BIOTRONIK - A Prospective Multicenter Study to Confirm 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 - VII
Conditions: Coronary Artery Disease, Atherosclerosis, Coronary, Myocardial Ischemia, Ischemic Heart Disease, Acute Coronary Syndrome, Angina Pectoris
Sponsor: Biotronik, Inc.

Clinical Protocol 
for the 
BIOFLOW-VII  
Study 
 
 
BIOTRONIK - A Prospective Multicenter Study to Confirm 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 - VII
November 6, 2019 
BIOTRONIK, Inc. 
6024 Jean Road 
Lake Oswego, Oregon 97035 
 
 
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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Table of Contents 
Primary Contacts ........................................................................................ 6 
Protocol Summary....................................................................................... 7 
1 
Introduction ........................................................................................ 14 
 
Study Overview ............................................................................... 14 
1.1
 
Background ..................................................................................... 14 
1.2
 
Rationale for the Study Design .......................................................... 14 
1.3
 
Orsiro Stent System Description ........................................................ 14 
1.4
 
Orsiro Clinical Data Summary ............................................................ 15 
1.5
2 
Study Design ....................................................................................... 18 
 
Study Endpoints .............................................................................. 19 
2.1
 
Primary Endpoint ....................................................................... 19 
2.1.1
 
Secondary Endpoints .................................................................. 20 
2.1.2
 
Additional Data of Interest ................................................................ 21 
2.2
 
Subject Status ................................................................................. 21 
2.3
3 
Protocol Requirements ........................................................................ 23 
 
Subject Population ........................................................................... 23 
3.1
 
Indications ................................................................................ 23 
3.1.1
 
Contraindications ....................................................................... 23 
3.1.2
 
Clinical Inclusion Criteria ............................................................. 23 
3.1.3
 
Clinical Exclusion Criteria ............................................................ 24 
3.1.4
 
Angiographic Inclusion Criteria .................................................... 25 
3.1.5
 
Angiographic Exclusion Criteria .................................................... 25 
3.1.6
 
Study Procedures and Visits .............................................................. 26 
3.2
 
Assessment Details .................................................................... 28 
3.2.1
 
Pre-Screening............................................................................ 28 
3.2.2
 
Post-Procedure Enrollment Visit ................................................... 28 
3.2.3
 
Follow-up Assessments ..................................................................... 30 
3.3
 
One (1) Month Follow-up (30 ± 7 Days) ....................................... 30 
3.3.1
 
One (1) Year Follow-up (360 ± 30 Days) ...................................... 30 
3.3.2
 
Long-Term Clinical Follow-Up at 2, 3, 4 and 5 Years Post-Procedure 
3.3.3
(Annually ± 60 Days) ............................................................................. 31 
 
Reporting of Unscheduled Evaluations .......................................... 31 
3.3.4
 
Study Exits ..................................................................................... 31 
3.4
 
Withdrawal of Consent ................................................................ 32 
3.4.1
 
Vital Status ............................................................................... 32 
3.4.2
 
Subject Death ........................................................................... 32 
3.4.3
 
Lost to Follow-up ....................................................................... 33 
3.4.4
 
Study Completion ...................................................................... 33 
3.4.5
 
Screen Failures .......................................................................... 33 
3.4.6
4 
Statistical Design and Analysis Plan .................................................... 34 
 
Analysis of Study Endpoints .............................................................. 34 
4.1

 
 
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Primary Endpoint ....................................................................... 34 
4.1.1
 
Secondary Endpoints .................................................................. 34 
4.1.2
 
Sample-Size Analysis ....................................................................... 34 
4.2
 
Assumptions for Primary Endpoint of TLF at 1 Year ........................ 35 
4.2.1
 
Maximum Number of Subjects per Site ......................................... 36 
4.2.2
 
Data Analysis Plan ........................................................................... 36 
4.3
 
Patient Demographics and Target Lesion Characteristics ................. 36 
4.3.1
 
