinetic Energy stent (IDE 
#G110147). 
Outside of the United States, BIOTRONIK conducted a multicenter, prospective, non-
randomized observational registry (ENERGY Registry) to evaluate long-term safety and 
clinical performance of the Co-Cr PRO-Kinetic Energy Coronary Stent System in a large 
patient population.  The primary endpoint for the ENERGY registry is 6-month MACE 
rate, which includes cardiac death, clinically-driven target lesion revascularization (TLR) 
and MI/acute MI (ST-elevated/non–ST-elevated).  A total of 1,016 subjects with 1,074 
lesions in 48 centers were enrolled from April to November 2010.  Clinical follow-up was 
scheduled at 6 and 12 months.  Six-month clinical data were available for 986 enrolled 
subjects and 12-month data were available for 916 subjects. 
At 6 months, MACE rate was 6.3% (62/986), including a 3.7% (36/986) rate of TLR; no 
probable stent thrombosis; and a 0.9% (9/986) rate of definite and possible stent 
thrombosis.  At 12 months, MACE rate was 8.8% (81/916), including a 4.6% (42/916) 
rate of TLR; no probable stent thrombosis; and a 1.1% (10/916) rate of definite and 
possible stent thrombosis.  Major adverse cardiac events at 12 months in pre-defined 
subgroups included 11.4% (17/149) for subjects with diabetes, 7.0% (16/229) for small 
vessels, and 9.5% (40/419) for subjects with acute coronary syndrome.  There was no 
statistically significant difference between these subgroups. 
PROBIO® Coating 
The entire surface of the underlying bare-metal stent is coated with amorphous silicon 
carbide that is saturated with hydrogen (a-SiC:H), referred to as PROBIO® coating, in a 
physical vapor deposition process.  The coating has a transparent appearance with a 
thickness in the range of 100 nm.  The a-SiC:H-coating material has been used since 
2000 on all of BIOTRONIK’s coronary stents, including the Rithron XR coronary stent 
system approved for commercial distribution in the United States on April 29, 2005 
(P030037), the Astron, Astron Pulsar, and Pulsar-18 Nitinol stents being evaluated in an 
IDE clinical study (IDE#G100002), and the PRO-Kinetic Energy stent being evaluated in 
an IDE clinical study (IDE #G110147). 

 
 
 
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The silicon carbide material encapsulates the stent and minimizes interaction between 
the metal stent and surrounding tissue.  Finally, the release of potentially allergenic ions 
from a silicon carbide–coated stent is reduced in comparison to an uncoated metal stent 
(Figure 3-2).   
Figure 3-2. Metal Ion Release with PROBIO® Coating 
 
In vitro studies have shown up to 96% reduction of allergenic metal ions when the stent surface is coated 
with silicon carbide (data on file, BIOTRONIK AG). 
3.1.2. Sirolimus 
Sirolimus is the drug substance utilized in the Orsiro stent system.  It is a natural 
macrocyclic lactone (Figure 3-3), first isolated from Streptomyces hygroscopicus in the 
mid-1970s.  It was approved by the US Food and Drug Administration (FDA) for 
prophylaxis of renal transplant rejection in 
1999. 
 
Sirolimus 
has 
potent 
antiproliferative, 
anti-inflammatory 
and 
immunosuppressive effects.  It acts by 
inhibiting activation of mammalian target 
of rapamycin (mTOR), ultimately causing 
arrest of the cell cycle by preventing 
progression from phase G1 to S.  The 
restenosis process is thus inhibited due to 
decreased proliferation of T cells as well 
as decreased proliferation and migration 
of smooth muscle cells.27,28 Sirolimus 
eluting stents have been shown to reduce 
neointimal thickening compared with both 
BMS and polymer-coated stents, in a 
broad array of various animal models and 
clinical studies.29,30,31,32,33 
Competitor A 
cobalt nickel alloy
Competitor B 
cobalt chromium alloy
Cobalt
Nickel
Tungsten
Chromium
PRO-Kinetic Energy 
with PROBIO® coating
25 000
20 000
15 000
10 000
5 000
0
Concentration in ng/l
Figure 3-3: Structural Formula of 
Sirolimus 

 
 
 
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The first DES to be approved for marketing was the Cypher Sirolimus Eluting Stent 
System.  The Cypher stent is associated with significant improvement in angiographic 
outcomes, including reduced rates of restenosis and need for revascularization 
compared with BMS,10,34 with durable benefit for up to 5 years based on current clinical 
data.  The efficacy of the Cypher and the improved Cypher Select+ Sirolimus Eluting 
Stent Systems (SESS) has been proven in populations ranging from highly selected 
subjects with single de novo lesions to unselected all-comers.35,36,37,38 Since the 
preliminary results from the first-in-man feasibility clinical investigation were presented, 
the Cypher SESS has become available in more than 80 countries (including Europe, 
Japan and the United States), receiving CE marking in 2002 and FDA approval in 2003.  
It is one of the most studied drug eluting stents, having been evaluated in more than 
200 clinical trials involving more than 155,000 subjects.  It was used to treat more than 
3 million patients with CAD39 until sales were discontinued in 2011. 
Like the Cypher stent, the Orsiro stent system also elutes Sirolimus.  Both stents have 
similar drug loads of 1.4 µg/mm2.   
3.1.3. Poly-L-Lactic Acid 
Poly-L-lactic acid (PLLA) is the polymer used as the excipient in the Orsiro stent 
system.  The Orsiro stent body surface is completely coated by a matrix consisting of 
the carrier PLLA and the drug substance Sirolimus (BIOlute).  The matrix has a maximal 
thickness on the ab-luminal surface of 25 µm.  The largest stent design has a maximal 
coating mass of 42.6 µg per millimeter of stent length.  PLLA is a highly biocompatible 
material.  There is existing published experience with PLLA as a stent and stent coating 
material in humans.46,40,41 Previously, this material was used in osteosynthesis and as 
suture material.  
This highly biocompatible polymer gently degrades over 3 years, avoiding increased 
inflammation, and ultimately metabolizes into CO2 and H2O via the Krebs cycle.  Studies 
in mini pigs have shown no residual PLLA and benign histology at 3 years. 
The first successful in-human experience with a fully biodegradable stent was described 
by Tamai et al. in 2000.42 The study included 15 subjects with 19 lesions treated with a 
monopolymer poly-L-lactic acid Igaki-Tamai stent with a zigzag helical coil pattern.  No 
death, MI or stent thrombosis occurred for up to 6 months, and only one subject with 
two lesions underwent repeat revascularization. 
Another fully biodegradable stent using PLLA is the everolimus eluting ABSORB stent.  
Two-year outcomes of the first-generation, first-in-man trial involving 30 subjects were 
encouraging, with only one myocardial infarction and no cardiac death, stent thrombosis 
or ischemia-driven target lesion revascularization (TLR), resulting in a MACE rate of 
3.6%.43 For the second-generation ABSORB stent, the MACE rate at 12 months was 
7.1% (7 of 101 subjects).44 Other stent systems using poly-L-lactic acid as 
biodegradable polymers, such as the BioMATRIX and Nobori stent, have also been 
proven safe and effective.45,46 

 
 
 
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3.1.4. Delivery System 
The delivery system of the Orsiro stent is a fast-exchange PTCA catheter compatible 
with a 5F guide catheter, with a working length of 140 cm.  As shown in Figure 3-4, the 
stent is securely crimped on a nylon balloon situated at the distal tip of the catheter 
between two radiopaque markers made of a platinum-iridium alloy.  The proximal shaft 
of the delivery system is a hypotube composed of polyamide-covered 304 or 304L 
stainless steel; it has a single luer port for connecting an inflation/deflation device to 
inflate/deflate the balloon. 
The distal section of the catheter comprises the inflation/deflation (balloon) lumen and 
the 29-cm-long guide wire lumen, which starts at the catheter tip and ends at the guide 
wire exit port.  It accepts guide wires of 0.014” diameter.  The stent delivery system is 
compatible with guiding catheters with a minimal inner diameter of ≥ 0.056” (1.42 mm).  
Shaft exit markers are located on the hypotube 92 cm (brachial technique) and 102 cm 
(femoral technique) from the distal end of the catheter to indicate when the delivery 
system tip exits from the guiding catheter. 
Figure 3-4. Orsiro Sirolimus Eluting Stent System 
 
3.1.5. Investigational Device Matrix 
Investigational device matrix for the BIOFLOW-V study is shown below in Table 3-1.  
Device sizes other than shown below cannot be used in this study.   
Table 3-1. Orsiro Stent System – Device Matrix for the BIOFLOW-V Study 
*  Orsiro LL  
Orsiro 
Nominal length [mm] 
Stent  
design 
Nominal Ø  
[mm] 
9 
13 
15 
18 
22 
26 
30 
35* 
40* 
T6S 
Ø 2.25 
x 
x
x
x
x
x
x
 
 
Ø 2.5 
x 
x
x
x
x
x
x
x 
x
Ø 2.75 
x 
x
x
x
x
x
x
x 
x
Ø 3.0 
x 
x
x
x
x
x
x
x 
x
T6M 
Ø 3.5 
x 
x
x
x
x
x
x
x 
x
Ø 4.0 
x 
x
x
x
x
x
x
x 
x

 
 
 
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The 2.25 x 35 mm and 2.25 x 40 mm sizes of Orsiro may be available outside of the 
US, but are not permitted to be utilized in the BIOFLOW-V subjects. 
  
3.2. Control Device Description 
The Xience family of Everolimus Eluting Coronary Stent Systems (Xience V™, Xience 
nano™, Xience Prime™, Xience PRIME™ LL, Xience Xpedition™, Xience Xpedition™ 
SV, Xience Xpedition™ LL, Xience Alpine™ and Xience Pro / Xience ProX [will be used 
only outside of the United States]), manufactured and marketed by Abbott Vascular, will 
be used as a control device in this study.   
Device description details of the different Xience stents can be found in the IFU 
provided with each system. 
3.2.1. Control Device Matrix 
Xience matrix for the BIOFLOW-V study is shown in Table 3-2 below.   
Table 3-2. Xience Family of Stent Systems – Devices Matrix for the BIOFLOW-V 
Study 
3.3. Indications for Use 
The Orsiro Sirolimus Eluting Coronary Stent System is indicated for improving coronary 
luminal diameter in subjects with symptomatic ischemic heart disease due to discrete de 
novo lesions or restenotic lesions from PTCA in native coronary arteries with a 
reference vessel diameter of 2.25–4.0 mm and lesion length of ≤ 36 mm. 
Xience  
Nominal length [mm]
Nominal Ø  
[mm] 
8 
12 
15 
18 
23 
28 
33* 
38* 
Ø 2.25** 
x 
x 
x 
x 
x 
x 
 
 
Ø 2.5 
x 
x 
x
x
x
x
x
x 
Ø 2.75 
x 
x 
x
x
x
x
x
x 
Ø 3.0 
x 
x 
x
x
x
x
x
x 
Ø 3.25*** 
x 
x 
x
x
x
x
x
x 
Ø 3.5 
x 
x 
x
x
x
x
x
x 
Ø 4.0 
x 
x 
x
x
x
x
x
x 
* Xience Prime™ LL and Xience Xpedition™ LL, Xience Alpine™, Xience ProX 
** Xience nano™, Xience Xpedition™ SV, Xience Prime™,  Xience Alpine™, Xience ProX 
*** Xience Xpedition™, Xience Xpedition™ LL,  Xience Alpine™, Xience ProX 

 
 
 
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3.4. Contraindications 
The Orsiro Sirolimus Eluting Coronary Stent System is contraindicated for use in 
subjects with: 
 A known hypersensitivity or allergy to stent coating materials (amorphous 
silicon carbide or PLLA polymer), to L-605 cobalt chromium alloy (including 
the major elements cobalt, chromium, tungsten and nickel) and to Sirolimus 
or its derivatives. 
 Subjects 
in 
whom 
antiplatelet 
and/or 
anticoagulation 
therapy 
is 
contraindicated. 
 A lesion judged to prevent complete inflation of an angioplasty balloon or 
proper placement of the stent or the stent system. 
 Transplant patients. 
 Subjects who would be considered unsuitable candidates for standard PCI. 
 Treatment of in-stent restenosis. 
3.5. Orsiro Clinical Data Summary 
The Orsiro stent is investigational in the United States. However, the stent received CE 
Mark on February 23, 2011 and is currently approved for marketing in more than 55 
countries worldwide with over 200,000 units distributed as of March 2014.   
The development of the Orsiro stent system has been supported by an extensive 
clinical trial program designed to collect data on over 3,000 Orsiro-treated subjects in 
studies using the Xience Everolimus Eluting Stent System as a comparator.  The Orsiro 
clinical trial program includes the BIOFLOW-I first-in-man study; the BIOFLOW-II 
international randomized study against the Xience Prime™ stent with intravascular 
ultrasound (IVUS) and optical coherence tomography (OCT) subsets; the BIOFLOW-III 
international all-comers registry; the BIOFLOW-IV international randomized study 
against the Xience Prime™/Xpedition™ stent with a pharmacokinetic subset, and the 
BIOSCIENCE international, randomized all-comers study against the Xience Prime™ 
stent. 
Table 3-3 summarizes the key design elements of each Orsiro study.  A brief 
description of the study, its status and results is provided in this section. 

 
 
 
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Table 3-3. Orsiro Clinical Trials Summary 
 

 
 
 
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BIOFLOW-I 
BIOFLOW-I was a 30-subject feasibility study conducted at two sites in Romania.  The 
purpose of the trial was to evaluate safety and efficacy of the Orsiro stent in treatment of 
single de novo lesions in native coronary arteries with a reference vessel diameter of 
2.5–3.5 mm and lesion length of ≤ 22 mm.  The primary efficacy endpoint was late 
lumen loss measured at 9 months post–index procedure.  The first subject was enrolled 
on July 2, 2009, and enrollment was completed on July 23, 2009. 
The primary endpoint of in-stent late lumen loss at 9 months was 0.05 ± 0.22 mm.  
Secondary safety endpoints included a composite rate of cardiac death, target vessel 
MI and clinically-driven TLR of 6.7% (2/30) at 1 year47 and 13.7% (4/30) at 2 years, and 
a composite rate of all-cause death, any MI and any revascularization of 16.7% (5/30) at 
2 years (Kaplan-Meier estimate). 
BIOFLOW-II 
BIOFLOW-II is a prospective, multicenter, randomized, controlled, non-inferiority trial 
that enrolled 458 and randomized 452 evaluable subjects at 24 clinical centers in 8 
European countries (clinicaltrials.gov identifier NCT01356888).  The purpose of this trial 
was to compare the Orsiro SES with the Xience Prime™ Everolimus Eluting Stent (EES) 
in subjects with single de novo coronary artery lesions in up to two coronary arteries of 
2.25–4.0 mm in diameter.  Subjects were randomized in a 2:1 fashion to receive the 
Orsiro stent or the Xience Prime™ stent.  All subjects underwent repeat angiography at 9 
months post–index procedure.  A subset of approximately 60 pre-specified subjects 
underwent IVUS examination at both baseline and 9 months.  Another subset of 
approximately 60 pre-specified subjects underwent OCT examination at both baseline 
and 9 months.  The primary efficacy endpoint was late lumen loss at 9 months post–
index procedure.  The first subject was enrolled in July 2011 and enrollment was 
completed in March 2012.  Subjects continue in the follow-up phase of the trial. 
Of the 452 enrolled subjects, 298 subjects were randomized to receive the Orsiro stent 
and 154 were randomized to receive the Xience Prime™ stent.  Follow-up angiography 
was completed in 85% of subjects at 9 months post-procedure and demonstrated a 
mean in-stent late lumen loss of 0.10 ± 0.32 mm for the Orsiro stent compared to 0.11 ± 
0.29 mm for the Xience Prime™ stent.  The non-inferiority hypothesis was confirmed 
with a P value of < 0.0001 (delta = 0.16 mm). 
At 12 months, clinical event rates were low, and there were no significant differences 
between the two arms.  TLF, a composite measure of safety (target vessel MI, cardiac 
death) and stent efficacy (clinically-driven TLR and emergent CABG) was measured in 
the BIOFLOW-II trial.  The TLF rate was evaluated, with Kaplan Meier estimates to be 
6.5% in the Orsiro group compared to 8.0% in the Xience Prime™ group at 12-month 
follow-up (log-rank = 0.5832). 
The BIOFLOW-II IVUS/OCT subset analyses showed comparable results between the 
Orsiro and Xience Prime™ groups at 9 months.  IVUS results at 9 months demonstrated 
complete stent apposition (no cases of stent malapposition) in both arms and a 
significantly lower neointimal hyperplasia area for Orsiro compared with the Xience 

 
 
 
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Prime™ (0.16 ± 0.33 mm2 vs. 0.43 ± 0.56 mm2, respectively; P = 0.0428).  The pre-
specified secondary OCT endpoints at 9 months showed a significant difference in 
tissue coverage between the Orsiro and the Xience Prime™ groups (98.3 vs. 97.5%, 
respectively; odds ratio 1.51; 95% confidence interval [CI] 1.02, 2.45; P = 0.042).  At 9 
months, the Orsiro stent was associated with thinner neointima thickness (0.094 vs. 
0.119 mm, P < 0.001).  No significant differences in incomplete strut apposition (ISA) 
were found between the treatment groups at 9 months.   
BIOFLOW-III 
The BIOFLOW-III study is an open-label prospective, non-randomized, multicenter, 
international, observational all-comers registry that enrolled a total of 1,356 subjects at  
43 centers in 14 countries across Europe and Chile (clinicaltrials.gov identifier 
NCT01553526).  The purpose of the registry was to evaluate safety and performance of 
the Orsiro Sirolimus Eluting Stent (SES) in a large series of subjects under real-world 
conditions. 
The primary endpoint was the 12-month rate of TLF, defined as cardiac death, target 
vessel Q-wave or non–Q-wave MI, emergent CABG or clinically driven TLR.  The first 
subject was enrolled in August 2011 and enrollment was completed in March 2012.  
The subjects are currently in the follow-up phase of the trial. 
The BIOFLOW-III registry enrolled an unselected subject population, including a high 
proportion of high-risk subjects presenting with diabetes (29.6%), small vessels 
(42.4%), acute MI (32.6%), and chronic total occlusions (4.3%).  The rate of TLF was 
5.1% at 12 months.  The rate of ARC-defined definite or probable stent thrombosis at 12 
months was 0.4%. 
While BIOFLOW-I and II had mandatory angiographic follow-up and BIOFLOW-III did 
not, rates of 12-month TLR were 6.7%, 3.5%, and 3.3% for BIOFLOW-I, II and III, 
respectively. 
Among subgroups, 12-month TLF rates were 7.7% in subjects with diabetes compared 
with 4.0% in non-diabetics, and 7.2% in subjects with acute myocardial infarction (AMI) 
compared with 4.0% in subjects without AMI. 
BIOFLOW-IV 
BIOFLOW-IV is a prospective, international, multicenter, randomized controlled trial 
designed to assess the Orsiro stent in the treatment of subjects with up to two de novo 
coronary artery lesions (clinicaltrials.gov identifier NCT01939249).  Approximately  
575–585 subjects at up to 50 sites in Japan and Europe will be enrolled in the trial to 
evaluate the safety and effectiveness of the Orsiro stent.  The BIOFLOW-IV clinical trial 
consists of the following: 
1. Randomized controlled trial (RCT) at up to 50 sites in Japan and Europe, which 
will enroll 555 subjects with up to two de novo lesions ≤ 26 mm in length in native 
coronary arteries 2.5–3.75 mm in diameter.  Subjects will be randomized in a 2:1 
fashion to receive the Orsiro stent or the Xience Prime™/Xpedition™ stent. 

 
 
 
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2. Concurrent, non-randomized pharmacokinetic (PK) sub-trial at 3–5 sites in 
Japan, which will enroll 20–30 subjects with up to two de novo lesions ≤ 26 mm 
in length in native coronary arteries 2.5–3.75 mm in diameter.  
The primary endpoint for the main RCT is the 12-month TVF rate, defined as any 
clinically-driven TVR, target vessel Q-wave or non–Q-wave MI, emergent CABG or 
cardiac death.  There is no primary endpoint for the PK sub-trial. 
BIOFLOW-IV enrolled the first subject in September 2013.  Enrollment was completed 
on January 25, 2015. 
BIOSCIENCE 
The BIOSCIENCE study is a prospective, multicenter, randomized controlled trial that 
enrolled 2,119 subjects at 13 clinical sites in Switzerland (clinicaltrials.gov identifier 
NCT01443104).  The purpose of this study was to directly compare the Orsiro stent with 
the Xience Prime™ stent in a large series of ‘all-comer’ subjects.  Subjects were 
randomized in a 1:1 fashion to receive the Orsiro stent or the Xience Prime™/ 
Xpedition™ stent.  The primary endpoint was 12-month TLF rate, defined as cardiac 
death, target vessel Q-wave or non–Q-wave MI, emergent CABG or clinically driven 
TLR.  The first subject was enrolled in February 2012, enrollment was completed in May 
2013 and the primary endpoint results were reported on September 1, 2014 by Pilgrim 
et al in the Lancet.48. 
Of the 2119 subjects (3139 lesions) included in the study, 407 (19%) patients presented 
with ST-segment elevation myocardial infarction.  A total of 1063 subjects (1594 
lesions) were randomized to receive the Orsiro stent and 1056 patients (1545 lesions), 
were randomized to receive the Xience stent.  At 12 months, the TLF rate for the Orsiro 
stent (69 subjects, 6.5%) was non-inferior to the Xience stent (70, 6.6%) at 12 months 
(absolute risk difference −0.14%, upper limit of one-sided 95% CI 1.97%, p for non-
inferiority <0.0004). No significant differences were noted in rates of clinical events, 
including stent thrombosis.  
 
 
 
 

 
 
 
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4. STUDY OBJECTIVES AND ENDPOINTS 
4.1. Study Objectives 
The objective of this study is to assess the safety and efficacy of the Orsiro Sirolimus 
Eluting Coronary Stent System in the treatment of subjects with up to three native de 
novo or restenotic (standard PTCA only) coronary artery lesions compared with the 
Xience coronary stent system. 
4.2. Primary Endpoint 
The primary endpoint is target lesion failure (TLF) rate at 12 months post–index 
procedure.  Target lesion failure is defined as all cardiac death, target vessel Q-wave or 
non–Q-wave MI, or clinically driven target lesion revascularization. 
4.3. Secondary Endpoints 
Secondary endpoints include the following measures: 
1. Device success, defined as attainment of < 30% residual stenosis of the target 
lesion using the assigned study stent only.  
Note: Post-dilatation is allowed to achieve device success. 
2. Lesion success, defined as attainment of < 30% residual stenosis of target lesion 
using any percutaneous method. 
3. Procedure success, defined as attainment of < 30% residual stenosis of the 
target lesion using the assigned study stent only without occurrence of in-hospital 
MACE. 
The following secondary clinical endpoints will be evaluated prior to discharge, at 1, 6 
and 12 months and annually thereafter through 5 years follow-up: 
4. Death. 
5. Myocardial infarction. 
6. Cardiac death or MI. 
7. MACE and individual MACE components (MACE: composite of all-cause death,  
Q-wave or non–Q-wave MI, and any clinically-driven TLR). 
8. TLF and individual TLF components (TLF: composite of cardiac death, target 
vessel Q-wave or non–Q-wave MI, and any clinically-driven TLR). 
9. TVF and individual TVF components (TVF: composite of cardiac death, target 
vessel Q-wave or non–Q-wave MI, and any clinically-driven TVR). 
10. Stent thrombosis (all, definite, definite/probable, probable, possible) according to 
Academic Research Consortium (ARC) criteria for acute, subacute, late, very late 
and cumulative stent thrombosis. 