Analysis Population Definition(s) .................................................. 36 
4.3.2
 
Analysis Methods ....................................................................... 37 
4.3.3
 
Handling of Missing Data ............................................................ 38 
4.3.4
 
Subgroup Analysis ..................................................................... 38 
4.3.5
 
Poolability Analysis ..................................................................... 38 
4.3.6
 
Sex Analysis .............................................................................. 38 
4.3.7
5 
Adverse Events ................................................................................... 39 
 
General Definitions ........................................................................... 39 
5.1
 
Protocol Defined Reportable Adverse Events ........................................ 41 
5.2
 
Reporting Adverse Events ................................................................. 41 
5.3
 
Site Reporting ........................................................................... 41 
5.3.1
 
Sponsor Reporting ..................................................................... 42 
5.3.2
6 
Additional Study Conditions ................................................................ 43 
 
Regulatory Compliance ..................................................................... 43 
6.1
 
IRB Approval ................................................................................... 43 
6.2
 
Other Institutions and Physicians ................................................. 43 
6.2.1
 
Informed Consent ............................................................................ 43 
6.3
7 
Data Collection .................................................................................... 44 
 
Electronic Data Capture (EDC) ........................................................... 44 
7.1
 
Electronic Case Report Forms (eCRFs) ................................................ 44 
7.2
 
Data Quality Control ......................................................................... 44 
7.3
 
Subject Data Confidentiality .............................................................. 45 
7.4
8 
Protocol Compliance ........................................................................... 46 
 
Protocol Violations ........................................................................... 46 
8.1
 
Protocol Deviations .......................................................................... 46 
8.2
 
IRB Reporting of Noncompliance ........................................................ 47 
8.3
 
Follow-up Compliance ....................................................................... 47 
8.4
 
Audits/Inspections ........................................................................... 47 
8.5
9 
Risk Analysis ....................................................................................... 48 
10 
Study Organization .......................................................................... 49 
 
Sponsor ....................................................................................... 49 
10.1
 
Clinical Events Committee .............................................................. 49 
10.2
 
Angiographic Core Laboratory ......................................................... 49 
10.3
 
Role of BIOTRONIK Personnel ......................................................... 50 
10.4

 
 
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11 
Monitoring ....................................................................................... 51 
 
Summary ..................................................................................... 51 
11.1
 
Monitors ...................................................................................... 52 
11.2
12 
Study Completion or Early Termination ............................................ 53 
13 
Records and Reports ........................................................................ 54 
 
Investigator Records ..................................................................... 54 
13.1
 
Investigator Reporting Responsibilities ............................................ 54 
13.2
 
Sponsor Records ........................................................................... 55 
13.3
 
Sponsor Reporting Responsibilities .................................................. 56 
13.4
14 
Publication Policy ............................................................................. 57 
15 
Prior Orsiro Clinical Trials ................................................................ 58 
16 
Abbreviations and Acronyms ........................................................... 63 
17 
Glossary ........................................................................................... 66 
18 
Study Milestones / Timeline ............................................................ 73 
19 
References ....................................................................................... 74 
 
Table of Tables
Table 1: Prior Orsiro Clinical Studies ............................................................... 16 
Table 2: Subject Status Definitions ................................................................. 22 
Table 3: Visit Assessment Schedule / Schedule of Events .................................. 27 
Table 4: 1-Year TLF Rates for DES Utilizing SCAI Definition of Peri-Procedural MI . 35 
Table 5: Primary Endpoint Sample Size ........................................................... 35 
Table 6: Study Analysis Populations ............................................................... 36 
Table 7: Adverse Event Definitions ................................................................. 39 
Table 8: Investigator Reporting Responsibilities ............................................... 55 
Table 9: Sponsor Reporting Requirements ....................................................... 56 
 
Table of Figures 
Figure 1. Image of Orsiro Stent ..................................................................... 15 
Figure 2: Study Design Flow Chart ................................................................. 19 
 