 
 
 
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5. STUDY DESIGN 
The BIOTRONIK BIOFLOW-V clinical trial is a prospective, multicenter, randomized, 
controlled trial combining data on the randomized subjects with data from two historical 
studies by employing a Bayesian approach. 
Subjects with CAD that qualify for PCI with stenting will be screened per the protocol 
inclusion and exclusion criteria to achieve a total of up to 1,400 randomized subjects.  
Eligible subjects will be randomized in a 2:1 ratio, stratified by study center, to undergo 
percutaneous coronary revascularization with either the Orsiro Sirolimus Eluting Stent 
System (treatment group) or the Xience Everolimus Eluting Stent System (control 
group). 
Subjects may receive treatment of up to three target lesions, one or two target lesions 
per target vessel, for a maximum of two target vessels.  The target lesion(s) must be de 
novo or restenotic lesion(s) of ≤ 36 mm in length in native coronary artery(ies), with a 
reference vessel diameter of 2.25–4.0 mm.  Treatment of restenotic lesions is allowed 
provided that the target lesion was previously treated with PTCA only.  All treatment 
with study stents is to be performed during a single index procedure.  Note: Concurrent 
treatment of non-target lesions during the index procedure is not allowed. 
Randomized subjects will have clinical follow-up at 1 month, 6 months, 12 months and 
at 2, 3, 4 and 5 years following the index procedure.   
To assess the non-inferiority of the Orsiro stent compared to the Xience stent, 
BIOFLOW-V randomized subjects will be combined with historical subjects from the 
BIOFLOW-II and BIOFLOW-IV randomized trials employing a Bayesian approach.  Only 
subjects who meet all clinical and angiographic eligibility criteria of the BIOFLOW-V trial 
will be included in the analysis.  The trial design is shown in Figure 5-1. 

 
 
 
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Figure 5-1. Trial Design of the BIOFLOW-V Trial 
 
 
5.1. Clinical Sites 
The trial will be conducted at up to 100 sites in the United States and 50 sites outside of 
the United States. 
5.2. Number of Subjects 
Sufficient number of subjects will be provisionally enrolled to achieve a total of 1,334 
randomized subjects.  It is expected that approximately 50% will be enrolled in the 
United States.  A maximum of 250 subjects may be enrolled at a single investigational 
site. 
5.3. Study Participation Status 
5.3.1. Status Definitions 
Provisionally enrolled - Subject who is fully informed about the specifics of the study 
by authorized site personnel and provides informed consent by properly signing an 
informed consent form after confirmation of the initial enrollment criteria.   
Subjects for whom consent was not obtained prior to participation in the study will not 
be considered provisionally enrolled.  No data collected from these “subjects” will be 
included in any analysis.  Failure to obtain consent will be reported as a protocol 
violation as outlined in Section 12.6.1. 

 
 
 
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Screen failure – Provisionally enrolled subject who withdraws consent prior to 
randomization or is unsuitable for randomization following laboratory assessments, pre-
procedure electrocardiogram (ECG), diagnostic angiogram at the index procedure or 
unsuccessful crossing of the first target lesion with a guide wire.  These subjects will be 
exited from the study once screen failure is confirmed.  Subject informed consent forms 
will be kept in the site’s administrative files. 
Enrolled (Randomized) – Provisionally enrolled subject who meets all clinical and 
angiographic eligibility criteria, and has been randomized.  These subjects will be 
followed in accordance with the protocol requirements.  
Study exit - early termination of study participation applicable to subjects that have 
signed an informed consent form.   
Study completion - subject who completes all protocol-required study procedures.   
5.3.2. Subject Study Exit 
Investigators should make every effort to ensure subjects complete all protocol-required 
procedures, including study follow-up visits.  However, subjects may be required to exit 
the study, despite an investigator’s best efforts.  Good Clinical Practice (GCP) 
guidelines describe the need for clear subject exit procedures, to include when and how 
to exit subjects from the study, as well as to outline the type and timing of the follow-up 
and data collection for these subjects.   
Subjects may be exited from this study in the following limited situations: 
 Subject death 
 Subject withdrawal of informed consent 
 Investigator believes it is in the best medical interest of the subject to discontinue 
study participation due to safety reasons  
 Subject is considered a screen failure 
In the event of major protocol non-compliance, each case will be evaluated individually 
to determine the appropriate course of action regarding subject study participation.  In 
any of the situations noted above, data collected up to and including the exit of the 
subject will be used in data analysis.  No data will be collected after the exit of the 
subject from the study.  Study exits are expected and will be taken into consideration 
during data analysis as described in Section 8.  Additionally, subject attrition has been 
calculated into the study sample size; therefore, all subjects exited from the study will be 
counted toward the randomization goal and will not be replaced.  Investigators must 
document, in subject medical records, the reasons and circumstances for all subject 
exits.  
Generally, subjects should not be removed from the study due to late identification of 
eligibility criteria violations, unless increased subject risk is indicated.  In cases where 
further participation in the study poses potential risk to the subject, study exit should be 
considered.  In addition to subject safety, consideration should be given to the scientific 

 
 
 
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validity of the primary endpoints when making decisions concerning subject exit.  Study 
follow-up options and requirements for subjects exited from the study should be 
determined and applied to all subjects exited for similar reasons.  Deviations in subject 
eligibility, as defined in the protocol, should be considered protocol violations and 
reported to the Institutional Review Board (IRB) or Ethics Committee (EC) immediately 
upon discovery, in accordance with local regulations.  Subjects that are randomized, but 
do not receive a study stent during the index procedure post-randomization (e.g. unable 
to cross the lesion with the predilatation balloon or stent, randomization error, or lack of 
sufficient disease, etc.) may be exited from the study after completion of the primary 
endpoint visit assessments (12-month follow-up). 
If a subject cannot continue to participate in the study but the investigator is able to 
maintain contact with the subject and they have not withdrawn consent to collect further 
data, then contact should be maintained per the original follow-up schedule and vital 
status data will be confirmed by the investigator and reported.  For example, a subject 
may change geographic location or move into a nursing home, but may still remain in 
contact with the investigator.  Identification of vital status will be handled at the 
investigational site level.  Subjects have the right to discontinue from the study at any 
time or be discontinued at the investigator’s discretion. 
 
5.3.2.1. Subject Lost to Follow-up 
Subjects may be unable to adhere to the regularly scheduled study visits.  Study sites 
should attempt to contact these subjects in order to maintain study visit compliance and 
all contact attempts should be documented.  At a minimum, the site should make two 
attempts to contact the subject by phone and one by certified mail.   
If the subject is able to be contacted, all efforts should be made to perform the required 
study visit and complete the relevant case report forms.  However, if a subject is 
contacted and a study visit cannot be performed, the study site should complete the 
relevant case report forms with any relevant data obtained from the subject contact.  
Any missed visits prior to and after contact with the subject will be counted as protocol 
compliance issues.  If a subject is unable to be contacted at any of the remaining study 
visits, either a missed visit will be entered for each visit or the subject may be exited as 
lost to follow-up, using the date of last actual contact as the study exit date.  Subjects 
are not eligible to be exited as lost to follow-up until after the 12-month follow-up visit.  
After the 12-month follow-up visit, if a minimum of two consecutive study visits have 
been missed, after making two attempts by phone and one by certified mail at each time 
point, lost to follow-up may be an acceptable reason for exit.   

 
 
 
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Likewise, due to unforeseen circumstances, subjects may change providers (e.g. 
changes in insurance coverage) or relocate during the course of the study and may no 
longer be able to return for study follow-up visits.  Attempts to collect data from these 
subjects should be made by the investigator in collaboration with the subject’s new 
provider.  All data that is obtained may be utilized in data analysis, but should be 
documented that it was collected by an unapproved investigator.  If any data cannot be 
collected from the subject’s new provider, the subject should be considered lost to 
follow-up and the site should follow the above procedures for continuing subject contact.  
The investigative site should make an attempt to verify the vital status of subjects that 
are lost-to-follow-up through means including, but not limited to, the National Death 
Index/ Social Security Death Index, as applicable.  BIOTRONIK and/or its designee may 
provide assistance to investigative sites to obtain vital status information, as permitted, 
for lost-to-follow-up subjects. 
 

 
 
 
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6. SUBJECT SELECTION 
During the study enrollment phase, patients from the general interventional cardiology 
population will be screened according to protocol inclusion and exclusion criteria.  
Subjects should be consented and sign the informed consent prior to initiating any 
study-specific procedures that are not considered routine standard of care clinical 
assessments. Subjects who have met all clinical inclusion and exclusion criteria and 
signed the IRB/EC–approved consent form will then be screened for angiographic 
criteria during an index procedure. 
6.1. Eligibility Criteria 
6.1.1. Clinical Inclusion Criteria 
Subjects must meet all of the following criteria to participate in the trial: 
1. Subject is ≥18 years or the minimum age required for legal adult consent in the 
country of enrollment. 
2. Subject is an acceptable candidate for PCI. 
3. Subject is an acceptable candidate for CABG. 
4. Subject has clinical evidence of ischemic heart disease, stable or unstable 
angina pectoris or documented silent ischemia. 
5. Subject is eligible for dual anti-platelet therapy treatment with aspirin plus either, 
clopidogrel, prasugrel, ticagrelor or ticlopidine. 
6. Subject has provided written informed consent. 
7. Subject is willing to comply with study follow-up requirements. 
6.1.2. Angiographic Inclusion Criteria 
Each target lesion/vessel must meet all of the following angiographic criteria for the 
subject to be eligible for the trial: 
1. Subject has up to three target lesions in up to two separate target vessels 
(twotarget lesions in one vessel and one target lesion in a separate vessel). 
2. Target lesion must be de novo or restenotic lesion in native coronary artery; 
restenotic lesion must have been treated with a standard PTCA only. 
3. Target lesion must be in major coronary artery or branch (target vessel). 
4. Target lesion must have angiographic evidence of ≥ 50% and < 100% stenosis 
(by operator visual estimate).  If the target lesion is < 70% stenosed, there should 
be clinical evidence of ischemia such as a positive functional study (e.g. exercise 
treadmill test, thallium stress test, SPECT, or stress echo), cardiac computed 
tomography (CT), electrocardiography, fractional flow reserve, or post infarct 
angina. 
5. Target vessel must have a Thrombolysis In Myocardial Infarction (TIMI) flow > 1. 

 
 
 
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6. Target lesion must be ≤ 36 mm in length by operator visual estimate. 
7. Target vessel must have a reference vessel diameter of 2.25–4.0 mm by 
operator visual estimate. 
8. Target lesion must be amenable to treatment with a maximum of two overlapping 
stents. 
6.1.3. Clinical Exclusion Criteria 
Subjects will be excluded from the trial if any of the following criteria are met: 
1. Subject has clinical symptoms and/or ECG changes consistent with acute ST 
elevation MI (STEMI) within 72 hours prior to the index procedure. 
Note:  Hemodynamically stable non-STEMI (NSTEMI) subjects are eligible for 
study enrollment. 
2. Subject is hemodynamically unstable. 
3. Subject is pregnant and/or breastfeeding or intends to become pregnant during 
the duration of the study. 
4. Subject has a known allergy to contrast medium that cannot be adequately pre-
medicated, or any known allergy to thienopyridine, aspirin, both heparin and 
bivalirudin, L-605 cobalt-chromium (Co-Cr) alloy or one of its major elements 
(cobalt, chromium, tungsten and nickel), acrylic, fluoropolymers, silicon carbide, 
PLLA, sirolimus or everolimus.   
5. Revascularization of any target vessel within 9 months prior to the index 
procedure or previous PCI of any non-target vessel within 30 days prior to the 
index procedure. 
6. Planned treatment of a lesion not meeting angiographic inclusion and exclusion 
criteria during the index procedure or after the index procedure. 
7. Planned surgery within 6 months of index procedure unless dual antiplatelet 
therapy can be maintained throughout the peri-surgical period. 
8. History of a stroke or transient ischemic attack (TIA) within 6 months prior to the 
index procedure. 
9. Subjects with active bleeding disorders, active coagulopathy, or any other 
reason, who are ineligible for DAPT. 
10. Subject will refuse blood transfusions. 
11. Subject has documented left ventricular ejection fraction (LVEF) < 30% as 
evaluated by angiography, echocardiogram, radionuclide ventriculography or any 
non-invasive imaging method within 90 days prior to the index procedure. 
12. Subject is dialysis-dependent. 
13. Subject has impaired renal function (i.e., blood creatinine > 2.5 mg/dL or 221 
μmol/L determined within 7 days prior to the index procedure). 

 
 
 
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14. Subject has leukopenia (i.e. < 3,000 white blood cells/mm3), thrombocytopenia 
(i.e. < 100,000 platelets/mm3) or thrombocytosis (i.e. > 700,000 platelet/mm3). 
15. Subject is receiving oral or intravenous immunosuppressive therapy (inhaled 
steroids are permitted), or has known life-limiting immunosuppressive or 
autoimmune disease (e.g., human immunodeficiency virus, systemic lupus 
erythematosus; diabetes mellitus is permitted). 
16. Subject is receiving chronic anticoagulation (e.g. coumadin, dabigatran, 
apixaban, rivaroxaban or any other agent). 
17. Subject has life expectancy of < 1 year. 
18. Subject is participating in another investigational (medical device or drug) clinical 
study.  Subjects may be concurrently enrolled in a post-market study, as long as 
the post-market study device, drug or protocol does not interfere with the 
investigational treatment or protocol of this study. 
19. In the investigator’s opinion, subject will not be able to comply with the follow-up 
requirements. 
6.1.4. Angiographic Exclusion Criteria 
Subjects will be excluded from the trial if any of the target lesions/vessels meets any of 
the following angiographic criteria: 
1. Target lesion is located within a saphenous vein graft or arterial graft. 
2. Target lesion is a restenotic lesion that was previously treated with a bare metal 
or drug eluting stent (in-stent restenosis). 
3. Target lesion has any of the following characteristics: 
a. Lesion location is within the left main coronary artery, or within 3 mm of 
the origin of the left anterior descending (LAD) or left circumflex (LCX). 
b. Involves a side branch of > 2.0 mm in diameter. 
Note: Lesions within 3 mm of the origin of the right coronary artery may be 
treated. 
4. Target vessel/lesion is excessively tortuous/angulated or is severely calcified, 
that would prevent complete inflation of an angioplasty balloon. This assessment 
should be based on visual estimation. 
5. Target vessel has angiographic evidence of thrombus. 
6. Target lesion is totally occluded (100% stenosis). 
7. Target vessel was treated with brachytherapy any time prior to the index 
procedure. 

 
 
 
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Figure 6-1. Clinical Study Design Flowchart 
 
 
 
Review Medical Record
Does subject meet pre-screening criteria?
Yes
Identify Potential Subject
Does subject have CAD and 
qualify for PCI procedure? 
Randomization
2:1 
Orsiro (889) : Xience (445) 
Follow-up Visits
 Hospital discharge 
 1-month (± 7 days) 
 6-month (± 14 days) 
 12-month (± 30 days) 
 2 year (± 60 days) 
 3 year (± 60 days) 
 4 year (± 60 days) 
 5 year (± 60 days) 
Yes
Yes
Pre-Procedure Testing
Are pre-procedure tests (performed according 
to investigative site’s standard of care) 
acceptable with protocol? 
Index Procedure
Does subject satisfy procedure-related eligibility 
criteria following diagnostic angiogram? 
Subject is a screen 
failure: exit from study 
No
Informed Consent
Did subject provide written informed 
consent (provisionally enrolled)? 
Subject is not a 
study candidate 
No
Subject is not a 
study candidate 
No
Yes
Yes
Subject is not a 
study candidate 
No
Repeat any pre-procedure tests (e.g., ECG or 
labs) according to protocol timing requirements, if 
necessary.  Are all test results acceptable? 
Subject is a screen 
failure: exit from study 
Yes
No
Yes
Subject is not a 
study candidate 
No

 
 
 
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7. TRIAL PROCEDURES AND ASSESSMENTS 
7.1. Schedule of Events 
Table 7-1. Schedule of Events 
 
Screening/Baseline 
Index 
Procedure 
Post-
Procedure2/ 
Discharge 
1 Month  
± 7 Days 
6 Months 
± 14 Days 
12 Months
± 30 Days 
2, 3, 4, 5 Years
±60 Days 
Unsch. 
Visit 
 
Within  
7 Days  
Prior to 
Procedure 
Within  
24 Hours 
Prior to 
Procedure 
Telephone 
Contact or 
Office Visit 
Telephone 
Contact or 
Office Visit 
Office Visit 
Telephone 
Contact or 
Office Visit 
 
Informed consent form1 
X1 
 
 
 
 
 
 
 
 
Demographics, medical and 
cardiac history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
Angina status 
X 
 
 
X 
X 
X 
X 
X 
X 
CBC with differential 
X 
 
 
 
 
 
 
 
 
Creatinine blood test 
X 
 
 
 
 
 
 
 
 
Pregnancy test3 
X 
 
 
 
 
 
 
 
 
12-lead ECG 
 
X 
 
X  
(within 24 hours) 
X4 
X4 
X 
 
 
CK and/ or CKMB5 (CKMB 
required) 
 
X5 
 
X5 
 
 
 
 
 
Troponin5 
(only if CKMB not available) 
 
X5 
 
X5 
 
 
 
 
 
ACT measurements 
(heparin only)6 
 
 
X 
X (immediately 
post-procedure) 
 
 
 
 
 
Angiography to assess pre- 
and post- procedure lesion 
characteristics 
 
 
X 
X 
 
 
 
 
X7 
Randomization8 
 
 
X 
 
 
 
 
 
 
AE/SAE monitoring9 
 
 
X 
X 
X 
X 
X 
X 
X 
Medication regimen 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC: complete blood count; ECG: electrocardiogram; CKMB: creatine kinase myocardial band isoenzyme MB; ACT: activated clotting time; AE: adverse event; 
SAE: serious adverse event; URL: upper range limit; MACE: major adverse cardiac event. 
1 Informed consent may be obtained within 30 days prior to the index procedure. 
2 End of procedure defined as removal of guide catheter. 

 
 
 
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3 For women of childbearing potential only per standard of care. 
4 12-leads ECG at 1- and 6-month visits is only if there are office visits at these time points. 
5 CKMB testing is required (or Troponin if CKMB is not available). Baseline pre-procedure sample may be obtained from the sheath during the index procedure 
prior to randomization.  CKMB (or Troponin if CKMB is not available) will be measured at 6–24 hours post index procedure.  If CKMB is > 3x URL or Troponin > 
3x URL, a series of CKMB (or Troponin) must be evaluated every 4-12 hours until values have returned to < 3x URL or until discharge, from when the first 
elevation is noted. 
6 ACT measurements are recommended but not required if the test is not performed as standard of care at the investigational institution.  If ACT is not performed, 
sufficient anticoagulation should be confirmed based on standard of care procedures and applicable clinical guidelines. 
7 Any repeat or unscheduled diagnostic or interventional coronary angiography performed should include a diagnostic assessment of the target lesion(s) and 
investigational stent(s).  Angiographic data collected during any repeat procedure on the target vessel(s) must be made available to the Clinical Events 
Committee (CEC) and angiographic core laboratory. 
8 Randomization only for subjects meeting all eligibility criteria and successful crossing of the first lesion by a guide wire. 
9 All AEs (serious and non-serious) will be reported for the entire study period to the extent required by national and/or local requirements.  For US sites only: After 
the 12-month follow-up visit, continuing AEs will be followed through to resolution or until event becomes stable, and only serious adverse events, including 
MACE and clinical study endpoints, will be recorded. 

  
 
 
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7.2. Screening and Baseline Procedures 
Individuals with CAD who qualify for a PCI procedure will be pre-screened by authorized 
site personnel by reviewing the medical record.  Potential subjects will undergo CAD 
screening according to each investigative site’s standard of care.  Prior to possible entry 
into the trial, site personnel will review and compare the subject’s medical history with 
the clinical inclusion and exclusion criteria to determine if they are an eligible candidate 
for the study.   
Pre-screening logs will be kept at each investigational site of all subjects identified 
through pre-screening who meet the clinical eligibility criteria.  For subjects who are not 
subsequently enrolled (consented), the reason for non-enrollment will be recorded.  
Potential study subjects will proceed with the following standard of care procedures to 
further assess eligibility. 
Pre-Procedure/Baseline Evaluations: 
 Physical assessment within 7 days prior to the index procedure, including weight, 
height and blood pressure. 
 Demographics within 7 day prior to the index procedure. 
 Medical history within 7 days prior to the index procedure: 
o General medical, cardiac, neurologic and renal history. 
o Cardiovascular history (e.g., prior MI, prior PCI, history of congestive heart 
failure). 
o Risk factors (e.g., dyslipidemia, hypertension, diabetes mellitus, tobacco use). 
o History of peripheral vascular disease, stroke, TIA. 
 Ischemic/anginal status assessment (according to Canadian Cardiovascular Society 
Classification [CCSC] or Braunwald). 
 Current cardiovascular and diabetic medications, including anti-platelet/anti-
coagulant medications within 7 days prior to the index procedure. 
 12-lead ECG according to each site’s standard of care to ensure suitability to 
undergo a PCI procedure, within 24 hours prior to the index procedure.  
 Routine laboratory assessments: 
o All subjects must have cardiac enzymes including CK and/or CKMB (CKMB is 
required [or troponin if CKMB is not available]), evaluated within 24 hours 
prior to the index procedure.  Baseline cardiac enzyme sample may be 
obtained from the sheath during the index procedure, prior to randomization. 
o All subjects must have a creatinine blood level assessed within 7 days prior to 
the index procedure.   