 

 
 
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BIOFLOW-VII 
Protocol Signature Page 
The signature below constitutes the receipt and review of the BIOFLOW-VII
protocol 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 U.S. federal regulations, ICH and 
GCP guidelines.   
Principal Investigator: 
 
 
Name (please print) 
 
 
 
Signature 
 
Date 

 
 
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Primary Contacts  
Sponsor 
BIOTRONIK, Inc.
Clinical Studies Department 
6024 Jean Road 
Lake Oswego, Oregon 97035 
 
Phone: 800-547-0394 
Email:  BIOFLOW-VII@biotronik.com 
  
Study Principal 
Investigator 
 
 

 
 
 
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Protocol Summary 
Title 
BIOTRONIK - A Prospective Multicenter Study to Confirm 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 – VII  
Purpose 
The purpose of this post-approval study is to confirm that the 
clinical performance of the Orsiro stent in a real-world setting is 
similar to the clinical performance observed for Orsiro in the 
BIOFLOW-V Investigational Device Exemption pivotal trial, as a 
condition of the US Food and Drug Administration (FDA) 
approval (P170030).   
Design 
Prospective, multi-center, single-arm study 
Study Device 
Orsiro® Sirolimus Eluting Coronary Stent System   
Subject 
Population 
Subjects with coronary artery disease (CAD), including those 
with diabetes mellitus, with symptomatic heart disease, stable 
angina, unstable angina, non-ST elevation myocardial infarction 
or documented silent ischemia due to atherosclerotic lesions in 
the native coronary arteries with a reference vessel diameter of 
2.25 mm to 4.0 mm and a lesion length of ≤ 36 mm. 
Enrollment 
556 subjects to achieve 500 evaluable subjects 
Clinical Sites 
Up to 50 clinical sites in the United States   
Visit Schedule 
and Follow-up 
Duration 
Subjects will be followed 5-years post-index procedure.  
Post-procedure follow-up intervals:  1 month and 1, 2, 3, 4 and 
5 years post-index procedure.  
Primary 
Endpoint 
Target lesion failure (TLF) at 1 year post-index procedure.  TLF 
is defined as a composite of cardiac death, target vessel 
myocardial infarction (MI), or clinically-driven target lesion 
revascularization (TLR). 

 
 
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Secondary 
Endpoints 
The following secondary endpoints will be evaluated prior to 
discharge, at 1 month, 1 year, and annually thereafter through 
5 years follow-up. 
1. All-cause death. 
2. MI. 
3. Cardiac death or MI. 
4. Major 
Adverse 
Cardiovascular 
Events 
(MACE) 
and 
individual MACE components (MACE: composite of all-
cause death, Q-wave or non–Q-wave MI, and any 
clinically-driven TLR). 
5. TLF (evaluated at 2, 3, 4, and 5 years) and individual TLF 
components (TLF: composite of cardiac death, target 
vessel Q-wave or non–Q-wave MI, and clinically-driven 
TLR). 
6. Target 
Vessel 
Failure 
(TVF) 
and 
individual 
TVF 
components [TVF: composite of cardiac death, target 
vessel Q-wave or non–Q-wave MI, and any clinically-
driven target vessel revascularization (TVR)]. 
7. Stent thrombosis (definite, definite/probable, probable) 
according to Academic Research Consortium (ARC)-21 
criteria 
for 
acute, 
subacute, 
late, 
very 
late and 
cumulative stent thrombosis. 
8. Device success, defined as attainment of < 30% residual 
stenosis of the target lesion (based on operator visual 
estimate) using the Orsiro study stent only. Note: Post-
dilatation is allowed to achieve device success. 
9. Lesion success, defined as attainment of < 30% residual 
stenosis of the target lesion (based on operator visual 
estimate) using any percutaneous method. 
10.Procedure success, defined as attainment of < 30% 
residual stenosis of the target lesion (based on operator 
visual estimate) using the Orsiro study stent only without 
occurrence of in-hospital MACE. 