  
 
 
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o Women of childbearing potential must have a negative pregnancy (serum 
and/or urine) test within 7 days prior to index procedure in accordance with 
the institutional standard of care.  Female subjects who are surgically sterile 
or post-menopausal are exempt from having a pregnancy test. 
o Complete blood count (CBC) with differential within 7 days prior to the index 
procedure.  If white blood cell count is within normal limits, differential is not 
required. 
If any of the Pre-procedure/ Baseline tests specified above are not routine 
standard of care or are required to be repeated in order to demonstrate protocol 
eligibility criteria leading up to the index procedure, written informed consent will 
be obtained before these tests are performed or repeated.  Subjects are considered 
provisionally enrolled with the signature on the written informed consent form, however 
a subject will only proceed to the baseline evaluations and index procedure if all initial 
and applicable procedure-related eligibility criteria are met. 
Written informed consent may be obtained on the day of the index procedure or within 
30 days prior to the index procedure.  The consenting process, including discussion of 
the study, with its possible benefits and risks, will be documented in the subject’s 
medical record. A copy of the completed informed consent document must be given to 
the subject; the original must be placed in the medical record.  Failure to obtain a signed 
and hand-dated informed consent prior to the procedure constitutes a protocol violation, 
which must be reported in accordance with all applicable regulations.   
7.3. Concomitant Medications 
Unless clinically contraindicated, all subjects should receive the recommended 
medication regimen listed in Table 7-2 at the investigator’s discretion in accordance with 
clinical guidelines.  The use of glycoprotein IIb/IIIa inhibitors is allowed and not 
mandatory. 
Pre-and post-procedure activated clotting time (ACT) measurements for subjects 
receiving heparin are strongly recommended but not required if the test is not performed 
as standard of care at the investigational institution.  If ACT is not performed, 
anticoagulation should be in accordance with standard of care procedures and 
applicable guidelines. 
All cardiovascular and diabetic medications administered should be recorded in the 
medical record and reported in the electronic case report form (eCRF) from 24 hours 
pre-procedure through the 12-month follow-up assessment.  Use of antiplatelet/anti-
coagulant therapy will be recorded throughout the 5-year follow-up period. 
Dual antiplatelet therapy (DAPT) administration post index procedure is recommended 
for a minimum of 6 months and highly recommended for 12 months for subjects who are 
not at a high risk of bleeding.   
 
 

  
 
 
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Table 7-2. Concomitant Medication Regimen Recommendations 
Timing 
Medication 
Regimen 
Prior to 
Procedure 
Acetylsalicylic acid 
A minimum of 150 mg (within 24 hours prior to 
procedure). 
Clopidogrel 
or 
Prasugrel/Ticagrelor 
Loading dose of 600 mg clopidogrel within 24 
hours prior to index procedure or immediately 
post-procedure (within 30 minutes). 
Alternatively, loading dose of 60 mg prasugrel 
or 180 mg ticagrelor. 
No loading dose is required for subjects on 
chronic thienopyridine therapy. 
During 
Procedure 
Heparin or  
Bivalirudin 
Per routine hospital practice.   
For heparin, a bolus of 50-80 units/kg is 
recommended.  If heparin is administered, it is 
recommended to maintain ACT of ≥ 250 
seconds (or ≥ 200 seconds if a glycoprotein 
IIb/IIIa receptor blocker is administered) 
throughout the interventional portion of the 
procedure. 
Glycoprotein IIb/IIIa inhibitor 
Per investigator’s discretion. 
Intracoronary nitroglycerin or 
Intracoronary isosorbide 
or dinitrate 
To eliminate coronary artery spasm that would 
interfere with accurate measurement of lumen 
obstruction due to plaque alone, 100–200 µg 
nitroglycerin or 1–3 mg of isosorbide or 
dinitrate must be administered prior to baseline 
and post-intervention angiograms. 
Post-Procedure 
DAPT 
Acetylsalicylic acid 
A minimum of 75 mg daily indefinitely. 
Clopidogrel 
or 
Prasugrel/ticagrelor/ticlopidine 
Post-procedure treatment with the same 
thienopyridine agent for a minimum of 6 
months, highly recommended for 12 months 
for subjects not at high risk for bleeding, as 
follows:  
Clopidogrel: 75 mg daily: 
Prasugrel: 10 mg daily; a lower dose of 5 mg 
daily is allowed for subjects < 60 kg.  
Ticagrelor: 90 mg twice daily. 
Ticlopidine: 250 mg twice daily. 
OUS investigators may follow medication administration recommendations in accordance with ESC 
guidelines, national guidelines and/or hospital standard of care. 

  
 
 
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7.4. Index Procedure 
7.4.1. Subject Preparation and Baseline Angiography 
Subject preparation and percutaneous access should be performed according to 
standard hospital policy for care of interventional cardiology patients unless otherwise 
specified in this investigational plan.  Both femoral and radial access techniques are 
acceptable.  The procedure begins once percutaneous access has been established, 
defined as the time of sheath insertion. 
Following intracoronary injection of nitroglycerin, isosorbide or dinitrate (see Table 7-2) 
baseline angiography of the vessels(s) will be performed in at least two orthogonal 
views to characterize the target lesion(s) and to confirm angiographic eligibility criteria.  
Assessment of angiographic eligibility criteria is based on visual assessment of the pre-
procedure angiogram. 
7.4.1. Randomization 
Subjects who have satisfied all general and angiographic inclusion and exclusion 
criteria, after successful crossing of the first target lesion with a guide wire, will then be 
randomized in a 2:1 ratio to receive either the Orsiro stent (treatment group) or the 
Xience stent (control group).  Each subject will receive one unique randomization 
number associated with a randomization assignment allocated via the BIOFLOW-V 
study EDC electronic Case Report Form (eCRF) website hosted by MedNet Solutions.  
Randomization will be stratified by study center and to prevent bias, the blocks and 
randomization schedules will be pre-defined prior to the first study enrollment and will 
be generated by HCRI.   
Once randomization is completed and a treatment is assigned, crossover is not 
permitted.  Once randomized the subject is considered enrolled in the trial and included 
in the intent-to-treat (ITT) population.  This includes subjects that are randomized, but 
do not receive the study stent or receive a stent not in accordance with the 
randomization assignment. 
7.4.2. Target Lesion(s) Pre-Dilatation 
The target lesion(s) must be pre-dilated with standard percutaneous transluminal 
balloon angioplasty.  The recommended sizes of pre-dilatation balloons are as follows: 
 2.0 mm for a 2.25-mm vessel. 
 2.0 mm for a 2.5-mm vessel. 
 2.5 mm for a 3.0-mm vessel. 
 3.0 mm for a 3.5-mm vessel. 
 3.5 mm for a 4.0-mm vessel. 
The selected pre-dilatation balloon should be a minimum of 2 mm shorter than the 
length of the stent that is planned to be implanted. 

  
 
 
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The use of rotational atherectomy devices or cutting balloons is allowed.  If rotational 
atherectomy is performed, it should be followed by successful balloon inflation prior to 
stenting. 
7.4.3. Stenting 
All target lesions should be treated with the assigned study stent per randomization.  
The stenting procedure will be performed according to the randomized stent IFU 
provided with each stent. 
The delivery system should be advanced over the guide wire, through the introducer, 
and to the target lesion site.  The stent should be positioned across the lesion and 
placement confirmed using the radiopaque marker bands on the delivery catheter and 
fluoroscopic angiographic test injections.  In all cases, the stent should extend into 
surrounding healthy tissue by a minimum of 2 mm proximally and distally. 
The stent should be deployed with a single inflation of the delivery system balloon 
according to the compliance table.  It is recommended that inflation be maintained for 
approximately 15–30 seconds.  The delivery system balloon must not be inflated 
beyond the labeled-rated burst pressure. 
A maximum of two study stents are to be used per target lesion.  If more than one stent 
is needed to cover the target lesion completely, the stents must overlap by at least 2 
mm.  However, Investigators are discouraged from treating two separate lesions with 
overlapping contiguous stents and should anticipate a minimum of 10 mm between 
stents when treating two lesions in the same target vessel.   
After stent placement, the investigator should ensure that the stent is in full contact with 
the arterial wall.  To achieve full contact, post-dilatation may be performed at the 
discretion of the investigator using the stent delivery system balloon or a shorter non-
compliance balloon catheter.  Optimal stent deployment is a visually (or by online 
quantitative coronary angiography [QCA]) estimated residual stenosis of < 30%. 
Persistent dissections should be treated conservatively, with low-pressure prolonged 
balloon inflation, or with an additional study stent implantation (in accordance with the 
original randomization treatment assignment) 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 be treated per standard practice.  All 
angiographic complications that occur must be documented by angiography, reported 
on the appropriate eCRF, and submitted to the angiographic core laboratory for 
analysis. 
7.4.4. End of Procedure 
In all subjects, final angiography of the vessel(s) must be performed following 
intracoronary injection of nitroglycerin, isosorbide or dinitrate (see Table 7-2) and in the 
same views that were taken at baseline. 
The end of the procedure is defined as the time the guide catheter is removed from the 
subject.  If the subject is returned to the procedure room and a guiding catheter is 

  
 
 
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reinserted, a dilatation is performed, and an interventional device is inserted into the 
catheter, this should be considered a repeat intervention. 
7.4.5. Bailout Procedures 
In the event of a major dissection or an occlusive complication manifested as decreased 
target vessel flow, chest pain or ischemic ECG changes after index procedure that do 
not respond to repeat balloon inflations or intracoronary vasodilators (nitroglycerin, 
verapamil, diltiazem, nitroprusside), other bailout procedures may be performed, which 
may include additional stenting.  Should an additional stent be used, it must be the 
assigned study stent unless clinically contraindicated. Multiple stenting with the Orsiro 
or Xience stents requires a 2-mm overlap.  Such procedures must be documented in 
the eCRF. 
All bailout procedures are considered adverse events (AEs) in this study.  Bailouts 
procedures that result in any of the consequences characteristic of a serious adverse 
event (SAE) (e.g. death, prolonged hospitalization, etc. see Section 9.1.3) are 
considered SAEs. 
7.4.6. Bailout-Staged Procedure 
Planned staged procedures are not allowed in this clinical investigation.  If during the 
intervention it becomes clinically necessary to postpone treatment of the second and/or 
third lesion to a later time point, this is regarded as a staged procedure and must be 
documented as such.  For staged procedures, the use of an investigational stent is not 
allowed.  Subjects requiring staged procedure should be treated according to the 
investigator’s discretion and standard of care.  These subjects should receive an 
approved, commercially available treatment and not a study stent. 
All bailout procedures are considered adverse events (AEs) in this study.   
7.5. Post-Procedure to Hospital Discharge 
7.5.1. Immediately Post-Procedure 
Immediately following the procedure: 
 Heparin or bivalirudin should be discontinued. 
 ACT should be monitored in accordance with hospital protocol. 
 Vascular sheaths should be removed according to standard hospital practice. 
 Approved vascular closure devices may be used at the discretion of the 
investigator in accordance with the manufacturer’s instructions. 
7.5.2. Clinical and Laboratory Assessments 
The following clinical assessments and laboratory tests should be performed after the 
index procedure and before hospital discharge: 

  
 
 
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 Cardiac biomarkers CK and/ or CKMB (CKMB is required, or troponin if CKMB is 
not available) will be measured once within 6–24 hours post index procedure.  
CKMB or troponin is required.   
Note: Every effort must be made to obtain cardiac biomarker values within the 
specified time ranges.  Results of all cardiac biomarker measurements, even 
measurements performed outside the time range, will be documented in the 
medical record and reported on the eCRF. 
If CKMB elevation (or troponin in the absence of CKMB) > 3x URL is noted post-
procedure, CKMB (or troponin in the absence of CKMB) measurements should 
be performed every 4-12 hours and documented in the medical record and 
reported on the eCRF until values have returned to < 3x URL or until discharge, 
starting from when the first elevation is noted. 
 A 12-lead ECG must be completed within 24 hours after the index procedure. 
 Ischemic/angina assessment according to CCSC or Braunwald classification just 
prior to discharge. 
 AE and SAE assessment. 
 Anti-platelet/anti-coagulant medical therapy post procedure. 
 Other cardiovascular and diabetic medications post procedure. 
Prior to discharge, review of the study follow-up requirements with the subject is 
recommended to help ensure compliance with the follow-up schedule.  In addition, 
confirmation of subject contact telephone numbers, including numbers for home, work 
numbers and primary physician, as applicable, should be completed.   
7.6. Antiplatelet/Anticoagulation Regimen 
Subjects will receive a minimum of 75 mg aspirin daily indefinitely, and 75 mg 
clopidogrel daily for a minimum of 6 months, 12 months are recommended for subjects 
who are not at high risk for bleeding.  
Clopidogrel may be substituted with 5 mg or 10 mg prasugrel daily or 90 mg ticagrelor 
twice daily or 250 mg ticlopidine twice daily. 
OUS investigators may follow medication administration recommendations in 
accordance with ESC guidelines, national guidelines and/or hospital standard of care. 
7.7. Follow-Up Assessments 
All randomized subjects will be followed through 5 years of follow-up, with assessments 
performed at 1 month, 6 months, 12 months and annually thereafter.    
Subjects who are randomized, but do not receive a study stent (i.e., subjects who don ot 
receive an Orsiro or Xience stent) will be followed for 12-months only. 
An office visit is required for the 12-month follow-up visit.  All other visits may be 
performed by telephone interview with the subject if the subject is unable to return for an 
office visit within the applicable follow-up window. 

  
 
 
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For each follow-up visit, all clinical assessments should be performed on the same date.  
Requirements of each follow-up evaluation are described below. 
7.7.1. One (1) Month Clinical Follow-Up (30 ± 7 Days) 
Subjects will be evaluated at 1 month post-procedure (± 7 days) by a telephone 
interview and/or an office visit.  The following assessments must be completed: 
 Ischemic/anginal status (according to CCSC or Braunwald). 
 AEs and SAEs since discharge. 
 Anti-platelet/anti-coagulant medical therapy since discharge. 
 Other cardiovascular and diabetic medications since discharge. 
 Any coronary intervention (e.g., repeat revascularization) that occurred since the 
post-procedure discharge. 
 12-lead ECG (if an office visit is performed). 
7.7.2. Six (6) Month Clinical Follow-Up (180 ± 14 Days) 
Subjects will be evaluated at 6 months post-procedure (180 ± 14 days) by a telephone 
interview or an office visit.  The following assessments must be completed: 
 Ischemic/anginal status (according to CCSC or Braunwald). 
 AEs and SAEs since the previous contact. 
 Anti-platelet/anti-coagulant medical therapy since the previous contact. 
 Other cardiovascular and diabetic medications since the previous contact. 
 Any coronary intervention (e.g., repeat revascularization) that occurred since the 
previous contact. 
 12-lead ECG (if an office visit is performed). 
7.7.3. Twelve (12) Month Clinic Visit (360 ± 30 Days) 
Subjects will be evaluated at 12 months post-procedure (360 ± 30 days).  The 12-month 
follow-up is required to be an office visit with the subject.  During the 12-month follow-up 
visit, the following assessments must be completed: 
 Ischemic/anginal status (according to CCSC or Braunwald). 
 AEs and SAEs since the previous contact. 
 Anti-platelet/anti-coagulant medical therapy since the previous contact. 
 Other cardiovascular and diabetic medications since the previous contact 
 Any coronary intervention (e.g., repeat revascularization) that occurred since the 
previous contact. 
 12-lead ECG. 

  
 
 
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7.7.4. Long-Term Clinical Follow-Up at 2, 3, 4 and 5 Years Post-Procedure 
(Annually ± 60 Days) 
Subjects will be evaluated at 2, 3, 4 and 5 years post-procedure (± 60 days) by a 
telephone interview and/or an office visit.  The following assessments must be 
completed: 
 Ischemic/anginal status (according to CCSC or Braunwald). 
 AEs and SAEs since the previous contact. 
Note: All AEs (serious and non-serious) will be reported for the entire study 
period to the extent required by national and/or local requirements.  For US sites 
only: After the 12-month follow-up visit, continuing AEs will be followed through to 
resolution or until event becomes stable and only serious adverse events, 
including MACE and clinical study endpoints, will be recorded. 
 Anti-platelet/anti-coagulant medical therapy since the previous contact. 
 Other cardiovascular and diabetic medications since the previous contact. 
 Any coronary intervention (e.g., repeat revascularization) that occurred since the 
previous contact. 
7.8. Unscheduled Study Visit 
Subjects may present to the clinic outside of the scheduled follow-up windows.  Such 
unscheduled study visits will be reported if the subject has experienced an AE.  For an 
unscheduled study visit, concomitant cardiac medications and data regarding adverse 
events will be collected. 
Subjects assessed at an unscheduled study visit may require diagnostic testing (e.g. 
ECG, angiogram, CK/CKMB levels) and/or a revascularization procedure to further 
evaluate and treat ischemic symptoms.  Any repeat procedure must be reported on the 
relevant case report forms, including any unscheduled visits prior to the repeat 
procedure and/or adverse events associated with the procedure.  Only commercially 
available stents are allowed during repeat procedures. Use of investigational stents is 
not permitted. 
Any repeat or unscheduled diagnostic or interventional coronary revascularization 
procedure performed should include a diagnostic assessment of the target lesion(s) and 
investigational stent(s).  Angiographic data collected during any repeat procedure on the 
target vessel(s) must be made available to the CEC for an independent review and 
assessment.  Likewise, the angiographic images should be submitted to the core 
laboratory for an independent review and assessment of the target lesion and 
investigational stent. 
7.9. Angiographic Core Laboratory 
The angiographic core laboratory will provide sites with a written procedural manual 
describing the acquisition and submission procedures for the baseline and subsequent 

  
 
 
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repeat angiograms.  Sites will be requested to obtain and submit a minimum of two 
orthogonal views at baseline and post-procedure in accordance with the manual. 
Baseline and procedural angiograms for all subjects will be sent to the independent 
angiographic core laboratory for evaluation.  In addition, any coronary angiograms 
performed during the trial follow-up period due to suspicion of restenosis of the target 
lesion(s) will be forwarded to the angiographic core laboratory for analysis. 
8. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The BIOFLOW-V clinical trial is a prospective, multicenter, randomized, controlled 
study.  A total of up to 1,400 subjects will be randomized, stratified by study center, in a 
2:1 ratio with 933 subjects randomized to receive the Orsiro stent and 467 subjects 
randomized to receive the Xience stent. 
The trial is designed to assess the non-inferiority of the Orsiro stent compared to the 
Xience stent with respect to the primary endpoint of 12-month TLF, defined as cardiac 
death, target vessel Q-wave or non–Q-wave MI, or any clinically-driven TLR. 
For this purpose, data from BIOFLOW-V randomized subjects will be combined with 
data from historical subjects from the BIOFLOW-II and BIOFLOW-IV randomized trials 
employing a Bayesian approach.  Only subjects who meet all clinical and angiographic 
eligibility criteria of the BIOFLOW-V trial will be included in the analysis. 
8.1. Prior Data 
The Orsiro clinical trial program includes BIOFLOW-II, BIOFLOW-IV and BIOSCIENCE, 
three randomized controlled trials in which subjects were randomized to the Orsiro stent 
against the Xience Prime™ or Xience Xpedition™ stents.  A brief description of these 
trials is provided in Section 3.5.  The inclusion and exclusion criteria for BIOFLOW-II 
and BIOFLOW-IV are nearly identical to those proposed for BIOFLOW-V, whereas the 
inclusion and exclusion criteria in BIOSCIENCE were more liberal to allow enrollment of 
a broadly inclusive real world population.  We propose to use data from the BIOFLOW-II 
and BIOFLOW-IV trials prospectively using a Bayesian approach in the final non-
inferiority analysis of the BIOFLOW-V study.  A summary of the comparison of the study 
design of BIOFLOW-II and –IV trials along with the proposed BIOFLOW-V study can be 
found in Table 8-1. The current status of the studies is as follows: 
 BIOFLOW-II – Enrollment into the trial was completed and 12-month results are 
available.  A total of 298 subjects were randomized to receive the Orsiro stent 
and 154 were randomized to receive the Xience Prime™ stent.  Of them, 287 
Orsiro subjects and 148 Xience subjects completed their 12-month follow-up.   
 BIOFLOW-IV - Enrollment into the trial is still ongoing and it is anticipated that 
370 Orsiro subjects and 185 Xience Prime™/Xpedition™ subjects will be 
contributed from this trial.  
To ensure the validity of data from subjects across trials, the following measures will be 
taken: 

  
 
 
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 Only subjects that meet all BIOFLOW-V clinical and angiographic eligibility 
criteria will be included. 
 Evaluation of the 12-month TLF rate (a primary endpoint in the BIOFLOW-V trial 
and a secondary endpoint in the BIOFLOW-II and BIOFLOW-IV trials) will be 
performed in a uniform fashion, using a consistent set of definitions and similar 
follow-up schedule: 
o The measurement schedule of cardiac enzymes is similar in all trials: 
cardiac enzymes are collected once within 6-24 hours post index 
procedure.  While all trials mandated collection of CK and CKMB, the 
BIOFLOW-II also mandated measurement of troponin.  The BIOFLOW-IV 
and BIOFLOW-V trials allow measurement of troponin if CK and CKMB 
are not used.  To address the differences in the collection of cardiac 
enzymes between the three trials, a uniform definition of peri-procedural 
MI that is based on CK and CKMB levels (with troponin levels used only in 
the absence of CK and CKMB) will be utilized.   
o All trials have similar clinical follow-up schedule at 1 month (telephone 
contact/clinic visit), 6 months (telephone contact/clinic visit) and 12 months 
(telephone contact/clinic visit for BIOFLOW-II clinic visit for BIOFLOW-IV 
and BIOFLOW-V). 
o The BIOFLOW-II and BIOFLOW-IV trials used the same independent 
angiographic core laboratory.  To ensure consistency, angiograms from 
the BIOFLOW-II, BIOFLOW-IV and BIOFLOW-V trials will be analyzed or 
validated by the same angiographic core laboratory. 
o All clinical endpoints (potential TLR, MI and death events) will be re-
adjudicated by the same independent CEC as will be employed for the 
BIOFLOW-V data, using uniform definitions. 
 Data quality will be confirmed in accordance with the monitoring plan of each 
trial. 

  
 
 
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Table 8-1. Subjects’ Poolability 
 
 
8.2. Bayesian Analysis 
To assess the non-inferiority of the Orsiro stent compared to the Xience stent in the 
BIOFLOW-V study, a Bayesian approach using hierarchical models to formally 
incorporate data from the BIOFLOW-II and BIOFLOW-IV trials will be employed.  The 
approach proposes using Binomial analysis for the presence of a TLF event and a 
Bayesian model that allows for a bias between the TLF event rates of the BIOFLOW-II 
and BIOFLOW-IV trials and the TLF event rates of the BIOFLOW-V trial in both the 
Orsiro and Xience groups.  The parameters defining the bias are selected so that the 
proposed method is robust to misspecifications of the initial assumptions.  Further 
details are presented in Section 8.7.  
8.3. Software 
Simulations were run in R statistical package (R citation) and OpenBUGS software,49 
version 3.2.2.  For each scenario, 10,000 datasets were generated in R.  OpenBUGS 
was then used to obtain samples from the posterior distribution of each parameter and 
to calculate the probability of success.  For each analysis, 50,000 samples were 
obtained from the posterior distributions after 1,000 samples were discarded. 