 
 
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Clinical 
Inclusion 
Criteria  
Subjects must meet all of the following criteria to be eligible for 
the trial: 
1. Subject is ≥ 18 years of age. 
2. Subject was an acceptable candidate for treatment with a 
drug eluting stent at the qualifying index procedure, in 
accordance with the applicable guidelines on percutaneous 
coronary interventions and manufacturer's Instructions for 
Use. 
3. Subject received at least one Orsiro stent during an index 
procedure occurring within 24 hours prior to informed 
consent, as assessed by the end time of procedure. If more 
than one stent was implanted during the index procedure, 
all stents were Orsiro stents. 
4. Subject is eligible for dual antiplatelet therapy (DAPT) 
treatment with aspirin plus either clopidogrel, prasugrel, 
ticagrelor or ticlopidine. 
5. Subject 
is 
willing 
to 
comply 
with 
study 
follow-up 
requirements. 
6. Subject has provided written informed consent as approved 
by the Institutional Review Board (IRB) of the respective 
clinical site. Legally authorized representatives are not 
allowed to consent on a subject’s behalf.  
Clinical 
Exclusion 
Criteria 
Subjects will be excluded from the trial if any of the following 
criteria are met: 
1. Subject had clinical symptoms and/or electrocardiogram 
(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 pregnant and/or breastfeeding or intends to 
become pregnant during the duration of the study. 
3. 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), silicon carbide, 
Poly-L-Lactic Acid (PLLA), sirolimus.   
4. Revascularization of any target vessel within 9 months prior 
to the index procedure or previous percutaneous coronary 
intervention (PCI) of any non-target vessel within 30 days 

 
 
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Clinical 
Exclusion 
Criteria 
(continued) 
prior to the index procedure or any PCI planned within the 
next 1 year. 
5. Presence of an untreated clinically significant stenosis post-
procedure whether treatment is planned or not. 
6. Planned surgery within 6 months of index procedure unless 
DAPT can be maintained throughout the peri-surgical period. 
7. History of a stroke or transient ischemic attack (TIA) within 
6 months prior to the index procedure. 
8. Subject has documented left ventricular ejection fraction 
(LVEF) < 30% prior to or during the index procedure. 
9. Subject is dialysis-dependent. 
10.Subject has impaired renal function (blood creatinine > 2.5 
mg/dL or 221 μmol/L prior to the index procedure). 
11.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). 
12.Any significant concurrent medical diagnosis that would 
potentially impact DAPT effectiveness or increase thrombotic 
risk. 
13.Subject is receiving chronic anticoagulation (e.g. coumadin, 
dabigatran, apixaban, rivaroxaban or any other agent). 
14.Subject has life expectancy of < 1 year. 
15.Subject is participating in an 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 
follow-up requirements of this study or does not involve a 
drug that may confound the interpretation of any relevant 
clinical events of 
interest (e.g. 
investigational DAPT 
therapy). 
16.In the investigator’s opinion, subject will not be able to 
comply with the follow-up requirements. 

 
 
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Angiographic 
Inclusion 
Criteria 
Each target lesion/vessel must have met all of the following 
angiographic criteria from the index procedure 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 
percutaneous 
transluminal 
coronary 
angioplasty (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. 
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 
2.25–4.0 mm by operator visual estimate. 
8. Target lesion must have been treated with a maximum of 
two overlapping stents. 

 
 
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Angiographic 
Exclusion 
Criteria 
Subjects will be excluded from the trial if any of the target 
lesions/vessels met any of the following angiographic criteria 
during the index procedure: 
1. Target lesion was located within or treated through a 
saphenous vein graft or arterial graft. 
2. Target lesion was a restenotic lesion that was previously 
treated with a bare metal or drug-eluting stent (in-stent 
restenosis). 
3. Target lesion had 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 was 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 had angiographic evidence of thrombus. 
6. Target lesion was totally occluded (100% stenosis). 
7. Target vessel was treated with brachytherapy any time prior 
to the index procedure. 
Study Principal 
Investigator 
 
 
 
Clinical Events 
Committee  
To Be Determined 
Core Lab 
To Be Determined 
Electronic Data 
Capture Vendor 
MedNet Solutions, Inc. 
 