  
 
 
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8.4. Criteria for Success 
The criterion for success is based on the posterior probability of the alternative 
hypothesis (i.e., of non-inferiority being met).  The Orsiro group will be declared non-
inferior to the Xience group if the posterior probability of the alternative hypothesis H୅ is 
large, that is 
ܲሺܪ஺|ܦܽݐܽሻൌܲሺߨ௑
௏െߨை
௏൐െߜ|ܦܽݐܽሻ൐ߨ∗ 
where πଡ଼
୚ and π୓
୚ are the 1-year TLF for the Xience and Orsiro groups of the BIOFLOW-
V study, respectively, δ is the non-inferiority margin and H୅: πଡ଼
୚െπ୓
୚൐െδ is the 
alternative hypothesis indicating that non-inferiority is met and π∗ is the level of 
evidence we require to declare the alternative hypothesis true.  
8.5. Sample Size Determination 
The BIOFLOW-V trial will assess non-inferiority of the 12-month TLF rate for the Orsiro 
stent vs. TLF rate in subjects treated with the Xience stent. 
The null hypothesis is that the Orsiro stent will have a primary endpoint (TLF) rate equal 
to or exceeding that of the Xience group by the non-inferiority margin or more. 
The alternative hypothesis is that the Orsiro stent will have TLF rate less than the 
Xience group rate plus the non-inferiority margin.  Specifically: 
H଴: ߨ௑
௏െߨை
௏൑െߜ 
H୅: ߨ௑
௏െߨை
௏൐െߜ 
Where ߨை
௏ is the true 12-month TLF rate for the Orsiro stent, ߨ௑
௏ is the true 12-month 
TLF rate for the Xience arm, and ߜ is the non-inferiority margin. 
The assumptions for this analysis are: 
 True 12-month TLF rate is 7.0% in both treatment groups (ߨ௑
௏ൌߨை
௏). 
 Power is 89%. 
 3.85% is the absolute non-inferiority margin (55% relative non-inferiority margin). 
 Discount the results of the BIOFLOW-IV data by 20% and BIOFLOW-II data by 
30%. 
 Standard deviation of the bias terms between the ODDS of BIOFLOW-II TLF 12-
month rates and ODDS of BIOFLOW-V 12-month rates is 0.3. 
 Standard deviation of the bias terms between the ODDS of BIOFLOW-IV TLF 12-
month rates and ODDS of BIOFLOW-V 12-month rates is 0.3. 
 Non-inferiority assessment will be assessed using the posterior probability of the 
alternative hypothesis as specified above, where ߨ∗ൌ0.975  
Rejection of the null hypothesis will signify that the Orsiro stent is not inferior to the 
Xience stent with regards to 12-month TLF.  A total of 1,200 subjects (800 in the Orsiro 

  
 
 
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group and 400 in the Xience group) will have 89.6% power to reject the above null 
hypothesis in favor of the alternative under the stated assumptions.  To account for loss 
to follow-up (expected to be approximately 10%), a total of 1,334 subjects will need to 
be randomized.  The one-sided type I error estimates are 4.0%, 3.3%, and 4.2% if the 
actual ODDS for the 12-month TLF rate of event in the Xience group of the BIOFLOW-
IV study are the same, 10% lower and 10% higher when compared with the ODDS for 
the 12-month TLF rate of event in the Xience group of the BIOFLOW-V study. 
True Rate 
The current assumption of the 12-month TLF rate of 7.0% is based on expected 
inclusion criteria for BIOFLOW studies and results from recent everolimus eluting stent 
trials.  
The BIOFLOW-IV trial remains in follow-up for its primary endpoint results.  An interim 
analysis of the observed TLF rate for Orsiro and Xience combined for the two historical 
trials will not be performed due to the timing of data availability.  To mediate the effect 
on power of possible discrepancies between the assumed rate in BIOFLOW-V and 
BIOFLOW-IV, the sample size may be increased by up to 60 additional subjects (40 in 
the Orsiro and 20 in the Xience arm).  The resultant group sizes, 840 Orsiro and 420 
Xience, for a total of 1260 subjects, will result in 89% power or higher. Taking into 
consideration loss for follow-up, the up to 1400 subjects may be enrolled.  
Non-Inferiority Margin 
The non-inferiority margin was calculated based on a meta-analysis rate of the 
difference in treatment effect between DES and BMS.  Randomized clinical trials 
comparing treatment with DES and treatment with BMS with 9 months or longer clinical 
follow-up data were included in the meta-analysis.  Nine-month rates were used 
whenever 12-month rates were not available, as shown in Table 8-2.  Depending on 
study definitions, TVF or MACE rates were used to match as closely as possible the 
TLF definition in this study. 
The meta-analytic rate of the difference in treatment effect between DES and BMS was 
10.0% with a lower bound of the 2-sided 95% CI of 8.2%.  A common practice is to take 
50% of this lower bound of the DES-BMS difference as the non-inferiority margin, 
therefore an absolute non-inferiority margin of 3.85%, which is approximately 46% of 
the lower bound, is supported.  
 

  
 
 
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Table 8-2. TVF/MACE Rates at 9 or 12 Months, DES vs. BMS 
 
Target Vessel Failure Rate 
Major Adverse Cardiac Event Rate 
 
9 Months 
12 Months 
9 Months 
12 Months 
Trial 
DES 
BMS 
DES 
BMS 
DES 
BMS 
DES 
BMS 
RAVEL1 
(MACE: death, MI, CABG, target lesion percutaneous 
revascularization) 
– 
– 
– 
– 
– 
– 
5.8% 
(7/120) 
28.8% 
(34/118) 
SIRIUS2 
(TVF: cardiac death, MI, target vessel repeated 
percutaneous or surgical revascularization) 
– 
– 
9.8% 
(52/533) 
24.8% 
(130/525) 
– 
– 
– 
– 
E-SIRIUS3 
(MACE: death, MI, CABG, TLR) 
– 
– 
– 
– 
8.0% 
(14/175) 
22.6% 
(40/177) 
– 
– 
C-SIRIUS4 
(MACE: death, MI, emergent CABG, clinically-driven TLR) 
– 
– 
– 
– 
4.0% 
(2/50) 
18.0% 
(9/50) 
– 
– 
TAXUS-I5 
(MACE: death, Q-wave MI, TVR, stent thrombosis) 
– 
– 
– 
– 
– 
– 
3.3% 
(1/30) 
10.0% 
(3/30) 
TAXUS-II6 
(MACE: death, MI, TVR) 
TAXUS-SR arm 
– 
– 
– 
– 
– 
– 
10.9% 
(14/129) 
22.0% 
(29/132) 
TAXUS-MR arm 
– 
– 
– 
– 
– 
– 
9.9% 
(13/131) 
21.4% 
(28/131) 
TAXUS-IV7 
(TVF: death, MI, ischemia-driven TVR; MACE: cardiac 
death, MI, ischemia-driven TVR) 
– 
– 
– 
– 
– 
– 
10.8% 
(69/639) 
20.0% 
(126/633)
TAXUS-V8 
(TVF: death, MI, ischemia-driven TVR; MACE: cardiac 
death, MI, ischemia-driven TVR) 
– 
– 
– 
– 
15.0% 
(84/560) 
21.2% 
(120/567) 
– 
– 
TAXUS-VI9 
(MACE: death, MI, TLR and TVR) 
– 
– 
– 
– 
16.4% 
(36/219) 
22.5% 
(51/227) 
– 
– 
ENDEAVOR II10 
(TVF: TVR, recurrent MI, cardiac death not clearly attributed 
to non-target vessel; MACE: death, MI, emergent CABG, 
TLR) 
7.9% 
(47/592) 
15.1% 
(89/591) 
– 
– 
– 
– 
– 
– 
1 Morice MC, Serruys PW, Sousa E et al. for the RAVEL Study Group. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary 
revascularization. New Eng J Med 2002;346:1773–1780. 
2 Weisz G, Leon MB, Holmes Jr DR et al. Two-year outcomes after sirolimus-eluting stent implantation results from the Sirolimus-Eluting Stent in de Novo Native 
Coronary Lesions (SIRIUS) Trial. J Am Coll Cardiol 2006;47:1350–1355. 
3 Schofer J, Schlüter M, Gershlick AH et al. for the E-SIRIUS Investigators. Sirolimus-eluting stents for treatment of patients with long atherosclerotic lesions in 
small coronary arteries: double-blind, randomised controlled trial (E-SIRIUS). Lancet 2003;362:1093–1099. 

  
 
 
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4 Schampaert E, Cohen EA, Schlüter MS et al. for the C-SIRIUS Investigators. The Canadian study of the sirolimus-eluting stent in the treatment of patients with 
long de novo lesions in small native coronary arteries (C-SIRIUS). J Am Coll Cardiol 2004;43:1110–1115. 
5 Grube E, Silber S, Hauptmann KE. TAXUS I: Six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de 
novo coronary lesions. Circulation 2003;107:38–42. 
6 Colombo A, Drzewiecki J, Banning A et al. for the TAXUS II study group. Randomized study to assess the effectiveness of slow- and moderate-release polymer-
based paclitaxel-eluting stents for coronary artery lesions. Circulation 2003;108:788–794. 
7 Stone GW, Ellis SG, Cox DA et al. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: The TAXUS-IV trial. Circulation 
2004;109:1942–1947. 
8 Stone GW, Ellis SG, Cannon L et al. for the TAXUS V investigators. Comparison of a polymer-based paclitaxel-eluting stent with a bare metal stent in patients 
with complex coronary artery disease: A randomized controlled trial. J Am Med Assoc 2005;294:1215–1223. 
9 Dawkins KD, Grube E, Guagliumi G et al. Clinical efficacy of polymer-based paclitaxel-eluting stents in the treatment of complex, long coronary artery lesions 
from a multicenter, randomized trial: Support for the use of drug-eluting stents in contemporary clinical practice. Circulation 2005;112:3306–3313. 
10 Fajadet J, Wijns W, Laarman G-J et al. Randomized, double-blind, multicenter study of the Endeavor zotarolimus-eluting phosphorylcholine-encapsulated stent 
for treatment of native coronary artery lesions: Clinical and angiographic results of the ENDEAVOR II trial. Circulation 2006;114:798–806. 
 

  
 
 
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8.6. Statistical Analysis Sets 
8.6.1. Intent-to-Treat Analysis Population 
The Intent-to-Treat (ITT) population is defined as all randomized subjects.  Subjects are 
analyzed according to the stent to which they were randomized (regardless of the actual 
stent that they received).  This is the primary analysis population. 
8.6.2. Per-Protocol Population 
The Per-Protocol (PP) population is defined as all randomized subjects who received at 
least one assigned study stent, have sufficient follow-up data (at least 11 months of 
follow-up or experienced the primary endpoint) and no major protocol eligibility 
violations (i.e. inclusion/exclusion criteria violations that could impact the primary 
endpoint).  
8.6.3. Modified Intent-to-Treat Analysis Population 
The Modified ITT population is defined as all randomized subjects who received at least 
one study stent according to their treatment assignment.   
8.7. Endpoint Analyses and Reporting of Results 
Descriptive statistics will be used to summarize clinically relevant demographic and 
background characteristics, and safety and effectiveness data collected in this study.  
The statistics for continuous variables will include sample sizes, means, medians, 
standard deviations, inter-quartile ranges, minimum and maximum values.  Categorical 
variables will be described with counts and percentages.  Proportions will be calculated 
using known non-missing values.  Unless otherwise indicated, all statistical tests and/or 
confidence intervals will be performed at α = 0.05 (2-sided). 
All descriptive statistical analyses will be performed using Statistical Analysis Software 
(SAS) for Windows (version 9.1 or higher). 
8.8. Analysis of Primary Endpoint 
Bayesian analyses will be performed using OpenBUGS49 version 3.2.2 or higher. This 
study will assess non-inferiority of the 12-month TLF rate for the Orsiro stent vs. the 
Xience stent.  The analysis will be carried out on the ITT set (primary) and PP analysis 
sets. 
The null hypothesis is that the Orsiro stent will have a primary endpoint (12-month TLF) 
rate equal to or exceeding that of the Xience group by the non-inferiority margin or 
more. 
The alternative hypothesis is that the Orsiro stent will have a 12-month TLF rate less 
than the Xience group rate plus the non-inferiority margin.   
H଴: ߨ௑
௏െߨை
௏൑െߜ 
H୅: ߨ௑
௏െߨை
௏൐െߜ 

  
 
 
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where ߨை
௏ is the true 12-month TLF rate for the Orsiro stent, ߨ௑
௏ is the true 12-month TLF 
rate for the Xience arm, and ߜ is the non-inferiority margin chosen to be 0.0385 (or 
3.85%). 
Due to the randomized nature of the study, we do not expect the two treatment groups 
to differ on clinically important baseline characteristics, therefore no adjustment is 
proposed in the primary analysis.   
The proposed model is a Bayesian hierarchical model that assumes a bias between the 
12-month TLF rates in BIOFLOW-II and BIOFLOW-V as well as BIOFLOW-IV and 
BIOFLOW-V studies.  Full details will be provided in the SAP. 
Center heterogeneity 
To assess consistency of treatment effect size across study centers, Bayesian models 
will be employed for the subject level data.  Any study center with less than 5 subjects 
per treatment group will be pooled with other study centers by geographic region prior to 
carrying out this assessment. 
Individual data, for treatment ݅, study ݆ and individual ݇ will be assumed to follow a 
Bernoulli distribution: 
ܻሾ݅, ݆, ݇ሿ~ܾ݀݁ݎ݊ሺ݌ሾ݅, ݆, ܿ݁݊ݐ݁ݎሾ݇ሿሿሻ 
where center is an index variable that indicates the center that the individual ݇ was 
recruited in.  
The assumptions are based on a similar model to the model proposed in Legrand et al. 
2005.50  The event rate is assumed to have an additive effect for center that varies with 
study: 
݈݋݃݅ݐ൫݌ൣ݅, ݆, ܿ݁݊ݐ݁ݎሾ݇ሿ൧൯ൌߜൣܿ݁݊ݐ݁ݎሾ݇ሿ൧൅൫ܾ݁ݐܽሾ݆ሿ൅ߛൣܿ݁݊ݐ݁ݎሾ݇ሿ൧൯∗ሺܴܶܶ௞ൌ݅ሻ 
The two random effects can be interpreted as the influence of the center on the overall 
TLF rate and on the overall treatment effect, respectively.  The center effects, 
ߜൣܿ݁݊ݐ݁ݎሾ݇ሿ൧ and ߛൣܿ݁݊ݐ݁ݎሾ݇ሿ൧, are assumed to be exchangeable and a priory to follow a 
normal distribution with mean mu_delta and mu_gamma and standard deviation 
sigma_delta and sigma_gamma, respectively.  As recommended by Geltman et al. 199551 
uniform prior on (0.1, 100) will be assumed on the two variances.  The standard 
deviation of the random effects can be viewed as a measure of heterogeneity across 
centers and treatment effect.  As indicated in Spiegelhalter 2004 (Spielgelhalter, D.J., 
Abrams, K.R. and Myles, J.P. (2004). Bayesian Approaches to Clinical Trials and 
Health-Care Evaluation, John Wiley and Sons, page 169) a value of 1 for standard 
deviation of random effects ‘…corresponds to substantial heterogeneity.’, therefore, if 
the posterior probability that ݏ݅݃݉ܽ_݈݀݁ݐܽ൐1 or ݏ݅݃݉ܽ_݃ܽ݉݉ܽ൐1 exceeds 0.85 and 
the credible intervals discussed above indicate the interaction is qualitative in nature, 
then this may preclude all sites from being pooled for the primary analysis, in which 
case the primary analysis may be re-run excluding study centers causing the 
interaction.  Additional details will be provided in the full SAP.     
Region (US/OUS) heterogeneity 

  
 
 
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To assess consistency of treatment effect size across regions (United States [US] vs. 
Outside United States [OUS]) region and an interaction of region and treatment will be 
included in the model. For the interaction coefficient, we will calculate p_int as the 2-
sided posterior probability of observing an interaction value that is more extreme than 0. 
This value is similar to a traditional p-value. If p_int<0.15 we will conclude that 
heterogeneity across region is significant and the treatment effect will be calculated and 
tested within region. 
 
8.9. Handling of Missing Data in the Analysis of Primary Endpoint 
Every effort will be undertaken to limit premature discontinuations and ascertain 
completeness of data collection.  The following analysis strategies will be adopted to 
handle missing data with results compared for consistency prior to carrying out the 
above analysis:  
1. Only subjects who experienced the primary endpoint (TLF at 12 months) or who 
had appropriate follow-up (at least 330 days post baseline, given the 30-day visit 
window allowed around the 12-month visit) will be included in the analysis. 
2. All subjects will be included in the analysis set including data for subjects missing 
primary endpoint status due to not experiencing the event and not reaching at 
least 330 days of follow-up.  Data for these subjects will be included as ‘NA’. A 
model will be used for the event probabilities: 
ܻሾ݅, ݆, ݇ሿ~ܾ݀݁ݎ݊ሺ݌ሾ݅, ݆, ܿ݁݊ݐ݁ݎሾ݇ሿሿ 
with 
݈݋݃݅ݐ൫݌ൣ݅, ݆, ܿ݁݊ݐ݁ݎሾ݇ሿ൧൯ൌܾ݁ݐܽ∗ܺሾ݇ሿ൅݈݋݃݅ݐሺ݌ሾ݅, ݆ሿሻ 
where ܺሾ݇ሿ are predictors values for subject ݇. A noninformative prior will 
be assumed on the slope parameters ܾ݁ݐܽ and similarly to the analysis of 
the primary endpoint, bias will be assumed between TLF rates in different 
studies. 
The following variables will be included in the model as covariates: 
 Age 
 Gender 
 Diabetes 
 Lesion length 
 Others (the complete set will be detailed in the full SAP) 
3. Time to event analysis using a Bayesian Cox regression analysis.  For each 
study, a separate hazard ratio comparing Xience to Orsiro stent will be included.  
Similar to the method proposed as a primary method, a bias will be assumed 
between the hazard ratio of BIOFLOW-II or BIOFLOW-IV and the hazard ratio of 
the BIOFLOW-V.  Further details will be provided in the full SAP. 

  
 
 
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4. A tipping point analysis will be carried out.  Here, it is assumed that for all Xience 
patients with missing primary endpoint (12-month TLF) status, TLF did not occur. 
For Orsiro patients with missing data, it will be first assumed that the primary 
endpoint of TLF occurred for exactly one such patient; then the primary analyses 
will be re-run to assess if non-inferiority is met under this assumption.  Then it will 
be assumed the primary endpoint occurred for exactly two Orsiro patients with 
missing data, and the primary non-inferiority analysis will be rerun.  The process 
will continue sequentially in this manner until all Orsiro patients with missing data 
are considered to have met the primary endpoint of TLF.  Of interest is the 
“tipping point”, or i.e., the number of imputed Orsiro TLFs where non-inferiority is 
not met in this analysis. 
 
8.10. Analysis of Secondary Endpoints 
Analyses of secondary endpoints will be carried out on the ITT, Modified ITT and PP 
analysis sets using the same method proposed for the primary endpoint.  Secondary 
Endpoints include the following measures:  
1. Device success 
2. Lesion success 
3. Procedure success 
The following secondary clinical endpoints will be evaluated prior to discharge, at 1-, 6- 
and 12-months and annually thereafter through 5 years follow-up: 
4. Death 
5. MI 
6. Cardiac death or MI 
7. MACE and individual MACE components  
8. TLF and individual TLF components  
9. TVF and individual TVF components  
10. Stent thrombosis according to ARC criteria  
Included in the analysis, will be subjects experiencing the event or who have adequate 
follow-up (e.g., at least 23 days for 1-month time point, at least 166 days for the 6-
month time point, and at least 330 days for the 12-month time point). 
As an additional analysis, for time-to-event endpoints, Bayesian Cox regression will be 
used.  For each study, a separate hazard ratio comparing Xience to Orsiro stent will be 
included.  Similarly to the method proposed as a primary method, a bias will be 
assumed between the hazard ratio of BIOFLOW-II or BIOFLOW-IV and the hazard ratio 
of the BIOFLOW-V.  All subjects will be included, where subjects not experiencing the 
event will be censored at last known follow-up or at the end of the relevant follow-up 
time, whichever is earlier.  

  
 
 
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8.11. Analysis of Baseline Demographics and Procedural Characteristics 
Although we do not expect differences between the two treatment groups due to 
randomization, a comparison of the demographic and baseline characteristics in 
between the two treatment groups will be performed.  Demographic, medical history and 
other clinically relevant baseline variables will be summarized by treatment using 
descriptive statistics (i.e. number of observations available, mean, standard deviation, 
minimum, and maximum for continuous variables and counts and percentages for 
qualitative variables).  Treatment difference on dichotomous variables will be evaluated 
using Fisher’s exact tests.  Categorical variables will be compared between treatments 
using the Cochran-Mantel-Haenszel (CMH) Modified Ridit Scores, i.e. CMH of general 
association for nominal variables and CMH of row mean score for ordinal variables).  
Continuous variables will be compared between treatments using a two-sample t-test.   
8.12. Subgroup Analysis 
Subgroups for secondary analysis of clinical endpoints include: 
 Reference vessel diameter ≤ 2.75 mm/ > 2.75 mm. 
Note: Subjects with at least one target lesion ≤ 2.75 mm will be classified with the 
small vessel subgroup.  
 Subjects > 75 years of age/subjects ≤ 75 years of age. 
 Women/men. 
 Subjects with diabetes/subjects without diabetes. 
 Lesion length > 26 mm and ≤ 26 mm in length  
 Single stents versus overlapping stents for lesion lengths > 26 mm  
Treatment group difference (Orsiro minus Xience) in the primary endpoint rate and the 
two-sided 95% credible interval of the difference will be presented within each 
subgroup.  A test of interaction on the primary endpoint will be performed to formally 
assess heterogeneity of treatment effect on the primary endpoint across subgroups in 
the same manner that will be used the assessment of region heterogeneity discussed 
above.  The purpose of this analysis is not to formally assess non-inferiority within each 
subgroup, but simply to assess consistency of results across the various subgroups.  
Subjects with an event or with appropriate follow-up will be included in this analysis. 
8.13. Adverse Event Analysis 
Only AEs whose frequency exceeds 10 will be compared between the two groups. For 
those AEs, if ݌ை and ݌௑ are the probability of the AE with the Orsiro and Xience stents, 
we will report the posterior distribution that ݌ை൐݌௑ , that is, the posterior probability that 
the probability of the AE is larger with the Orsiro stent than with Xience stent. Non-
informative independent priors Beta (0.1,0.1) will be assumed on ݌ை and ݌௑, 
respectively. 
 
 

  
 
 
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9. ADVERSE EVENTS 
In this study, subjects should be encouraged to report adverse events (AEs) 
spontaneously or in response to general, non-directed questioning (e.g., “How has your 
health been since the last visit?”).  Any time during the study, the subject may volunteer 
information that resembles an adverse event.  If it is determined that an AE has 
occurred, the investigator should obtain all information required to complete the AE 
eCRF. 
 
9.1. Definitions 
9.1.1. Adverse Events 
An adverse event is defined as any untoward medical occurrence, unintended disease 
or injury, or untoward clinical signs (including abnormal laboratory findings) in clinical 
trial subjects, whether or not related to the investigational medical device. 
NOTE 1: This definition includes events related to the investigational medical 
device or the comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
NOTE 3: Abnormal laboratory findings will be considered AEs, only if determined 
by the investigator to be clinically significant. 
Any current condition that is recorded as a pre-existing condition either in the medical 
history of physical examination section, unless there is a change in nature, severity, or 
degree of incidence, is not an AE. 
Adverse events shall be assessed and documented throughout the course of the trial 
beginning after the subject has been enrolled.  All adverse events should be recorded 
on the appropriate subject eCRF and followed through to their resolution regardless of 
time window. 
9.1.2. Adverse Device Effect 
An adverse device effect (ADE) is a device-related adverse event, i.e., any adverse 
event for which a causal relationship between the device and the event is at least a 
reasonable possibility (the relationship cannot be excluded).  Note that this definition 
includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation or operation, or any malfunction of the 
investigational medical device, as well as any event resulting from user error or from 
intentional misuse of the investigational medical device. 
Device Failure: A device has failed if it is used in accordance with the IFU, but 
does not perform according to IFU and negatively impacts treatment. 
Device Malfunction (ISO 14155:2011): Failure of an investigational medical 
device to perform in accordance with its intended purpose when used in 
accordance with the IFU or Clinical Investigation Protocol (CIP). 

  
 
 
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Device Deficiency (ISO 14155:2011): Inadequacy of a medical device with 
respect to its identity, quality, durability, reliability, safety or performance.  Device 
deficiencies include malfunctions, user errors and inadequate labeling. 
Near Incident: Malfunction or deterioration in characteristics and/or performance 
of the device, which might have led to death or serious deterioration in health; 
incident occurred and is such that if it occurred again, it might lead to death or 
serious deterioration in health. 
User Error: Act or omission of an act that results in a different medical device 
response than intended by the manufacturer or expected by the user.  User error 
includes slips, lapses and mistakes.  An unexpected physiological response of 
the subject does not in itself constitute a user error. 
9.1.3. Serious Adverse Event 
Due to the international conduct of the study, the ISO 14155 definition of serious 
adverse events and device effects will be utilized.  
A serious adverse event (SAE) is an adverse event that leads to: 
 Death. 
 Serious deterioration in the health of the subject that either results in life-
threatening illness or injury; permanent impairment of a body structure or a body 
function; hospitalization or prolonged hospitalization; or medical or surgical 
intervention to prevent life-threatening illness, injury or permanent impairment to 
a body structure or a body function. 
 Fetal distress, fetal death, congenital abnormality or birth defect 
Note that planned hospitalization for pre-existing condition (scheduled prior to the 
subject signing the informed consent for the study), or a procedure required by the 
clinical study plan, without a serious deterioration in health, is not considered to be an 
SAE. 
Also note that in the European Union and OUS countries, SAEs also include device 
deficiencies that might have led to an SAE if suitable action had not been taken, 
intervention had not been made, or if circumstances had been less fortunate.  These 
are handled under the SAE reporting system. 
9.1.4. Serious Adverse Device Effect 
A serious adverse device effect is an adverse device effect that results in any of the 
consequences characteristic of a serious adverse event. 
9.1.5. Anticipated Adverse Event 
An anticipated adverse event is any undesirable experience (sign, symptom, illness, 
abnormal laboratory value or other medical event) occurring to a subject, whether or not 
considered related to the investigational product(s) or drug regimen prescribed as part 

  
 
 
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of the clinical protocol, pre-defined in the clinical protocol and/or IFU, that is identified or 
worsens during a clinical study. 
For anticipated AEs that have been identified as possible complications of the Orsiro 
stent, please see Section 13.1. 
9.1.6. Unanticipated Adverse Device Effect or Unanticipated Serious 
Adverse Device Effect 
An unanticipated adverse device effect (UADE) is defined in 21 CFR 812.3(s) as 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 any 
other unanticipated serious problem associated with a device that relates to the rights, 
safety or welfare of a subject. 
In the European Union and other OUS countries, the term unanticipated serious 
adverse device effect (USADE) as defined in ISO14155:2011, is any 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. 
9.1.7. Device Failures, Malfunctions and Misuse 
Investigators are instructed to report all possible device failures, malfunctions or misuse 
observed during the course of the trial.  These incidents will be documented in the 
electronic case report form provided as follows: 
Device Failure: A device failure has occurred when the device is used in 
compliance with the IFU, but does not perform as described in the IFU and also 
negatively impacts treatment of the study subject. 
Device Malfunction: Failure of an investigational medical device to perform in 
accordance with its intended purpose when used in accordance with the IFU or 
CIP. 
Device Misuse: Any use of the investigational device by an investigator that is 
contradictory to the application described in the IFU will be categorized as device 
misuse and is to be reported as a significant protocol deviation. 
9.2. Documentation 
Adverse events must be listed on the appropriate eCRF.  All adverse events will be 
characterized by the following criteria: 
 Relatedness to the study device and procedure 
 Outcome 
 Treatment or action taken 
All adverse events (serious and non-serious) will be reported for the entire study period 
in accordance with national laws.   

  
 
 
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For US sites only: All adverse events will be reported for the first 12 months of the 
subject’s study participation until the primary endpoint is determined.  After the 12-
month follow-up visit, continuing AEs will be followed through to resolution or until event 
becomes stable and only serious adverse events, including MACE and clinical study 
endpoints, are required to be reported.   
9.3. Relatedness 
The Principal Investigator (PI) will evaluate if the AE or SAE is related to the 
investigational device or study procedure.  Relatedness is defined in the following 
manner: 
Not related: The PI has determined that the complication is not related to the 
study device. 
Possible: The PI has determined that the event has a possible relationship to the 
use of the investigational device. 
Definite: The PI has determined that the complication is related to the 
investigational device. 
Both possible and definite relationship designations will be considered device-related for 
reporting purposes. 
9.4. Reporting of Serious Adverse Events 
All participating study sites should report SAEs to BIOTRONIK or its designee as soon 
as possible, preferably by completing an Adverse Event eCRF.   
OUS centers should report SAEs immediately upon awareness of the event and 
completes the AE eCRF Serious Adverse Event section, which will then trigger an initial 
SAE notification to a pre-defined recipient list.  
The investigator should notify BIOTRONIK or its designee as soon as possible 
concerning any subject death during the study in EDC.  The death should be reported 
on the Study Exit eCRF.  In addition, the precipitating cause of death should be 
recorded on an Adverse Event eCRF, reflecting an outcome of death, once determined.  
Documentation of the death event should be sent to BIOTRONIK as soon as it is 
available, and should include the appropriate completed CRFs, a death certificate and a 
copy of the notification of the death sent to the IRB/EC, as required.  If a death 
certificate is not available, a detailed statement (death report) signed by the investigator 
should be provided.   
The death report should include all of the following, if available: 
 Date, time and place of death 
 Immediate cause of death 
 Circumstances surrounding the death 
 Relationship to the investigational stent and/or any study-related procedures 

  
 
 
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It is the responsibility of each investigator to report all SAEs to the reviewing IRB/EC, 
according to national regulations and IRB/EC requirements.  A copy of the IRB/EC 
report should be forwarded to the sponsor or its authorized representative. 
Additionally, at OUS sites, SAEs will be reported to the competent authorities in 
accordance with applicable regional/national regulations.  BIOTRONIK or its authorized 
representative, and/or the investigator will report SAEs to the applicable regulatory 
agencies in accordance with national regulations. 
OUS Sites Primary contact for Serious Adverse Events: 
BIOFLOW–V Safety Team 
Harvard Clinical Research Institute 
930-W Commonwealth Ave. 
Boston, MA 02215-1212 
 
Tel:  +1 617 307–5200 
Fax: +1 617 307–5656 
HCRIBIOFLOW-VSAFETY@hcri.harvard.edu 
9.5. Reporting of Adverse Events 
Study sites are required to adhere to applicable US FDA regulations, as well as ISO 
requirements for EU sites, as well as local IRB/EC adverse event reporting.  In specific 
OUS regions, there may also be requirements for OUS investigators to report specific 
adverse events directly to their competent authority or national regulatory body. 
Table 9-1. Adverse Events Reporting 
Adverse Event 
Report in 
EDC 
 
Report to 
IRB/EC 
Report to 
CA – OUS sites only 
Event resulting in death* 
Required 
Required 
CA-dependent 
Unanticipated adverse device effect 
Required 
Required 
CA-dependent 
Procedure and/or stent related 
adverse event 
Required 
IRB/EC-dependent 
CA-dependent 
Serious adverse event (not stent or 
procedure related) 
Required 
IRB/EC-dependent 
CA-dependent 
Other adverse events – not related** 
Required 
IRB/EC-dependent 
CA-dependent 
CA: Competent Authority; EC: Ethics Committee; IRB: Institutional Review Board; OUS: Outside of 
United States 
* The cause of death to the extent available should be reported as an adverse event, with the outcome reflected 
as death.  Reporting to EC in accordance with local requirements. 
** US sites only: reporting required through the 12-month follow-up visit or longer if required by the IRB/EC. 

  
 
 
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9.5.1. Reporting Adverse Device Effects 
All participating study sites should report adverse device effects (ADE) and serious 
adverse device effects (SADE) to BIOTRONIK or its designee as soon as possible, 
preferably upon awareness of the event (OUS sites), by completing an Adverse Event 
eCRF.   
At sites in the OUS or other participating countries where the Orsiro stent is market-
released, these events must also be reported in addition to the product complaint 
management department of BIOTRONIK.  The retrievable part of the devices should be 
returned to BIOTRONIK for analysis.  If there is also a suspected relation to accessory 
material (guide wire, etc.) the accessory material in question should also be sent to 
BIOTRONIK for analysis. 
Complaint Management Department 
BIOTRONIK AG 
Ackerstrasse 6 
8180 Bülach 
Switzerland 
cnf.vi@biotronik.com  
Fax: +41 44 864 5181 
Investigational stents that are returned to the US will be sent to BIOTRONIK AG, 
Bülach, Switzerland, for analysis.  Those analyses will be trended (as appropriate) and 
reported to FDA as soon as they are available.  
9.5.2. Reporting of Unanticipated Adverse Device Effects or Unanticipated 
Serious Adverse Device Effects 
If an adverse event occurs that the investigator believes may be a potential 
UADE/USADE, the site should immediately contact the sponsor or its authorized 
representative to determine reporting requirements.  In addition, when there is a reason 
to believe a device may have malfunctioned, causing potential harm to a subject, the 
site should immediately notify the sponsor. 
The investigator shall submit to BIOTRONIK and the reviewing IRB/EC a report of any 
potential UADE occurring during the study as soon as possible, but in no event later 
than 10 calendar days after the investigator first learns of the effect in accordance with 
FDA regulations.  In the EU or other OUS countries, any potential USADE shall be 
reported according to national regulations.  All UADEs/USADEs must be documented 
by the investigator, including date of onset, complete description of event, possible 
reason(s) for event, severity, duration, actions taken and outcome.  Copies of all 
supporting documents should be submitted concurrently with the AE eCRF 
documenting the UADE/ USADE. 
Subsequently, BIOTRONIK or its designee will submit a report to FDA (and any other 
applicable competent authorities) and to all reviewing IRBs/ECs and participating 
investigators within 10 calendar days after the Sponsor first receives notice of the effect.  
The Sponsor or its designee will submit other reports as required by the FDA and other 

  
 
 
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applicable regulatory agencies.  The final determination of an event being classified as 
an unanticipated event will be initially determined by HCRI, and confirmed by 
BIOTRONIK. 
 
9.6. Reporting of Study Endpoint Adverse Events 
Whenever a clinical event related to a study endpoint is suspected or identified, all 
supporting 
source 
documents 
(i.e. 
progress 
notes, 
discharge 
summaries, 
catheterization lab reports, ECGs, lab results, etc.) should be submitted according to 
CEC source documentation collection procedures as soon as they are available.  The 
source documentation required for each reported event is listed in the CEC charter. 
 
 

  
 
 
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9.7. Reporting Responsibilities 
Table 9-2. Investigator Reporting Responsibilities 
ASAP: as soon as possible; EC: Ethics Committee; FDA: Food and Drug Administration; IDE: 
investigational device exemption; IRB: Institutional Review Board. 
* Reporting to IRB/EC only where required by local legal requirements. 
** FDA requires 10 working days. 
 
 
Type of Report 
Investigator Reporting Responsibilities 
Report 
Prepared 
For 
Reporting Timeframe 
FDA-Defined Reports 
Unanticipated adverse device 
effect 
Sponsor 
 
IRB/EC* 
As soon as possible, upon awareness of the effect. 
Written: within 10 calendar** days after the investigator first 
learns of the effect. 
Subject’s death 
Sponsor and 
IRB/EC* 
Written: as soon as possible and as required by reviewing 
IRB/EC, but not to exceed 10 days from date of site 
notification of subject death. 
Withdrawal of IRB/EC approval 
or other action on part of the 
IRB/EC that affects the study 
Sponsor 
Written: within 5 working days of IRB/EC decision. 
Progress reports 
IRB/EC* 
At regular intervals, but in no event less than yearly. 
Significant deviations from 
investigational plan 
Sponsor and 
IRB/EC* 
Emergency: ASAP but in no event later than 5 working 
days after deviation occurs to protect the life or physical 
well-being of a subject in an emergency. 
Non-emergency: prior approval by Sponsor and, if 
deviation may affect scientific soundness of the trial or the 
rights, safety or welfare of subject, also by the IRB/EC and 
FDA as an IDE supplement. 
Informed consent not obtained 
Sponsor and 
IRB/EC* 
Within 5 working days of use of the investigational device. 
Final report 
Sponsor and 
IRB/EC* 
Within 3 months after termination or completion of study or 
termination of site’s participation. 
Other Reports 
Adverse Events 
Sponsor and 
IRB/EC* 
In accordance with the protocol, applicable local 
regulations, and IRB/ EC requirements.   

  
 
 
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Table 9-3. Sponsor Reporting Responsibilities 
Type of Report 
Sponsor Reporting Responsibilities 
Report Prepared For 
Reporting Timeframe 
FDA-Defined Reports 
Unanticipated adverse device 
effects/unanticipated serious 
adverse device effects 
FDA, all reviewing 
IRBs/ECs*, participating 
investigators and appropriate 
CAs* 
Written: within 10 calendar** days 
from the time the sponsor first learns 
of the effect. 
Withdrawal of IRB/EC approval 
FDA, all reviewing 
IRBs/ECs*, participating 
investigators and appropriate 
CAs* 
Written: within 5 working days. 
Withdrawal of FDA approval 
Reviewing IRBs/ECs*, 
participating investigators 
and appropriate CAs* 
Written: within 5 working days. 
Device recall 
FDA, all reviewing 
IRBs/ECs*, participating 
investigators and appropriate 
CAs* 
Written: within 30 working days. 
Progress reports 
FDA, all reviewing 
IRBs/ECs*, participating 
investigators and appropriate 
CAs* 
At regular intervals, but in no event 
less than yearly. 
Current Investigator List 
FDA 
Names and addresses of 
participating investigators at 6-
month intervals (starting at 6 months 
after FDA approval). 
Informed consent not obtained 
FDA and appropriate CAs* 
Within 5 working days of notification. 
Study closure 
FDA, all reviewing 
IRBs/ECs*, participating 
investigators and appropriate 
CAs* 
Within 30 working days of 
completion or decision to terminate 
the study. 
Final report 
FDA, all reviewing 
IRBs/ECs*, participating 
investigators and appropriate 
CAs* 
Within 6 months of study closure. 
Other Reports 
Periodic SAE / ADE summaries 
Reviewing EC* and 
appropriate CAs* 
In accordance with EU regulations 
or other OUS national regulations, 
and/or local legal requirements, or 
upon request.   
CA: Competent Authority; EC: Ethics Committee; FDA: Food and Drug Administration;  
IRB: Institutional Review Board 
*EC and CA reporting to the extent required by national, local laws and EC-specific requirements. 

  
 
 
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**FDA requires 10 working days. 
10. DATA HANDLING AND RECORD KEEPING 
The investigator is required to prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the 
investigation on each individual treated with the investigational product or entered as a 
control in the investigation. 
10.1. Electronic Data Capture 
MedNet Solutions Incorporated is a privately-held company that specializes in web-
based clinical database and data management technology. MedNet will partner with 
BIOTRONIK in the development, implementation, and on-going support of a system for 
EDC of clinical trial data for the study.  MedNet may host the database utilized for the 
EDC system. This system will be 21 CFR Part 11 compliant and will be the conduit for 
the electronic case report form (eCRF) data entry, data validation, and access to real-
time configured functions, tools, and reports for BIOTRONIK, specified study sites and 
any other parties authorized by BIOTRONIK. 
10.2. Electronic Case Report Form Completion 
An electronic data capture (EDC) system will be built for the study.  The EDC system 
will include electronic case report forms (eCRFs) designed to capture study information, 
which are completed by trained site staff.   
eCRFs documenting SAEs, U(S)ADEs, device failures and device malfunctions, should 
be submitted via the EDC system as soon as possible, preferably within 24 hours after 
the investigator becomes aware of the event.   
All other eCRFs should be completed in a timely manner, preferably within 5-10 days of 
the subject’s enrollment or follow-up visit.  
All angiographic media should be prepared and sent to the angiographic core laboratory 
preferably within 7 working days of data collection. 
All collected study data will be made available (and sent in the appropriate format) to 
the sponsor, if requested, after the study has reached its primary endpoint at 12 months 
post-procedure. 
10.3. Investigator Records 
Investigators are required to maintain on file the following accurate, complete and 
current records relating to this study: 
 All correspondence relating to the study with another investigator, an IRB/EC, 
BIOTRONIK, a monitor, the FDA (e.g., a letter sent from the investigator to the 
IRB/EC), or any other regulatory agency. 
 All clinical forms and documentation, including: 
o A copy of the signed subject consent form 
o Date and time of exposure to investigational stent 

  
 
 
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o All procedure and follow-up report forms, including supporting documents 
o Records of any adverse event, including supporting documentation 
o Records pertaining to subject deaths during the study 
o Documentation and rationale for any deviations from the clinical protocol 
o Any other records required by BIOTRONIK 
10.4. Sponsor Records 
BIOTRONIK will maintain the following records: 
 All correspondence pertaining to study with the investigator(s), IRB/EC and FDA 
(or any other competent authority) 
 Investigational stent shipment and inventory reconciliation reports (US sites only) 
 Investigator agreements, financial disclosures and current curriculum vitae 
 Name and address of each investigator and each IRB/EC involved with the study 
 Adverse events and complaints 
 Adverse device effects (whether anticipated or unanticipated) 
 Completed eCRFs 
 Confirmation of completed subject informed consent forms 
 Clinical Investigational Plan and report of prior studies 
 Screening visit reports 
 Monitoring reports 
 Clinical progress reports 
 Any other records that FDA requires to be maintained by regulation or by specific 
requirement for a category of investigation or a particular investigation. 
 Records pertaining to DMC and CEC activities. 
 Statement of the extent to which the good manufacturing practice regulation Part 
21 CFR 820 will be followed in manufacturing the stent 
11. STUDY COMMITTEES 
11.1. Steering Committee 
The steering committee is composed of the US and OUS study principal investigators, 
the steering committee chairman and experts representing the field of cardiology, 
interventional radiology and statistics.  The steering committee participates in sponsor-
requested meetings to review study progress and conduct, and to provide feedback to 
the sponsor on an ad hoc basis. Steering committee membership will be decided by the 
sponsor. 

  
 
 
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11.2. Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will have responsibility for 
monitoring safety and efficacy aspects of the study.  Its conduct will be governed by a 
written charter describing its rules of operation and responsibilities.  It will be composed 
of at least four members with experience in clinical trial research: three physicians from 
the fields of cardiology and interventional cardiology and one biostatistician who are not 
directly involved in the conduct of the trial. 
The DMC will review aggregate and individual subject data related to safety, data 
integrity, and overall conduct of the trial on a periodic basis, to be defined at their first 
meeting prior to enrollment of the first subject in the study.  The DMC will be unblinded 
to BIOFLOW-V treatment group assignment.   
The primary responsibility of the DMC will be to provide oversight on safety aspects of 
the study.  The DMC may make three primary types of recommendations to the steering 
committee and study Sponsor as a result of its monitoring activities:  
 Continuing the study without changes;  
 Stopping the study for safety reasons; or, 
 Continuing the study with changes to its protocol or conduct. 
There is no planned formal interim efficacy analysis for the DMC to inspect.  The study 
will not be stopped for accumulating evidence of benefit or futility.  
Any material changes to the study protocol or conduct recommended by the DMC that 
affect the collection or evaluation of scientific evidence, or terms and conditions of the 
IDE approval, and which the sponsor desires to implement, will be subject to prior 
review and approval by the FDA. 
11.3. Clinical Events Committee 
The clinical events committee (CEC) for this study will consist of the standing members 
of the CEC who are not participants in the study.  The CEC is charged with the 
development of specific criteria used for the categorization of clinical events and clinical 
endpoints in the trial. 
Explicit rules outlining the minimum amount of data required, and the algorithm followed 
to classify study endpoint–related clinical events will be established and provided in a 
separate CEC charter and adjudication manual.  The CEC will then meet regularly to 
review and adjudicate study endpoint–related clinical events in which the required 
minimum data are available.  The committee will also review and rule on all deaths that 
occur throughout the trial.  All members of the CEC will be blinded to the randomized 
treatment group of the subject and to the primary results of the trial. 
To ensure consistency and poolability of subjects across trials, the BIOFLOW-V CEC 
will perform re-adjudication to validate the potential study endpoint–related clinical 
events (TLR,  MI and cardiac deaths) occurring in the BIOFLOW-II and BIOFLOW-IV 
studies using the same criteria established for the BIOFLOW-V. 
 