 

 
 
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Sponsor 
BIOTRONIK, Inc.   
Clinical Studies Department 
6024 SW Jean Road 
Lake Oswego, Oregon  97035 
 
Referred to as “BIOTRONIK” for the remainder of this protocol. 
 
For technical assistance 24 hours a day, call:  
800-547-0394 
 

 
 
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1 Introduction 
  Study Overview 
1.1
The BIOFLOW-VII study is a prospective, multi-center, single-arm study to confirm 
that the clinical performance of the Orsiro® Sirolimus Eluting Coronary Stent 
(hereinafter referred to as Orsiro) in a real-world setting is similar to the clinical 
performance observed for Orsiro in the BIOFLOW-V Investigational Device 
Exemption (IDE) pivotal trial.  The study will enroll 556 subjects at up to 50 sites in 
the United States (US).  Clinical outcomes will be collected and reported through 5 
years post-index procedure.   
 Background  
1.2
The Orsiro stent has been studied extensively (refer to Section 1.5) and first 
received CE Mark on February 23, 2011. The safety and the effectiveness of the 
Orsiro stent was demonstrated by the pivotal BIOFLOW-V IDE study and Premarket 
Approval (PMA) application approval (P170030) was received on February 22, 2019. 
As part of the PMA approval, FDA has requested post-approval data collection for 
the performance of the Orsiro stent in a real-world setting. 
 Rationale for the Study Design 
1.3
A prospective, single-arm study design has been proposed for this post-approval 
study as the study population and key endpoints are well-defined and patient-level 
data is available from multiple prior studies. The design includes comparison 
against a performance goal based on the BIOFLOW-V trial Orsiro target lesion 
failure (TLF) rate, taking into consideration TLF rates from other US market-
released drug-eluting stents (DES). 
 Orsiro Stent System Description 
1.4
The Orsiro stent system is a drug-eluting balloon-expandable stent that is pre-
mounted on a fast-exchange percutaneous transluminal coronary angioplasty 
(PTCA) catheter delivery system with a working length of 140 cm. There are two 
stent configurations - small (2.25 – 3.0 mm stent inner diameter) and medium (3.5 
– 4.0 mm stent inner diameter).  
The stent is made from a cobalt chromium alloy (L-605) and the stent geometry 
consists of circular end segments, a transition zone, and repeating helical segments 
which are connected by three interconnecting longitudinal struts.  
The stent is intended as a permanent implant and is completely covered with a thin 
layer of amorphous silicon carbide (referred to as proBIO™ coating). The stent 
surface is circumferentially coated with BIOlute™, a bioabsorbable drug matrix 
consisting of the drug substance sirolimus and polymer poly-l-lactide (PLLA). The 
nominal drug content of the stent is 1.4 μg of sirolimus per mm². The stent is 
positioned between two radiopaque markers for fluoroscopic visualization. 

 
 
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A full description of the Orsiro stent system and the Indications and 
Contraindications for use are located in the Instructions for Use (IFU) / Technical 
Manual available online (https://manuals.biotronik.com).  Figure 1 shows an 
image of the Orsiro stent. 
Figure 1. Image of Orsiro Stent 
 