  
 
 
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12. ETHICAL AND REGULATORY CONSIDERATIONS 
This study will be conducted in accordance with the principles outlined in the 
Declaration of Helsinki and all local GCP requirements. 
12.1. Role of the Study Sponsor 
BIOTRONIK as the study sponsor, has the overall responsibility for the conduct of the 
study, including ensuring that the study meets and is conducted within the regulatory 
requirements specified by each reviewing regulatory authority.  In this study, the 
sponsor will have certain direct responsibilities and may delegate other responsibilities 
to Harvard Clinical Research Institute (HCRI) and/or other designees.  The sponsor, 
HCRI and/or other designees will ensure adherence to the sponsor general duties, 
selection of investigators, monitoring, supplemental applications, maintaining records 
and submitting reports. 
12.2. General Duties 
BIOTRONIK’s general duties include submitting the application to appropriate regulatory 
authorities and obtaining overall regulatory approval. 
BIOTRONIK is responsible to obtain the approval from the competent authority, if 
applicable, prior to any site initiation. BIOTRONIK will report to the competent 
authorities any new information that may affect the safety of the subjects or the conduct 
of the clinical investigation, as applicable. 
The sponsor or its designees are responsible for ensuring informed consent is obtained, 
proper clinical site monitoring is performed, providing quality data that satisfy 
regulations, and informing study investigators of UADE/USADE and deviations from the 
protocol, as appropriate. 
As the designated data coordinating center, BIOTRONIK or its designee will prepare 
written reports and a final report as directed, and will coordinate data collection and 
transfer with the angiography core laboratory and other vendors. 
12.3. Subject Confidentiality 
Subject confidentiality will be maintained throughout the clinical study in a way that 
assures that data can always be tracked back to the source data.  For this purpose, a 
unique subject identification code (ID number and subject name code) will be used that 
allows identification of all data reported for each subject. 
Data relating to the study might be made available to third parties (e.g., in case of an 
audit performed by regulatory authorities) provided the data are treated as confidential 
and that the subject’s privacy is guaranteed. 
“Protected health information” will be treated and maintained in compliance with the 
Health Insurance Portability and Accountability Act (HIPAA) of 1996 privacy rule, the 
directive 95/46/EC (European Directive for data protection law) and applicable local 
laws on the protection of individuals with regard to the processing of personal data and 
on the free movement of such data. 

  
 
 
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The duration of storage time of personal data at the investigational sites will be in 
accordance with national regulations. 
12.4. Informed Consent and Institutional Review Board or Ethics Committee 
Prior to the subject's participation in the study, written informed consent is required from 
all subjects in accordance with their IRB/EC.  Informed consent should be obtained in 
accordance with the FDA regulations (21CFR, Part 50), ISO 14155, ICH/GCP 
Guidelines, the Declaration of Helsinki and any other national or local requirements.  
The investigator is required to inform BIOTRONIK and the reviewing IRB/EC within five 
days if any subject has not appropriately consented to participate in the study.  
BIOTRONIK is then required to report any failure to obtain subject consent to the FDA 
within five working days of learning of such an event.  In order to assist with the consent 
process, BIOTRONIK will provide a subject consent template form to study sites as a 
basis for adaptation to local requirements and submission to their IRB/ EC for approval. 
IRB/EC approval is required from each institution prior to participation in this clinical 
study.  Subject enrollment may not begin until the IRB/EC and BIOTRONIK have 
granted approval for the study site.  IRB/EC approval is also required throughout the 
duration of this clinical study.  If IRB/EC approval is withdrawn, BIOTRONIK must be 
notified within 5 working days. 
12.5. Monitoring 
Qualified monitors representing the sponsor will conduct on-site monitoring visits to 
ensure that all investigators conduct the study in compliance with the protocol and 
investigators’ agreements.  The site will receive notification prior to each monitoring visit 
during the course of the study.  It is expected that the investigator and/or sub-
investigator, research coordinator assigned to the study, and other appropriately trained 
study staff will be available on the day of the visit. 
The progress of the study will be monitored by: 
 Ensuring completed eCRFs match source documents, and resolution of any 
discrepancies.  Direct access to complete source documents must be made 
available during monitoring visits for verification of eCRF data. 
 Periodic on-site visits and, if necessary, remote monitoring of data. 
 Frequent telephone or email communications between the investigator and 
assigned study site monitors. 
12.5.1. 
Visits 
Periodic monitoring visits will be made in accordance with the approved monitoring plan 
throughout the clinical study to ensure that the investigator’s obligations are fulfilled and 
all applicable regulations and guidelines are being followed.  These visits will ensure 
that the facilities are still acceptable, the protocol and investigational plan are being 
followed, the IRB/EC has been notified of approved protocol changes as required, 
complete records are being maintained, appropriate and timely reports have been made 

  
 
 
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to the sponsor and the IRB/EC, device and device inventory are controlled, and the 
investigator is executing all agreed-upon activities. 
The sponsor or its designees retain the right to remove either the investigator or the 
investigational site from the study for issues of non-compliance with the protocol or 
regulatory requirements.  BIOTRONIK or its designee will perform the monitoring 
responsibilities according to its standard operating procedures. 
On one or more occasions, the study site may be inspected or audited by the sponsor, 
its designee, or applicable regulatory authorities.  The investigator will be informed in 
advance of this audit and is expected to allow access to the original medical records 
and provide all requested information. 
A representative or designee of the sponsor may accompany the study site monitor to 
the site. 
12.6. Protocol Compliance 
The investigator is required to conduct the study in accordance with the signed 
investigator agreement and clinical protocol.  The investigator shall notify BIOTRONIK 
and the reviewing IRB/EC in writing, no later than 5 working days after any significant 
deviation from the study plan, to protect the life or physical well-being of a subject in an 
emergency.  Except in such emergency, prior approval by BIOTRONIK is required for 
significant deviations from the study plan.   
BIOTRONIK categorizes instances of protocol non-compliance as either violations or 
deviations. 
12.6.1. 
Protocol Violations 
Protocol violations are defined as instances where the protocol requirements and/or 
regulatory guidelines were not followed and are generally more serious in nature.  
Protocol violations are considered to potentially affect the scientific soundness of the 
study and/or the rights, safety or welfare of subjects. 
Protocol violations include, but are not limited to: 
 Failure to obtain informed consent 
 An unapproved (BIOTRONIK and IRB/EC) investigator implanting an 
investigational stent for study purposes 
 Subject inclusion/exclusion violations and protocol requirement violations that 
affect the primary endpoints of the study design 
In some instances, compliance issues with the consent process may occur. The 
investigator should seek guidance from the site’s IRB/EC to ensure the subject received 
appropriate information to consider their participation in the study.  The investigator is 
obligated to take any action the IRB/EC feels is necessary, including subject removal 
from the study.   

  
 
 
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Deviations in the consent process for subjects that the IRB/EC allows to continue in the 
study will be considered protocol violations in the analysis of study data. 
All violations will be reported to FDA in accordance with applicable regulatory timelines. 
The study site should report the protocol violation to the reviewing IRB/EC and provide 
a copy of the notification to BIOTRONIK.  The site should also report the protocol 
violation to BIOTRONIK on the applicable CRF. 
12.6.2. 
Protocol Deviations 
Protocol deviations are defined as instances where protocol requirements are not 
followed in such a manner whereby data is unusable or unavailable.  Protocol 
deviations are less serious in nature and do not require IRB/EC notification, as long as 
they do not have an effect on the rights, safety or welfare of the study subject. 
Protocol deviations include, but are not limited to: 
 Procedure not performed within the allowed follow-up window 
 Required data not obtained 
 Follow-up procedure performed at an unapproved location 
The study site should report the protocol deviation on the applicable CRF. Both protocol 
deviations and violations will be reported to FDA in progress reports. 
12.7. Device Accountability and Storage 
Tracking of the investigational product used in this study will be consistent with  
21 CFR Part 821 and ISO 14155:2011, and in accordance with location-specific 
requirements. 
If an Orsiro stent is opened, but not implanted, it must be returned to the sponsor in 
accordance with the sponsor’s packaging and shipping instructions. 
Subject to availability, the sponsor will provide the site with replacement consignment 
inventory of the Orsiro stent.  Additionally, the PI or designee will ensure that an 
adequate supply of Orsiro stents is on hand to support uninterrupted enrollment of 
subjects in the study.  Orders for additional devices must originate from the PI or 
designated study personnel.  Orders for additional devices will be fulfilled by delivery 
directly to the PI or to study personnel designated by the PI. 
Note: in the EU or other participating countries where the Orsiro stent is market-
released, specific investigational handling restrictions may not apply. 
12.7.1. 
Labeling 
The Orsiro stent and its associated components will have a label that will be visible on 
the pertinent shipping cartons and storage containers.  The required labels or manuals 
will bear the following information: 
 Name, model and lot number of the stent  
 Name and addresses of the manufacturer and distributor 

  
 
 
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 Labeling statement: “CAUTION - Investigational Device.  Limited by United 
States Law to Investigational Use.”  - applicable for US sites only 
 Quantity of contents 
 All relevant contraindications, hazards, adverse device effects, interfering 
substances or devices, warnings and precautions 
 Expiration date 
12.8. Supplemental Applications 
If required, the sponsor will submit changes in the investigational plan to the appropriate 
regulatory authorities for approval and investigators to obtain IRB/EC approval to 
implement the changes. 
12.9. Other Institutions and Physicians 
The study is not transferable to other institutions attended by the investigator unless 
prior approval is obtained from BIOTRONIK, the governing competent authority (if 
applicable) and the appropriate IRB/EC.   Additional sites may be included in this study, 
but may not exceed the limits set by the FDA.  Only approved investigators are 
authorized to participate in the study; however, there are certain situations where an 
investigator might not be immediately available to provide the necessary medical care 
for a subject with an investigational stent (e.g. when a subject goes to the emergency 
room for medical treatment).   In any such situations, the IRB/EC and the investigator 
must continue to provide oversight for that subject’s medical care and rights as a 
research subject. BIOTRONIK will ensure that the necessary support is available to any 
physician providing immediate care for a subject in order to answer questions about the 
investigational stent and provide guidance in collecting the necessary documentation 
required for the clinical study. Documentation obtained will then be forwarded to the 
approved investigator for review and signature before this data may be used to support 
the endpoints of the study. 
12.10. 
Subject Insurance 
Subjects who participate in this study will be insured against study related injury 
according to local regulatory requirements.  
BIOTRONIK has issued clinical trial liability insurance with appropriate coverage for the 
continuation of the entire study. 
 
 

  
 
 
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13. RISK ANALYSIS 
13.1. Potential Risks 
Risks associated with the use of the Orsiro stent include those seen with currently 
marketed drug eluting stents. Possible adverse events associated with PTCA and 
Orsiro stent placement include but are not limited to: 
 Cardiac events: Myocardial infarction or ischemia, abrupt closure of coronary 
artery, restenosis of treated artery (greater than 50% obstruction), cardiogenic 
shock, angina, tamponade, perforation or dissection of coronary artery or aorta, 
cardiac perforation, emergency cardiac surgery, pericardial effusion, aneurysm 
formation 
 Arrhythmic events: Ventricular tachycardia, ventricular fibrillation, atrial fibrillation, 
bradycardia 
 Stent system events: Failure to deliver stent to intended site, stent dislodgement 
from the delivery system, stent misplacement, stent deformation, stent 
embolization, stent thrombosis or occlusion, stent fracture, stent migration, 
inadequate apposition or compression of stent/s, inflation difficulties, rupture or 
pinhole of the delivery system balloon, deflation difficulties, withdrawal difficulties, 
embolization of catheter material 
 Respiratory events: Acute pulmonary edema, congestive heart failure, respiratory 
insufficiency or failure 
 Vascular 
events: 
Access 
site 
hematoma, 
hypotension/ 
hypertension, 
pseudoaneurysm, arteriovenous fistula formation, retroperitoneal hematoma, 
vessel dissection or perforation, restenosis, thrombosis or occlusion, vasospasm, 
peripheral ischemia, dissection, distal embolization (air, tissue debris, thrombus) 
 Neurologic events: Permanent (stroke) or reversible (TIA) neurologic event, 
femoral nerve injury, peripheral nerve injury  
 Bleeding events: Access site bleeding or hemorrhage, hemorrhage requiring 
transfusion or other treatment 
 Allergic reactions to contrast media, antiplatelets, anticoagulants, amorphous 
silicon carbide, L-605 cobalt chromium alloy (including the major elements cobalt, 
chromium, tungsten and nickel), PLLA polymer matrix, Sirolimus or Sirolimus 
derivatives. 
 Infection and sepsis 
 Death 
Potential adverse events related to Sirolimus (following oral administration) include but 
are not limited to: 
 Abnormal liver function tests  
 Anemia  

  
 
 
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 Arthralgia  
 Diarrhea  
 Hypercholesterolemia 
 Hypersensitivity, including anaphylactic/anaphylactoid type reactions  
 Hypertriglyceridemia 
 Hypokalemia 
 Infections 
 Interstitial lung disease 
 Leukopenia 
 Lymphoma and other malignancies 
 Thrombocytopenia 
 Renal events: renal insufficiency/renal failure 
The potential risks related to the Xience stent and Everolimus may be found in the 
current product Instructions for Use.. 
13.2. Potential Benefits 
There are no guaranteed benefits from participation in this study; however, it is possible 
that treatment with the Orsiro stent may reduce the potential for late and very late stent 
thrombosis, a complication associated with the occurrence of MI and death. 
Moreover, in this clinical investigation all subjects will have a more intense medical 
follow-up compared with standard practice, which can be beneficial to the long-term 
clinical outcome of study participants. 
Additionally, information gained from the conduct of this study may be of benefit to 
others with the same medical condition.  Efficacy and safety data collected on the Orsiro 
stent will contribute to expand the knowledge of use of drug eluting stents in 
interventional cardiology. 
13.3. Risk Mitigation 
All subjects will receive chronic daily antiplatelet therapy for a minimum of 6 months and 
for the recommended 12 months post-procedure (per American Heart Association 
Scientific Advisory guidelines) to reduce risk of stent thrombosis and provide extended 
protection for potentially delayed endothelialization.  Subjects will also receive a 
minimum of 75 mg aspirin daily, to be taken indefinitely.  
To minimize potential risks associated with study procedures, all efforts will be made to 
select investigators who are experienced and skilled in using interventional devices.  
Additionally, at study initiation all investigators will be trained regarding the IFU and 

  
 
 
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protocol.  All enrolling investigators will be instructed on appropriate subject selection in 
an effort to minimize the risk of recruiting ineligible subjects to the study. 
Subjects will be monitored closely throughout the trial duration and will be evaluated at 
pre-specified time points to assess their clinical status. 
An independent data monitoring committee will monitor safety of study participants 
throughout the trial (see Section 0). 
For participating OUS subjects, the Orsiro stent is CE-marked and routinely being used 
in Europe.  The safety and efficacy profile is known.  Moreover, OUS subjects in 
participating countries with market approval, may be treated with this device regardless 
of their participation in the study or not, if the physician determines the device to be the 
best treatment option for that subject. 
13.4. Sex and Gender in Coronary Heart Disease 
Coronary heart disease (CHD) is recognized as the single leading cause of death 
among both American men and women.52,53  Although CHD has historically been 
perceived as affecting more men, heart disease killed 26% of both the men and women 
who died in 2006 (http://www.cdc.gov/nchs).  This impact of CHD on women highlights 
the need to analyze both disease trends and treatment patterns in women to further 
understand if sex-specific outcomes exist in clinical evaluations of investigational 
devices. 
Prevalence 
The total prevalence of CHD among U.S adult men is 8.3% and is 6.1% for US adult 
women.  Among women, CHD prevalence is highest among non-Hispanic blacks at 
7.6%.  More specifically, the overall prevalence of MI among US adult men is 4.3% and 
is 2.2% for US adult women, with the highest prevalence among women in non-
Hispanic blacks.53 
Diagnosis and Treatment Patterns 
The increasing impact of CHD in women is compounded by the diagnosis and treatment 
patterns of women with heart disease.  According to the American Heart Association, 
64% of women who die suddenly of CHD have no previous symptoms, which greatly 
impacts the evaluation and appropriate management of CHD, leading to potential sex-
based clinical outcomes.  Likewise, the American Heart Association reports that 
following a first MI in subjects over 45 years of age, a greater proportion of women are 
likely to die, develop recurrent MI, fatal CHD, heart failure or stroke.  Because of the 
increased association of asymptomatic, fatal CHD, along with the increased risk for 
further, fatal CHD associated with a first MI, women have a lower likelihood of receiving 
treatment for their heart disease.  A recent Mayo Clinic study found that women were 
55% less likely than men to participate in cardiac rehabilitation following an MI.54  
Likewise, a study at Massachusetts General Hospital in 2005 found that women with 
both diabetes and CHD were significantly less likely to be prescribed aspirin than men 
or when treated for hypertension or hyperlipidemia, were significantly less likely to have 
blood pressure levels < 130/80 mmHg or LDL cholesterol levels < 100 mg/dl.55 

  
 
 
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Proportions and Clinical Outcome Differences for Women in Past Studies 
A total of five PMA approvals for coronary, bare-metal stents were found in the past 10 
years.56,57,58,59,60  Each of the IDE clinical studies conducted to support the PMA 
application had a similar subject population as that proposed for this study.  The 
approximate average proportion of women enrolled in the five clinical studies was 30%.  
A gender analysis was provided in four of the safety summaries, with each noting no 
difference in clinical outcomes for the investigational device based on gender. 
Clinical Study Enrollment Plan for Women 
Historically, women have been under-represented or excluded from enrollment in 
clinical studies, which has led to a lack of information regarding the risks and benefits of 
many medical treatments.  For the purposes of this study, an enrollment goal of 30% 
women will be targeted to match the proportion of women in past coronary clinical 
studies.  In order to enhance enrollment of women into this IDE study, the following will 
occur: 
 Investigational sites in more densely populated, urban areas will be targeted to 
where recruitment of women can be more easily facilitated 
 Women physicians will be targeted as enrolling investigators 
 Screening logs will be periodically reviewed for screen failures to identify reasons 
for non-enrollment into the study” 
14. USE OF INFORMATION AND PUBLICATION 
BIOTRONIK intends to publish the results of this clinical investigation.  BIOTRONIK 
reserves the right to include the report of this clinical investigation in any regulatory 
documentation or submission or in any informational materials prepared for the medical 
profession.  The ownership of the data shall at all times be held by BIOTRONIK.  
BIOTRONIK and the Steering Committee reserve the right for the first publication of the 
clinical investigation results.  BIOTRONIK agrees that investigators shall be permitted to 
present at symposia, national or regional professional meetings, and to publish in 
journals, theses or dissertations, or otherwise of their own choosing, methods and 
results of the clinical investigation after the first publication.  Any prior publication in any 
way or form is not permitted, without approval by BIOTRONIK.  
Institution and Investigator reserve the right to publish the results of data obtained solely 
at their investigational site for the study.  Before publishing, however, the institution and 
Principal Investigator shall submit copies of any manuscript proposed for publication to 
BIOTRONIK for review at least 30 days in advance of submission for publication or 
presentation to a publisher or other third party.  The Study National Principal 
Investigators and/or Study Steering Committee reserve the right to review and approve 
all manuscripts prior to publication.  The Sponsor reserves the right to delete any 
confidential information or other proprietary information (including trade secrets and 
patent protected materials) that is being utilized and inappropriately released, and to 
provide input from other investigators in the study regarding the content and 
conclusions of the publication or presentation.  In addition, the Sponsor may extend 

  
 
 
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such review period for another 90 days, if deemed necessary, but will not unreasonably 
delay review and comment. 
15. PREMATURE TERMINATION OF THE STUDY 
No formal statistical rule for early termination of the trial due to insufficient effectiveness 
or safety issues has been defined.  However the DMC may define rules by which an 
early termination may be recommended. 
BIOTRONIK reserves the right to discontinue the clinical trial at any stage, with suitable 
written notice to the investigator.  Possible reason(s) may include but are not limited to: 
 An unanticipated adverse device effect occurs and it presents an unreasonable 
risk to subjects. 
 The 
Data 
Monitoring 
Committee 
or 
Steering 
Committee 
makes 
a 
recommendation for the early termination of the trial. 
 Further product development is cancelled. 
Should discontinuation of the trial occur, the investigator shall return all clinical trial 
materials (including devices) to the sponsor, and provide a written statement to the 
IRB/EC explaining reasons for premature termination.   In the event of a premature 
termination of the clinical investigation enrolled subjects will be followed up as per the 
institution’s standard of care.  
 

  
 
 
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16. APPENDIX A: ABBREVIATIONS AND ACRONYMS 
Abbreviation/Acronym 
Complete Term 
ACT 
activated clotting time 
ADE 
adverse device effect 
AE 
adverse event 
AMI 
acute myocardial infarction 
ARC 
Academic Research Consortium 
atm 
atmosphere 
BMS 
bare metal stent 
CABG 
coronary artery bypass graft 
CAD 
coronary artery disease 
CBC 
complete blood count 
CCSC 
Canadian Cardiovascular Society Classification 
CEC 
clinical events committee 
CIP 
clinical investigational plan 
CK 
creatine kinase 
CKMB 
creatine kinase myoglobin band 
cm 
centimeter 
Co-Cr 
cobalt-chromium 
CT 
computed tomography 
CRO 
clinical research organization 
DAPT 
dual antiplatelet therapy 
DES 
drug eluting stent 
dl 
deciliter 
DMC 
data monitoring committee 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EES 
everolimus eluting stent 
EU 
European Union 

  
 
 
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Abbreviation/Acronym 
Complete Term 
ESC 
European Society of Cardiology 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GPIIb/IIIa 
glycoprotein IIb/IIIa 
GUSTO 
Global Use of Strategies to Open Occluded Coronary 
Arteries 
h 
hour 
HbA1c 
hemoglobin A1c 
HIPAA 
Health Insurance Portability and Accountability Act 
IDE 
investigational device exemption 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
ISA 
incomplete strut apposition 
ITT 
intent-to-treat 
IVUS 
intravascular ultrasound 
L 
liter 
LAD 
left anterior descending 
LBBB 
left bundle branch block 
LCX 
left circumflex 
LVEF 
left ventricular ejection fraction 
MACE 
major adverse cardiac events 
µg 
microgram 
mg 
milligram 
MI 
myocardial infarction 
mm 
millimeter 
mmol 
millimole 
MOP 
manual of operating procedures 
MRI 
magnetic resonance imaging 
mTOR 
mammalian target of rapamycin 
OCT 
optical coherence tomography 
OpenBUGS 
OpenBUGS software for Bayesian analyses 

  
 
 
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Abbreviation/Acronym 
Complete Term 
OUS 
Outside the United States 
PCI 
percutaneous coronary artery intervention 
PI 
principal investigator 
PK 
pharmacokinetic 
PLLA 
poly-L-lactic acid 
PP 
per-protocol 
PTCA 
percutaneous transluminal coronary angioplasty 
QCA 
quantitative coronary angiography 
RCT 
randomized controlled trial 
RVD 
reference vessel diameter 
SAE 
serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SES 
sirolimus eluting stent 
SESS 
sirolimus eluting stent system 
STEMI 
ST elevation myocardial infarction 
TIA 
transient ischemic attack 
TIMI 
thrombolysis in myocardial infarction 
TLF 
target lesion failure 
TLR 
target lesion revascularization 
TVF 
target vessel failure 
TVR 
target vessel revascularization 
UADE 
unanticipated adverse device effect 
URL 
upper range limit 
USADE 
unanticipated serious adverse device effect 
WH 
workhorse 

  
 
 
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17. APPENDIX B: DEFINITIONS 
ACUTE CLOSURE 
Occurrence of new (during the procedure) severely reduced flow (TIMI grade 0–1) 
within the target vessel that persists and requires rescue by stenting or other treatment, 
or results in myocardial infarction 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 mean “no reflow” (due to 
microvascular flow limitation), in which the epicardial artery is patent but had reduced 
flow.  Abrupt closure also does not mean transient closure with reduced flow in which 
the index treatment application does reverse the closure. 
Subacute Closure: Abrupt closure that occurs after procedure is completed (and subject 
left the catheterization laboratory) and before the 1-month follow-up evaluation. 
Threatened Acute Closure: Grade-B dissection and 50% diameter stenosis or any 
dissection of grade C or higher. 
ACUTE GAIN 
Immediate dimensional change in minimal luminal diameter (mm) that occurred after the 
final post-dilatation as compared with the minimal luminal diameter at baseline and 
measured by quantitative coronary angiography from the average of two orthogonal 
views. 
ADVERSE DEVICE EFFECT (ADE) 
An adverse device effect (ADE) is a device-related adverse event, i.e., any adverse 
event for which a causal relationship between the device and the event is at least a 
reasonable possibility (the relationship cannot be excluded).  Note that this definition 
includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation or operation, or any malfunction of the 
investigational medical device, as well as any event resulting from user error or from 
intentional misuse of the investigational medical device. 
ADVERSE EVENT 
An adverse event is defined as any untoward medical occurrence, unintended disease 
or injury, or untoward clinical sign (including abnormal laboratory finding) in clinical trial 
subjects, whether or not related to the investigational medical device. 
NOTE 1: This definition includes events related to the investigational medical 
device or the comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
NOTE 3: abnormal laboratory findings will be considered AEs, only if determined 
by the investigator to be clinically significant. 
 
 

  
 
 
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ANTICIPATED ADVERSE EVENT 
Any undesirable experience (sign, symptom, illness, abnormal laboratory value or other 
medical event) occurring to a subject, whether or not considered related to the 
investigational product(s) or drug regimen prescribed as part of the clinical protocol, pre-
defined in the clinical protocol and/or Instructions for Use, that is identified or worsens 
during a clinical study. 
BLEEDING COMPLICATION 
According to the GUSTO (Global Use of Strategies to Open Occluded Coronary 
Arteries) classification of severe, moderate and mild bleeding events: 
Severe or Life-Threatening: 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 moderate or severe bleeding. 
BRAUNWALD CLASSIFICATION OF UNSTABLE ANGINA 
Severity 
Class 1: New onset of severe or accelerated angina.  Patients with new onset (< two 
months in duration) exertional angina pectoris that is severe or frequent (> three 
episodes/day) or patients with chronic stable angina who develop accelerated angina 
(i.e., angina distinctly more frequent, severe, longer in duration or precipated by 
distinctly less exertion than previously) but who have not experienced pain at rest during 
the preceding months. 
Class 2: Angina at rest, subacute.  Patients with one or more episodes of angina at rest 
during the preceding month but not within the preceding 48 hours. 
Class 3: Angina at rest, acute.  Patients with one or more episodes of angina at rest 
within the preceding 48 hours. 
Clinical Circumstances in Which Unstable Angina Occurs 
Class A: Secondary unstable angina.  Patients in whom unstable angina develops 
secondary to a clearly identified condition extrinsic to the coronary vascular bed that has 
intensified myocardial ischemia.  Such conditions reduce myocardial oxygen supply or 
increase myocardial oxygen demand and include anemia, fever, infection, hypotension, 
uncontrolled hypertension, tachyarrhythmia, unusual emotional stress, thyrotoxicosis 
and hypoxemia secondary to respiratory failure. 
Class B: Primary unstable angina.  Patients who develop unstable angina pectoris in the 
absence of an extra-cardiac condition that has intensified ischemia, as in Class A. 
Class C: Post-infarction unstable angina.  Patient who develop unstable angina within 
the first two weeks after a documented acute myocardial infarction. 

  
 
 
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CANADIAN 
CARDIOVASCULAR 
SOCIETY 
CLASSIFICATION 
(CCSC) 
OF 
ANGINA1,2 
Class I: 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 II: Slight limitation of ordinary activity.  Angina upon walking or climbing stairs 
rapidly, walking uphill, walking or stair climbing after meals, or in cold or wind, or under 
emotional stress, or only during the first hours after awakening.  Angina if walking more 
than two blocks on the level and climbing more than one flight of ordinary stairs at a 
normal pace and in normal conditions. 
Class III: Marked limitations of ordinary physical activity.  Walking one to two blocks on 
the level and climbing one flight of stairs in normal conditions and at a normal pace. 
Class IV: Inability to carry on any physical activity without discomfort.  Angina syndrome 
may be present at rest. 
CEREBROVASCULAR ACCIDENT or STROKE 
Cerebrovascular accident is defined as the occurrence of cerebral infarction (ischemic 
stroke) or intracerebral hemorrhage and subarachnoid hemorrhage (hemorrhagic 
stroke).  Stroke is defined as sudden onset of vertigo, numbness, dysphasia, weakness, 
visual field defects, dysarthria or other focal neurological deficits due to vascular lesions 
of the brain such as hemorrhage, embolism, thrombosis or rupturing aneurysm that 
either: 
1. Persists > 24 hours or results in death in < 24 hours, or 
2. Persists < 24 hours duration if the following treatments were used: 
a. Pharmacologic, i.e. thrombolytic drug administration, or 
b. Non-pharmacologic, i.e. neurointerventional procedure (e.g. intracranial 
angioplasty) 
3. Persists < 24 hours but has neuro-radiological (MRI or CT) diagnostic changes 
suggestive of acute tissue injury. 
CLINICALLY DRIVEN TARGET LESION REVASCULARIZATION (TLR) 
Revascularization at the target lesion associated with positive functional ischemia study 
or ischemic symptoms and an angiographic minimal lumen diameter stenosis 50% by 
QCA, or revascularization of a target lesion with diameter stenosis 70% by QCA 
without either angina or a positive functional study. 
                                                 
1 Campeau L. The Canadian Cardiovascular Society grading of angina pectoris revisited 30 years later. 
Can J Cardiol 2002;18:371–379. 
2 Campeau L. Letter: Grading of angina pectoris. Circulation 1976;54: 522–523. 

  
 
 
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CLINICALLY-DRIVEN TARGET VESSEL REVASCULARIZATION (TVR) 
Revascularization in the target vessel associated with positive functional ischemia study 
or ischemic symptoms and an angiographic minimal lumen diameter stenosis 50% by 
QCA, or revascularization of a target vessel with diameter stenosis 70% by QCA 
without either angina or a positive functional study. 
DE NOVO LESION 
A native coronary artery lesion not previously treated. 
DEATHS 
All deaths are considered cardiac unless an unequivocal non-cardiac cause can be 
established.  Specifically, any unexpected death even in subjects with coexisting 
potentially fatal non-cardiac disease (e.g., cancer, infection) should be classified as 
cardiac. 
Cardiac Death: Death due to immediate cardiac cause (e.g., myocardial infarction, low-
output failure, fatal arrhythmia).  Unwitnessed death and death of unknown cause will 
be classified as cardiac death.  This includes all procedure-related deaths, including 
those related to concomitant treatment. 
Vascular Death: Death due to cerebrovascular disease, pulmonary embolism, ruptured 
aortic aneurysm, dissecting aneurysm or other vascular cause. 
Non-Cardiovascular Death: Death not covered by the above definitions, including death 
due to infection, sepsis, pulmonary causes, accident, suicide or trauma. 
DEVICE SUCCESS 
Attainment of < 30% residual stenosis of the target lesion using the assigned study stent 
only. 
Note: Post-dilatation is allowed to achieve device success. 
DISSECTION, 
NHLBI 
(National 
Heart, 
Lung, 
and 
Blood 
Institute) 
CLASSIFICATION3 
Grade A: Small radiolucent area within vessel lumen disappearing with passage of 
contrast material. 
Grade B: Appearance of contrast medium parallel to vessel lumen disappearing within a 
few cardiac cycles. 
Grade C: Dissection protruding outside vessel lumen persisting after passage of 
contrast material. 
Grade D: Spiral-shaped filling defect with or without delayed run-off of contrast material 
in antegrade flow. 
                                                 
3 Detre K, Holubkov R, Kelsey S et al. One-year follow-up results of the 1985–1986 National Heart, Lung, 
and Blood Institute’s percutaneous transluminal coronary angioplasty registry. Circulation 1989;80:421–
428. 

  
 
 
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Grade E: Persistent luminal filling defect with delayed run-off of contrast material in 
distal lumen. 
Grade F: Filling defect accompanied by total coronary occlusion. 
DISTAL EMBOLIZATION 
New abrupt cut-off or filling defect distal to the treated lesion. 
EMERGENT BYPASS SURGERY 
Coronary bypass surgery performed on an urgent or emergent basis for severe vessel 
dissection or closure, or treatment failure resulting in new ischemia. 
IN-SEGMENT MEASUREMENT 
Measurements either within stented segment or within 5 mm proximal and distal to stent 
edges. 
IN-STENT MEASUREMENT 
Measurements within boundaries of the stent. 
INTRACORONARY THROMBUS 
Presence of a filling defect within lumen, surrounded by contrast material seen in 
multiple projections in absence of calcium within the filling defect, or persistence of 
contrast material within lumen, or a visible embolization of intraluminal material 
downstream. 
LATE LOSS INDEX 
Ratio of late loss to acute gain. 
LATE LUMEN/LUMINAL LOSS 
Difference between post-procedure minimal lumen diameter and follow-up angiography 
minimal lumen diameter. 

  
 
 
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LESION CLASS (American College of Cardiology/American Heart Association 
Class)4 
Type A: Minimally complex, discrete (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, absence of 
thrombus. 
Type B: Moderately complex, tubular (length 10–20 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 guide wires, some thrombus present. 
 
Type B1: one adverse characteristic. 
Type B2: two or more adverse characteristics. 
Type C: 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, degenerated vein grafts 
with friable lesions. 
LESION SUCCESS 
Attainment of < 30% residual stenosis of target lesion using any percutaneous method. 
MAJOR ADVERSE CARDIAC EVENTS (MACE) 
All-cause death, myocardial infarction (Q-wave or non–Q-wave), any clinically-driven 
target lesion revascularization. 
MINIMAL LUMINAL DIAMETER 
Average of two orthogonal views (when possible) of the narrowest point within the area 
of assessment – in lesion, in stent or in segment.  Visually estimated during 
angiography by the investigator and measured during QCA by the angiographic core 
laboratory. 
 
 
                                                 
4 Smith SC Jr, Dove JT, Jacobs AK et al. ACC/AHA guidelines of percutaneous coronary interventions 
(revision of the 1993 PTCA guidelines) –Executive summary. A report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines (committee to revise the 1993 
guidelines for percutaneous transluminal coronary angioplasty). J Am Coll Cardiol 2001;37:2215–2239. 

  
 
 
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MYOCARDIAL INFARCTION – PROTOCOL DEFINITION5 
I. 
PCI (PERCUTANEOUS CORONARY INTERVENTION) 
Ia. 
Baseline Biomarkers of Myocardial Damage  
Periprocedural < 48 hours post PCI 
A.  Baseline CKMB and Troponin < 1*URL  
Appropriate cardiac enzyme data: 
a1. Confirmed by :  
- 
CKMB > 3*URL or  
- 
in the absence of CKMB, Troponin > 3*URL or 
- 
in the absence of CKMB and Troponin: CEC decision upon clinical scenario 
B.  Baseline CKMB or Troponin > 1*URL  
Appropriate cardiac enzyme data: 
b1. Confirmed by :  
- 
A rise in CKMB   50% above the previous level and > 3* URL or 
- 
In absence of CKMB, a rise in Troponin  50% above the previous level and > 
3*URL. 
- 
in the absence of CKMB and Troponin: CEC decision upon clinical scenario 
 AND 
b2. Evidence that cardiac biomarker values were decreasing (e.g., two samples at 
least 4 hours apart) prior to the suspected MI. 
C.  New pathologic q waves in  2 contiguous ECG leads 
URL = upper range limit, defined as 99th percentile of normal reference range 
 
Ib. 
If Baseline Biomarkers of Myocardial Damage: CK and/or CKMB > 1*URL or 
acute MI in progress  
Myocardial infarction, re-infarction (extension) < 48 hours post PCI 
A. If CK (or CKMB) from index MI has not yet reached its maximum level: 
- 
Recurrent thoracic chest pain or ischemia equivalent > 20 minutes (or new ECG 
changes consistent with MI)  
                                                 
5 Adapted from Vranckx P, Cutlip DE, Mehran R, Kint PP, Silber S, Windecker S, Serruys PW. Myocardial 
infarction adjudication in contemporary all-comer stent trials: Balancing sensitivity and specificity. 
Addendum to the historical MI definitions used in stent studies. EuroIntervention 2010;5:871–874. 

  
 
 
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AND 
- 
Appropriate cardiac enzyme data: 
- 
A rise in CK within 24 hours of the index event > 2*URL (confirmed by either 
CKMB or Troponin > 1*URL) and  50% above the previous level or 
- 
In absence of CK: a (post PCI) rise in CKMB within 24 hours of the index event > 
3*URL and  50% above the previous level 
or 
- 
In absence of CK and CKMB: a (post PCI) rise of Troponin within 24 hours of the 
index event > 3*URL and  50% above the previous level.  
B. If elevated CK (or CKMB) following the index MI has peaked AND CK level has returned 
< URL then any new rise in: 
- 
CK > 2*URL(confirmed by either CKMB > URL or Troponin > URL) or 
- 
in the absence of CK: CKMB > 3*URL or 
- 
in the absence of CK and CKMB, Troponin > 3*URL 
C. If CK (or CKMB) following the index MI has peaked AND CK level has NOT returned to < 
URL: 
- 
A rise in CK  50% above the previous level and > 2 URL confirmed by either CKMB 
> URL or Troponin > URL or 
- 
In absence of CK, when CKMB has NOT returned < URL, a rise in CKMB  50% 
above the previous level and > 3* URL or 
- 
In absence of CK, when CKMB and Troponin has not returned < URL a rise in 
Troponin  50% above the previous level and > 3*URL 
 
 
 

  
 
 
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Spontaneous MI > 48 hours(PCI) 
A. Recurrent thoracic chest pain or ischemic equivalent AND 
New pathologic q waves in  2 contiguous ECG leads AND 
- 
any CKMB > 1*URL or 
- 
in the absence of CKMB: Troponin > 1*URL or 
- 
in the absence of CKMB and Troponin: CK > 1*URL or 
- 
in the absence of CKMB and Troponin and CK: CEC decision upon clinical scenario 
B. Appropriate cardiac enzyme data (respecting top-down hierarchy): 
b1. CK  2* URL Confirmed by: 
- 
CKMB > 1*URL or  
- 
in the absence of CKMB: Troponin > 1*URL or 
- 
in the absence of CKMB and Troponin: CEC decision upon clinical scenario 
OR 
b2. In the absence of CK: CKMB > 3*URL 
OR 
b3. In the absence of CK and CKMB: Troponin > 3*URL 
OR 
b4. In the absence of CK, CKMB and Troponin, clinical decision based upon clinical 
scenario. 
 
 
 

  
 
 
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II. 
CABG (CORONARY ARTERY BYPASS GRAFTING) 
IIa. 
Baseline Biomarkers of Myocardial Damage (CK and CKMB and Trop < 
1*URL) and not acute MI in progress. 
Periprocedural < 72 hours post CABG 
A. New pathologic q waves in  2 contiguous ECG leads or recurrent signs or symptoms 
consistent with myocardial ischemia AND 
- 
CKMB > 5x URL or 
- 
in the absence of CKMB: Troponin > 5*URL or 
- 
in the absence of CKMB and Troponin: CK > 5 URL or 
- 
in the absence of CKMB and Troponin and CK: CEC decision upon clinical scenario 
B. Appropriate cardiac enzyme data  
- 
CKMB  10* URL or 
- 
In the absence of CKMB: Trop > 10*URL. or 
- 
- In the absence of CKMB and Troponin: CK > 10*URL 
IIb. 
If Baseline Biomarkers of Myocardial Damage: CK and/or CKMB > 1*URL or 
acute MI in progress 
Myocardial infarction, re-infarction (extension) < 72 hours post CABG 
A. If Peak CK (or CKMB) from index MI has not yet reached its maximum level: 
- 
Clinical signs or symptoms consistent with recurrent myocardial ischemia 
AND 
- 
Appropriate cardiac enzyme data: 
- 
A rise in CKMB within 24 hours of the index event > 10*URL and  50% above 
the previous level. 
- 
In absence of CKMB: a rise in Troponin within 24 hours of the index event 
 > 10*URL and  50% above the previous level. 
- 
In absence of CKMB and Troponin: a rise in CK within 24 hours of the index 
event > 10*URL and  50% above the previous level. 
B. If elevated CK (or CKMB) following the index MI has peaked AND CKMB level has 
returned < URL, any new rise in: 
- 
CKMB > 10*URL or 
- 
in the absence of CKMB: Troponin > 10*URL or 
- 
in the absence of CKMB and Troponin: CK > 10*URL 
 
C. If elevated CK (or CKMB) following the index MI has peaked AND CKMB level has NOT 

  
 
 
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returned < URL: 
- 
A rise in CKMB  50% above the previous level and > 10 URL or 
- 
In absence of CKMB: a rise in Troponin  50% above the previous level and > 10* 
URL or 
- 
In absence of CKMB and Troponin: a rise in CK  50% above the previous level and 
> 10*URL 
 
 
 

  
 
 
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MYOCARDIAL INFARCTION (MI) – ACADEMIC RESEARCH CONSORTIUM (ARC) 
DEFINITION6 
Classification 
Biomarker Criteria* 
Additional Criteria
Peri-procedural PCI 
(within 48 h after PCI)† or 
Troponin > 3 times URL
or 
CKMB > 3 times URL 
Baseline value < URL 
Peri-Procedural CABG 
(within 72 h after CABG) 
Troponin > 5 times URL
or CKMB > 5 times 
URL 
Baseline value < URL and any of the
following: new pathologic‡ Q waves or LBBB, 
new native or graft vessel occlusion, imaging 
evidence of loss of viable myocardium 
Spontaneous 
(> 48 h following PCI,  
> 72 h following CABG) 
Troponin > URL or
CKMB > URL 
Baseline value < URL and any of the
following: symptoms of ischemia, ECG 
changes indicative of new ischemia (new  
ST-T changes or new LBBB), development of 
pathological Q waves, or imaging evidence of
new loss of viable myocardium or new 
regional wall motion abnormality 
Silent 
No biomarker data
available 
New pathologic‡ Q waves or LBBB 
Sudden Death 
Death before biomarkers 
obtained or before 
expected to be elevated 
Symptoms suggestive of ischemia and any of 
the following: new ST elevation or LBBB, 
documented thrombus by angiography or 
autopsy 
Reinfarction, spontaneous 
and peri-procedural (base 
definition; infarction 
extension) 
Stable or decreasing
values on 2 samples > 6 h
apart and 20% increase 
3–6 h after second 
sample 
If biomarkers not stable (increasing or peak 
not reached), then insufficient data to 
diagnose recurrent myocardial infarction 
Adapted from Global Task Force Universal Definition of Myocardial Infarction, Thygesen et al. 
 
PCI: percutaneous coronary intervention; h: hour; URL: upper range limit (99th percentile of 
normal reference range); CKMB: creatinine kinase myocardial band isoenzyme MB; CABG: 
coronary artery bypass graft; LBBB: left bundle branch block; ECG: electrocardiogram. 
 
*Baseline biomarker value required before study procedure and presumes a typical rise and fall. 
†Assessment of CKMB is preferred over assessment of troponin for diagnosis of peri-procedural MI, 
if possible. 
‡Pathologic Q waves may be defined according to the Global Task Force, Minnesota code or 
Novacode. 
 
NO REFLOW 
Sustained or transient reduction in antegrade flow not associated with an obstructive 
lesion at treatment site. 
                                                 
6 Cutlip DE, Windecker S, Mehran R et al. for the Academic Research Consortium. Clinical endpoints in 
coronary stent trials: A case for standardized definition. Circulation 2007;115:2344–2351. 

  
 
 
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PERCENT DIAMETER STENOSIS 
The value calculated as 100 x (RVD – MLD)/RVD using the mean values from two 
orthogonal views (when possible) by quantitative coronary angiography.  (RVD: 
reference vessel diameter; MLD: minimal lumen diameter.) 
PERFORATION 
Perforations will be classified as follows: 
Angiographic Perforation: Perforation detected by clinical site or core laboratory at any 
point during procedure. 
Clinical Perforation: Perforation requiring additional treatment (including efforts to seal 
perforation or pericardial drainage), or resulting in significant pericardial effusion, acute 
closure, myocardial infarction or death. 
Pericardial Hemorrhage/Tamponade: Perforation resulting in cardiac tamponade. 
PERCUTANEOUS CORONARY INTERVENTION (PCI) 
All interventional cardiology methods for treatment of coronary artery disease. 
PERSISTING INCOMPLETE APPOSITION 
Incomplete apposition at follow-up that was present post-procedure.  See also 
Incomplete Apposition. 
PROCEDURE SUCCESS 
Attainment of < 30% residual stenosis of the target lesion using the assigned study stent 
only without occurrence of in-hospital major adverse cardiac events (MACE). 
RESTENOTIC LESION 
Lesion in a vessel segment that has undergone prior percutaneous treatment with or 
without a stent placement. 
REFERENCE VESSEL DIAMETER (RVD) 
Average of normal segments within 10 mm proximal and distal to target lesion from two 
orthogonal views using quantitative coronary angiography. 
SERIOUS ADVERSE DEVICE EFFECT 
Adverse device effect that results in any of the consequences characteristic of a serious 
adverse event. 