 Orsiro Clinical Data Summary 
1.5
The development of the Orsiro stent system has been supported by an extensive 
clinical trial program.  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; the BIOFLOW-V IDE international randomized 
study against the Xience™ stent; the BIOSCIENCE international, randomized all-
comers study against the Xience Prime stent; and the BIO-RESORT randomized 
study against the Synergy™ and Resolute Integrity™ stents.* 
BIOTRONIK and Investigator sponsored trials represent more than 48,500 subjects 
who have enrolled in an Orsiro clinical trial.  Overall, more than 70,000 subjects are 
planned to enroll in greater than 70 Orsiro clinical trials that have started or are 
planned.  These trials are designed to collect both short and long-term safety and 
performance measures. The vast majority of these study designs include a 
randomized comparison of Orsiro against comparator DES evaluating long-term 
safety and performance, often with follow-up durations up to five years.  
Table 1 summarizes the key design elements of the major Orsiro clinical studies.  A 
more detailed description of each study and its results is provided in Section 15.    
 
 
 
 
 
*Xience, Xience Prime, and Xience Xpedition are trademarks of the Abbott Group of Companies. 
Synergy is a trademark of Boston Scientific. Resolute Integrity is a trademark of Medtronic. 

 
 
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Table 1: Prior Orsiro Clinical Studies   
BIOFLOW
-I 
BIOFLOW
-II 
BIOFLOW
-III 
BIOFLOW
-IV 
BIOFLOW
-V 
BIO 
SCIENCE 
BIO-
RESORT 
Location 
Romania
Europe 
Europe, 
Chile 
Europe, 
Japan, 
Israel, 
Australia 
United 
States, 
Europe, Asia 
Pacific 
Switzerland 
The 
Netherlands 
Design 
• Prospective 
• Multi-
center 
• Non-
randomized 
• Single-arm 
• Prospective 
• Multi-
center 
• Randomized 
(2:1 vs 
Xience 
Prime) 
• Prospective 
• Multi-
center 
• Non-
randomized 
• Single-arm 
• Open label 
• Prospective 
• Multi-
center 
• Random-
ized (2:1 
vs Xience 
Prime/ 
Xpedition) 
• Prospective
• Multi-
center 
• Randomized 
(2:1 vs 
Xience) 
• Prospective 
• Multi-
center 
• Randomized 
(1:1: vs 
Xience 
Prime/ 
Xpedition) 
• Prospective 
• Multi-
center 
• Randomized 
(1:1:1 vs 
Synergy 
and 
Resolute 
Integrity) 
 
Primary 
endpoint 
Late lumen 
loss at 9 
months 
Late lumen 
loss at 9 
months 
Target 
lesion 
failure at 12 
months 
Target 
vessel 
failure at 12 
months 
Target 
lesion 
failure at 12 
months 
Target 
lesion 
failure at 12 
months 
Target 
vessel 
failure a 12 
months 
Number 
of 
Subjects  
30 
452 (Orsiro: 
298, Xience 
Prime: 154) 
1,356 
575 (Orsiro 
385, Xience 
Prime/ 
Xpedition: 
190) 
1,334 
(Orsiro: 
884, 
Xience: 
450) 
2,119 
(Orsiro: 
1063, 
Xience 
Prime/ 
Xpedition: 
1056)  
3,514 
(Orsiro: 
1169, 
Synergy: 
1172, 
Resolute 
Integrity: 
1173) 
Lesion 
Criteria 
• Single, de 
novo 
lesion 
• Native 
artery 
• ≥50 to 
<100% 
 