  
 
 
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SERIOUS ADVERSE EVENT 
Adverse event that leads to: 
 Death. 
 Serious deterioration in the health of the subject that either results in life-
threatening illness or injury; permanent impairment of a body structure or a body 
function; hospitalization or prolonged hospitalization; or medical or surgical 
intervention to prevent life-threatening illness, injury or permanent impairment to 
a body structure or a body function. 
 Fetal distress, fetal death, congenital abnormality or birth defect. 
STENT THROMBOSIS – ACADEMIC RESEARCH CONSORTIUM (ARC) DEFINITION 
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 
guiding catheter has been removed and the subject has left the catheterization lab. 
Timing 
 
Acute stent thrombosis* 
 
0–24 hours post–stent implantation 
 
Subacute stent thrombosis* 
> 24 hours–30 days post–stent implantation 
 
Late stent thrombosis† 
 
30 days–1 year post–stent implantation 
 
Very late stent thrombosis† 
> 1 year post–stent implantation 
*Acute/subacute can also be replaced by early stent thrombosis.  Early stent thrombosis 
(0–30 
days) 
is 
a 
definition 
currently 
used 
in 
the 
community. 
†Including primary as well as secondary late stent thrombosis.  Secondary late stent 
thrombosis is a stent thrombosis after a target segment revascularization. 
Categories (Definite, Probable and Possible) 
Definite Stent Thrombosis 
Definite stent thrombosis is considered to have occurred by either angiographic or 
pathologic confirmation. 
Angiographic Confirmation of Stent Thrombosis* 
Presence of an intracoronary that originates in the stent or in the segment 5 mm 
proximal or distal to the stent, and presence of at least one of the following 
criteria within a 48-hour time window: 
 Acute onset of ischemic symptoms at rest. 
 New ischemic ECG changes that suggest acute ischemia. 
 Typical rise and fall in cardiac biomarkers (refer to definition of 
spontaneous MI). 

  
 
 
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Non-occlusive: Intracoronary thrombus is defined as a spheric, ovoid or irregular 
non-calcified filling defect or lucency surrounded by contrast material (on 3 sides 
or within a coronary stenosis) seen in multiple projections, or persistence of 
contrast material within the lumen, or a visible embolization of intraluminal 
material downstream. 
Occlusive Thrombus: TIMI 0 or TIMI 1 intra-stent or proximal to a stent up to the 
most adjacent proximal side branch or main branch (if originates from side 
branch). 
Pathological Confirmation of Stent Thrombosis 
Evidence of recent thrombus within the stent determined at autopsy or via 
examination of tissue retrieved following thrombectomy. 
*The incidental angiographic documentation of stent occlusion in the absence of clinical signs or 
symptoms is not considered a confirmed stent thrombosis (silent occlusion). 
Probable Stent Thrombosis 
Probable stent thrombosis is considered to have occurred after intracoronary stenting in 
the following cases: 
 Any unexplained death within first 30 days.† 
 
Regardless of time after index procedure, any MI related to documented acute 
ischemia in the territory of the implanted stent without angiographic confirmation 
of stent thrombosis and in the absence of any other obvious cause. 
†For studies with ST-elevation MI population, exclusion of unexplained death within 30 days may 
be considered evidence of probable stent thrombosis. 
Possible Stent Thrombosis 
Possible stent thrombosis is considered to have occurred with any unexplained death 
from  
30 days after intracoronary stenting until end of trial follow-up. 
STROKE 
See Cerebrovascular Accident or Stroke. 
STUDY DEVIATION 
Incident in which the investigator or site personnel did not conduct the study according 
to the clinical protocol or investigator agreement. 
Major Deviation: Any deviation from subject inclusion and exclusion criteria or subject 
informed consent procedures. 
Minor 
Deviation: 
Deviation 
from 
a 
clinical 
protocol 
requirement 
such 
as 
incomplete/inadequate subject testing procedures, non-compliance with study 
thienopyridine medication regimens, follow-ups performed outside specified time 
windows, etc. 

  
 
 
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TARGET LESION FAILURE (TLF) 
Cardiac death, target vessel myocardial infarction (Q-wave or non–Q-wave), or 
clinically-driven target lesion revascularization. 
TARGET LESION REVASCULARIZATION (TLR) – ACADEMIC RESEARCH 
CONSORTIUM (ARC) DEFINITION 
Repeat percutaneous intervention of target lesion or bypass surgery of target vessel 
performed for restenosis or other complication of target lesion. 
Target lesion is defined as the treated segment starting 5 mm proximal to the stent and 
ending 5 mm distal to the stent. 
See also Clinically Driven Target Lesion Revascularization. 
TARGET VESSEL FAILURE (TVF) 
Composite endpoint comprised of cardiac death, target vessel myocardial infarction or 
clinically-driven target vessel revascularization. 
Target vessel failure will be reported when any of the following events occur: 
 Recurrent MI occurs in territory not clearly attributed to a vessel other than target 
vessel. 
 Cardiac death not clearly due to a non-target vessel endpoint. 
 Target vessel revascularization is determined. 
TARGET VESSEL MYOCARDIAL INFARCTION (MI) 
Myocardial infarction that occurs in a territory that cannot be clearly attributed to a 
vessel other than the target vessel. 
TARGET VESSEL REVASCULARIZATION (TVR) – ACADEMIC RESEARCH 
CONSORTIUM (ARC) DEFINITION 
Repeat percutaneous intervention or surgical bypass of any segment of the target 
vessel. 
Target vessel is defined as the entire major coronary vessel proximal and distal to target 
lesion, including upstream and downstream branches and the target lesion itself. 
See also Clinically Driven Target Vessel Revascularization. 
THROMBOLYSIS IN MYOCARDIAL INFARCTION (TIMI) CLASSIFICATION7 
TIMI 0: No perfusion. 
TIMI 1: Penetration with minimal perfusion.  Contrast fails to opacify entire bed distal to 
stenosis for duration of cine run. 
                                                 
7 TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. N Engl J Med 
1985;312: 932–936. 

  
 
 
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TIMI 2: Partial perfusion.  Contrast opacifies entire coronary bed distal to stenosis.  
However, rate of entry and/or clearance is slower in coronary bed distal to obstruction 
than in comparable areas not perfused by 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 
Lesion with no flow (TIMI 0).  Total occlusions are usually classified as persisting less 
than or more than 3 months (chronic total occlusion). 
TRANSIENT ISCHEMIC ATTACK (TIA) 
Focal neurological abnormality of sudden onset and brief duration (lasting less than 24 
hours) that reflects dysfunction in the distribution of the affected artery.  TIAs include 
transient monocular blindness (e.g., amaurosis fugax, defined as a transient episode of 
monocular blindness, or partial blindness, lasting 10 minutes or less) and transient 
hemispheric attacks. 
UNANTICIPATED 
ADVERSE 
DEVICE 
EFFECT 
(UADE) 
or  
UNANTICIPATED SERIOUS ADVERSE DEVICE EFFECT (USADE) 
An unanticipated adverse device effect (UADE) is defined in 21 CFR 812.3(s) as 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 any 
other unanticipated serious problem associated with a device that relates to the rights, 
safety or welfare of a subject. 
In the OUS countries, the term unanticipated serious adverse device effect (USADE) is 
used for serious adverse device effect that by its nature, incidence, severity or outcome 
has not been identified in the current version of the risk analysis report. 
UNSTABLE ANGINA 
Per the American College of Cardiology/American Heart Association 2002 Guideline 
Update for the Management of Patients With Unstable Angina and Non–ST-Segment 
Elevation Myocardial Infarction, there are 3 principal presentations of unstable angina8: 
1. Rest Angina: Angina occurring at rest, and prolonged, usually > 20 minutes. 
2. New-Onset Angina: New-onset angina of at least CCS class III severity. 
3. Increasing Angina: Previously diagnosed angina that has become distinctly more 
frequent, longer in duration or lower in threshold (i.e., increased by greater than 
or equal to one CCS class to at least CCS class III severity). 
                                                 
8 Braunwald E, Antman EM, Beasley JW et al. ACC/AHA 2002 guideline update for the management of 
patients with unstable angina and non-ST-segment elevation myocardial infarction – Summary article: A 
report of the American College of Cardiology/American Heart Association task force on practice 
guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 
2002;40:1366–1374.  

  
 
 
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VASCULAR COMPLICATIONS 
Vascular complications may include the following: 
1. Pseudoaneurysm. 
2. Arteriovenous fistula. 
3. Peripheral ischemia/nerve injury. 
4. Vascular event requiring transfusion or surgical repair. 
 
 

  
 
 
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18. REFERENCES 
                                                 
1 WHO. The global burden of disease: 20update. Available at: 
www.who.int/healthinfo/global_burden_disease/2004_report_update/en/index.html; 
accessed 07 December 2013. 
 
2 Mathers CD, Loncar D. Projections of global mortality and burden of disease from 
2002 to 2030. PLoS Med 2006;3:e442. 
 
3 Nikolsky E. "Restenosis following percutaneous coronary interventions: A clinical 
problem," Handbook of Drug-Eluting Stents 3: 2006. 
 
4 Popma JJ, Topol EJ. Factors influencing restenosis after coronary angioplasty. Am J 
Med 1990;88:16N–24N. 
 
5 Erbel R, Schatz R, Dietz U et al. Balloon dilatation and coronary vascular stent 
implantation. Versicherungsmedizin 1989;41:82–84. 
 
6 Stone GW, Ellis SG, Colombo A et al. Offsetting impact of thrombosis and restenosis 
on the occurrence of death and myocardial infarction after paclitaxel-eluting and bare 
metal stent implantation. Circulation 2007;115:2842–2847. 
 
7 Kastrati A, Mehilli J, Dirschinger J et al. Restenosis after coronary placement of 
various stent types. Am J Cardiol 2001;87:34–39. 
 
8 Al Suwaidi J, Berger PB, Holmes DR, Jr. Coronary artery stents. J Amer Med Assoc 
2000;284:1828–1836. 
 
9 Stettler C, Wandel S, Allemann S et al. Outcomes associated with drug-eluting and 
bare-metal stents: A collaborative network meta-analysis. Lancet 2007;370:937–948. 
 
10 Doostzadeh J, Clark LN, Bezenek S, Pierson W, Sood PR, Sudhir K. Recent progress 
in percutaneous coronary intervention: Evolution of the drug-eluting stents, focus on the 
XIENCE V drug-eluting stent. Coron Artery Dis 2010;21:46–56. 
 
11 Lagerqvist B, James SK, Stenestrand U, Lindbäck J, Nilsson T, Wallentin L. Long-
term outcomes with drug-eluting stents versus bare-metal stents in Sweden. N Engl J 
Med 2007;356:1009–1019. 
 
12 Kabir AM, Selvarajah A, Seifalian AM. How safe and how good are drug-eluting 
stents? Future Cardiol 2011;7:251–270. 
 

  
 
 
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13 Pfisterer M, Brunner-La Rocca HP, Buser PT et al. Late clinical events after 
clopidogrel discontinuation may limit the benefit of drug-eluting stents: An observational 
study of drug-eluting versus bare-metal stents. J Am Coll Cardiol 2006;48:2584–2591. 
 
14 Farb A, Boam AB. Stent thrombosis redux – The FDA perspective. N Engl J Med 
2007;356:984–987. 
 
15 Cook S, Ladich E, Nakazawa G et al. Correlation of intravascular ultrasound findings 
with histopathological analysis of thrombus aspirates in patients with very late drug-
eluting stent thrombosis. Circulation 2009;120:391–399. 
 
16 Guagliumi G, Costa MA, Sirbu V et al. Strut coverage and late malapposition with 
paclitaxel-eluting stents compared with bare metal stents in acute myocardial infarction: 
Optical coherence tomography substudy of the Harmonizing Outcomes with 
Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) Trial. 
Circulation 2011;123:274–281. 
 
17 Sanchez-Recalde A, Moreno R, Barreales L et al. Risk of late-acquired incomplete 
stent apposition after drug-eluting stent versus bare-metal stent. A meta-analysis from 
12 randomized trials. J Invasive Cardiol 2008;20:417–422. 
 
18 Cook S, Wenaweser P, Togni M et al. Incomplete stent apposition and very late stent 
thrombosis after drug-eluting stent implantation. Circulation 2007;115:2426–2434. 
 
19 Nakazawa G, Otsuka F, Nakano M et al. The pathology of neoatherosclerosis in 
human coronary implants bare-metal and drug-eluting stents. J Am Coll Cardiol 
2011;57:1314–1322. 
 
20 Waksman R, Maluenda G. Polymer drug-eluting stents: Is the future biodegradable? 
Lancet 2001;378:1900–1902. 
 
21 Kadota K, Muramatsu T, Iwabuchi M et al. Randomized comparison of the nobori 
biolimus A9-eluting stent with the sirolimus-eluting stent in patients with stenosis in 
native coronary arteries. Catheter Cardiovasc Interv 2011. Doi: 10.1002/ccd.23280. 
 
22 Byrne RA, Kastrati A, Massberg S et al. Biodegradable polymer versus permanent 
polymer drug-eluting stents in patients with coronary artery disease. J Am Coll Cardiol 
2011;58:1325–1331. 
 
23 Xu B, Dou KF, Han YL et al. A prospective multicenter parallel-controlled trial of 
TIVOLI biodegradable-polymer-based sirolimus-eluting stent compared to ENDEAVOR 
zotarolimus-eluting stent for the treatment of coronary artery disease: 8-month 
angiographic and 2-year clinical follow-up results. Chin Med J 2011;124:811–816. 
 

  
 
 
CIP FINAL V 4.0, 11 FEB 2016 
BIOTRONIK CONFIDENTIAL 
Page 110 of 113 
REPRODUCTION, DISCLOSURE OR UNAUTHORIZED USE OF ANY PART OF THIS DOCUMENT IS STRICTLY 
PROHIBITED. 
                                                                                                                                                             
24 Windecker S, Serruys PW, Wandel S et al. Biolimus-eluting stent with biodegradable 
polymer versus sirolimus-eluting stent with durable polymer for coronary 
revascularisation (LEADERS): A randomised non-inferiority trial. Lancet 
2008;372:1163–1173. 
 
25 Barlis P, Regar E, Serruys PW et al. An optical coherence tomography study of a 
biodegradable vs. durable polymer-coated limus-eluting stent: A LEADERS trial sub-
study. Eur Heart J 2010;31:165–176. 
 
26 Stefanini GG, Kalesan B, Serruys PW et al. Long-term clinical outcomes of 
biodegradable polymer biolimus-eluting stents versus durable polymer sirolimus-eluting 
stents in patients with coronary artery disease (LEADERS): 4 year follow-up of a 
randomised non-inferiority trial. Lancet 2011;378:1940–1948. 
 
27 Serruys PW, Regar E, Carter AJ. Rapamycin eluting stent: The onset of a new era in 
interventional cardiology. Heart 2002;87:305–307. 
 
28 Poon M, Marx SO, Gallo R, Badimon JJ, Taubman MB, Marks AR. Rapamycin 
inhibits vascular smooth muscle cell migration. J Clin Invest 1996;98:2277–2283. 
 
29 Suzuki T, Kopia G, Hayashi S et al. Stent-based delivery of sirolimus reduces 
neointimal formation in a porcine coronary model. Circulation 2001;104:1188–1193. 
 
30 Sousa JE, Costa MA, Farb A et al. Images in cardiovascular medicine. Vascular 
healing 4 years after the implantation of sirolimus-eluting stent in humans: A 
histopathological examination. Circulation 2004;110:e5–6. 
 
31 Sousa JE, Costa MA, Abizaid A et al. Four-year angiographic and intravascular 
ultrasound follow-up of patients treated with sirolimus-eluting stents. Circulation 
2005;111:2326–2329. 
 
32 Klugherz BD, Llanos G, Lieuallen W et al. Twenty-eight-day efficacy and 
pharmacokinetics of the sirolimus-eluting stent. Coron Artery Dis 2002;13:183–188. 
 
33 Sousa JE, Costa MA, Abizaid A et al. Lack of neointimal proliferation after 
implantation of sirolimus-coated stents in human coronary arteries: A quantitative 
coronary angiography and three-dimensional intravascular ultrasound study. Circulation 
2001;103:192–195. 
 
34 Weisz G, Leon MB, Holmes DR Jr. Five-year follow-up after sirolimus-eluting stent 
implantation results of the SIRIUS (Sirolimus-Eluting Stent in De-Novo Native Coronary 
Lesions) trial. J Am Coll Cardiol 2009;17;53:1488–1497. 
 

  
 
 
CIP FINAL V 4.0, 11 FEB 2016 
BIOTRONIK CONFIDENTIAL 
Page 111 of 113 
REPRODUCTION, DISCLOSURE OR UNAUTHORIZED USE OF ANY PART OF THIS DOCUMENT IS STRICTLY 
PROHIBITED. 
                                                                                                                                                             
35 Moses JW, Leon MB, Popma JJ et al. Sirolimus-eluting stents versus standard stents 
in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323. 
 
36 Urban P, Gershlick AH, Guagliumi G et al. Safety of coronary sirolimus-eluting stents 
in daily clinical practice: One-year follow-up of the e-Cypher registry. Circulation 2006 
21;113:1434–1441. 
 
37 Gao RL, Xu B, Lu SZ et al. Safety and efficacy of the CYPHER Select Sirolimus-
eluting stent in the “Real World” – Clinical and angiographic results from the China 
CYPHER Select registry. Int J Cardiol 2008;125:339–346. 
 
38 Schampaert E, Cohen EA, Schlüter M et al. The Canadian study of the sirolimus-
eluting stent in the treatment of patients with long de novo lesions in small native 
coronary arteries (C-SIRIUS). J Am Coll Cardiol 2004;43:1110–1115. 
 
39 In patients with heart attacks, Cypher sirolimus-eluting coronary stent results 
sustained out to four years compared to bare metal stents. Cordis Corporation, Warren, 
NJ, USA, press release, 19 May 2009. 
 
40 Ormiston JA, Serruys PW, Regar E et al. A bioabsorbable everolimus-eluting 
coronary stent system for patients with single de-novo coronary artery lesions 
(ABSORB): A prospective open-label trial. Lancet 2008;371:899–907. 
 
41 Tsuji T, Tamai H, Igaki K et al. Biodegradable polymeric stents. Curr Interv Cardiol 
Rep 2001;3:10–17. 
 
42 Tamai H, Igaki K, Kyo E et al. Initial and 6-month results of biodegradable poly-l-lactic 
acid coronary stents in humans. Circulation 2000;102:399–404. 
 
43 Serruys PW, Ormiston JA, Onuma Y et al. A bioabsorbable everolimus-eluting 
coronary stent system (ABSORB): 2-year outcomes and results from multiple imaging 
methods. Lancet 2009;373:897–910. 
 
44 Serruys PW, Onuma Y, Dudek D et al. Evaluation of the second generation of a 
bioresorbable everolimus-eluting vascular scaffold for the treatment of de novo coronary 
artery stenosis: 12-month clinical and imaging outcomes. J Am Coll Cardiol 
2011;58:1578–88. 
 
45 Chevalier B, Serruys PW, Silber S et al. Randomised comparison of Nobori, biolimus 
A9-eluting coronary stent with a Taxus(R), paclitaxel-eluting coronary stent in patients 
with stenosis in native coronary arteries: The Nobori 1 trial. EuroIntervention 
2007;2:426–434. 
 

  
 
 
CIP FINAL V 4.0, 11 FEB 2016 
BIOTRONIK CONFIDENTIAL 
Page 112 of 113 
REPRODUCTION, DISCLOSURE OR UNAUTHORIZED USE OF ANY PART OF THIS DOCUMENT IS STRICTLY 
PROHIBITED. 
                                                                                                                                                             
46 Grube E, Hauptmann KE, Buellesfeld L, Lim V, Abizaid A. Six-month results of a 
randomized study to evaluate safety and efficacy of a Biolimus A9 eluting stent with a 
biodegradable polymer coating. EuroIntervention 2005;1:53–57. 
 
47 Hamon M, Niculescu R, Deleanu D, Dorobantu M, Weissman NJ, Waksman R. 
Clinical and angiographic experience with a third-generation drug-eluting Orsiro stent in 
the treatment of single de novo coronary artery lesions (BIOFLOW-I): A prospective, 
first-in-man study. EuroIntervention. 2013;8:1006–1011 
 
48 Pilgrim T, Heg D, Roffi M, et al. Ultrathin strut biodegradable polymer sirolimus-eluting 
stent versus durable polymer everolimus-eluting stent for percutaneous coronary 
revascularisation (BIOSCIENCE): a randomised, single-blind, non-inferiority trial. The 
Lancet 2014.  Early Online Publication, 01 September 2014.  
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2961038-
2/fulltext. 
 
49 Andrew Thomas, Bob O Hara, Uwe Ligges, and Sibylle Sturtz. Making BUGS Open. 
R News 6: 12-17. 
 
50 Legrand C, Ducrocq V, Janssen P, Sylvester R, Duchateau L. A Bayesian approach 
to jointly estimate centre and treatment by centre heterogeneity in a proportional 
hazards model. Stat Med 2005; 24(24):3789-804. 
 
51 Gelman A, Carlin JB, Stern HS, Rubin DB. Bayesian Data Analysis, 1995 Chapman & 
Hall 
 
52 Heron MP, Hovert DL, Murphy SL, Xu JQ, Kochanek KD, Tejada-Vera B. Deaths: 
Final Data for 2006. National Vital Statistics Reports 2009;57(14). 
 
53 Roger VL, Go AS, Lloyd-Jones D et al. Heart Disease and Stroke Statistics – 2010 
Update. Heart Disease and Stroke Statistics – 2011 Update: A Report From the 
American Heart Association. 
 
54 Witt BJ, Jacobsen SJ, Weston SA et al. Cardiac rehabilitation after myocardial 
infarction in the community. J Am Coll Cardiol 2004;44:988–996. 
 
55 Wexler DJ, Grant RW, Meigs JB et al. Sex disparities in treatment of cardiac risk 
factors in patients with type 2 diabetes. Diabetes Care 2005;28:514–520. 
 
56 U.S. Food and Drug Administration, Center for Devices and Radiologic Health. 
Express and Express2 Coronary Stent Systems. P020009 (accessed February 28, 
2011). 
 

  
 
 
CIP FINAL V 4.0, 11 FEB 2016 
BIOTRONIK CONFIDENTIAL 
Page 113 of 113 
REPRODUCTION, DISCLOSURE OR UNAUTHORIZED USE OF ANY PART OF THIS DOCUMENT IS STRICTLY 
PROHIBITED. 
                                                                                                                                                             
57 U.S. Food and Drug Administration, Center for Devices and Radiologic Health. 
Rithron-XR Coronary Stent System. P030037 (accessed February 28, 2011). 
 
58 U.S. Food and Drug Administration, Center for Devices and Radiologic Health. 
MULTI-LINK VISION RX AND MULTI-LINK VISION OTW Coronary Stent Systems. 
P020047 (accessed February 28, 2011). 
 
59 U.S. Food and Drug Administration, Center for Devices and Radiologic Health. Driver 
Over-The-Wire, Rapid Exchange and Multi-Exchange Coronary Stent System. P030009 
(accessed February 28, 2011). 
 
60 U.S. Food and Drug Administration, Center for Devices and Radiologic Health. 
NIRflex Premounted Coronary Stent System. P020040 (accessed February 28, 2011).