• 1-2 de 
novo 
lesions 
• Native 
arteries 
• ≥50 to 
<100% 
• LL ≤ 26 
mm 
• RVD 2.25 
- 4.0 mm 
• All-comers 
• 1 or 2 de 
novo 
lesions 
• Native 
arteries 
• ≥50 to 
<100%  
• LL ≤ 26 
mm 
• RVD 2.50 
-3.75 mm  
• ≤ 3 de 
novo/ 
PTCA 
restenotic 
lesions/ 2 
TV 
• Native 
arteries 
• ≥50 to 
<100% 
• LL ≤ 36 
mm  
• RVD 2.25 
- 4.0 mm 
• All-comers 
• >50% 
• RVD 
correspond
ing with 
stent 
diameter 
of  2.25 – 
4.0 mm 
• All-comers 
(de novo/ 
restenotic) 
Follow-
up 
1, 4, 9mos, 
1, 2, 3 yrs  
1, 6, 9mos, 
1, 2, 3, 4, 
5yrs 
6mos,  
1, 3, 5yrs 
1, 6mos,  
1, 2, 3, 4, 
5yrs 
1, 6mos, 
1, 2, 3, 4, 
5yrs
1mo,  
1, 2, 5yrs 
1mo,  
1, 2, 3, 4, 
5yrs 
Clinical 
Trials. 
gov 
Number 
NCT 
01214148 
NCT 
01356888 
NCT 
01553526 
NCT 
01939249 
NCT 
02389946 
NCT 
01443104 
NCT 
01674803 
The BIOFLOW-VII study is a prospective, multi-center, single-arm study to confirm 
that the clinical performance of the Orsirostent in a real-world setting is similar to 
the clinical performance observed for Orsiro in the BIOFLOW-V IDE pivotal trial.   
BIOFLOW-V is a prospective, multicenter, randomized, controlled trial designed to 
assess the safety and efficacy of the BIOTRONIK Orsiro Sirolimus Eluting Coronary 
Stent System compared with the Xience Everolimus Eluting Coronary Stent System 

 
 
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(Abbott Vascular, Santa Clara, CA) in subjects with up to three native de novo or 
restenotic (after standard PTCA only) coronary artery lesions2 (ClinicalTrials.gov 
identifier NCT02389946). A total of 1,334 subjects were enrolled into the BIOFLOW-
V trial. BIOTRONIK completed the BIOFLOW-V study as the pivotal US IDE trial for 
the Orsiro stent system. 
The primary endpoint was TLF at 1 year, defined as the composite of cardiac death, 
target 
vessel 
myocardial 
infarction 
(MI) 
or 
clinically-driven 
target 
lesion 
revascularization (TLR). For the analysis of the primary endpoint, the trial combined 
data on the randomized subjects with data from two prior studies (BIOFLOW-II and 
BIOFLOW-IV) by employing a Bayesian approach.  
The 1-year Orsiro TLF rate in the BIOFLOW-V study was 6.2%3 utilizing the 
protocol-definition for peri-procedural MI and 2.6% utilizing the Society for 
Cardiovascular Angiography and Interventions (SCAI) definition4 for peri-procedural 
MI.  

 
 
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2 Study Design 
The BIOFLOW-VII study is a prospective, multi-center, single-arm study to confirm 
that the clinical performance of the Orsiro stent in a real-world setting is similar to 
the clinical performance observed for Orsiro in the BIOFLOW-V IDE pivotal trial.  
Subjects who undergo an on-label percutaneous coronary intervention (PCI) with a 
placed Orsiro stent within the prior 24 hours will be screened per the protocol 
inclusion and exclusion criteria to achieve the desired evaluable subject counts 
(N=500) for the primary endpoint.  The study will enroll subjects at up to 50 sites 
in the US.   
Subjects may have received treatment of 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).  The target lesion(s) must have been de novo or restenotic (PTCA 
only) atherosclerotic lesion(s) of ≤ 36 mm in length in native coronary artery(ies), 
with a reference vessel diameter of 2.25–4.0 mm.  All lesions treated during a 
single index procedure must meet target lesion criteria.  
Enrolled subjects will have clinical follow-up at 1 month, 1 year and then annually 
at 2, 3, 4 and 5 years following the index procedure.  The study design flow chart is 
shown in Figure 2. 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Figure 2: Study Design Flow Chart  
 
 Study Endpoints 
2.1
 Primary Endpoint 
2.1.1
The primary endpoint will evaluate the rate of TLF at 1 year post-index procedure.  
TLF is defined as a composite of cardiac death, target vessel myocardial infarction 
(MI) or clinically-driven target lesion revascularization (TLR).  
The BIOFLOW-V trial utilized a primary protocol target vessel-MI definition adapted 
from Vranckx P et al5. The adjudication of peri-procedural MI to this definition 
requires compliance and availability of pre- and post-index procedure cardiac 
biomarkers, which is feasible in a well-controlled IDE clinical trial. However, 
measurement of cardiac biomarkers pre- and/or post-index procedure is not 
standard of care at all sites. Due to standard of care differences in cardiac 
biomarker collection, the BIOFLOW-VII protocol design has been adjusted to 
account for this potential difference in a real-world post-approval registry. To 
minimize the overall impact of potentially missing pre- and/or post-index procedure 

 
 
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cardiac biomarkers, the SCAI4 peri-procedural MI definition will be used for the 
primary endpoint analysis. The BIOFLOW-V definition will be used for spontaneous 
MI.  
The BIOFLOW-VII post-approval study will consent subjects within 24 hours post-
index procedure. Pre- and post-procedural cardiac biomarker data will be collected, 
if testing is performed per standard of care. It is anticipated that cardiac biomarker 
testing per standard of care generally would include subjects with positive cardiac 
biomarkers prior to the procedure, patients with procedural complications and 
patients with signs or symptoms of possible coronary ischemia post procedure. 
The Clinical Events Committee (CEC) adjudicated event classification will be utilized 
for calculation of the TLF rate.  
 Secondary Endpoints   
2.1.2
The following secondary endpoints will be evaluated prior to discharge, at 1 month, 
1 year, and annually thereafter through 5 years follow-up. 
1. All-cause death. 
2. MI. 
3. Cardiac death or MI. 
4. Major 
Adverse 
Cardiovascular 
Events 
(MACE) 
and 
individual 
MACE 
components (MACE: composite of all-cause death, Q-wave or non–Q-wave 
MI, and clinically-driven TLR). 
5. TLF (evaluated at 2, 3, 4, and 5 years) and individual TLF components (TLF: 
composite of cardiac death, target vessel Q-wave or non–Q-wave MI, and 
clinically-driven TLR). 
6. Target vessel failure (TVF) and individual TVF components [TVF: composite 
of cardiac death, target vessel Q-wave or non–Q-wave MI, and clinically-
driven target vessel revascularization (TVR)]. 
7. Stent thrombosis (definite, definite/probable, probable) according to 
Academic Research Consortium (ARC)-21 criteria for acute, subacute, late, 
very late and cumulative stent thrombosis. 
8. Device success, defined as attainment of < 30% residual stenosis of the 
target lesion (based on operator visual estimate) using the Orsiro study stent 
only.  
Note: Post-dilatation is allowed to achieve device success. 
9. Lesion success, defined as attainment of < 30% residual stenosis of the 
target lesion (based on operator visual estimate) using any percutaneous 
method. 
10.Procedure success, defined as attainment of < 30% residual stenosis of the 
target lesion (based on operator visual estimate) using the Orsiro study stent 
only without occurrence of in-hospital MACE. 

 
 
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  Additional Data of Interest 
2.2
Additional information will be collected to characterize the study population, 
implanted device(s), and progress of the study. Specifically, data of interest will 
include: 
• 
Baseline demographics, including age, gender, race and ethnicity, weight, 
height, blood pressure, New York Heart Association (NYHA) classification, left 
ventricular ejection fraction (LVEF), ischemic/angina status. 
• 
Medical history, cardiac history [including prior PCI or coronary artery bypass 
graft (CABG)], indication for PCI, co-morbidities, other risk factors (e.g. 
smoking, diabetes), and relevant laboratory values. 
• 
Index 
procedure 
information 
including 
pre- 
and 
post-procedure 
lesion 
characteristics, lesion preparation including pre-dilatation, residual stenosis, and 
procedure and antiplatelet/anticoagulant medications.  
• 
Implanted Orsiro device information, including lot number, model, variant (e.g. 
length, diameter), device identifier (lot number), and implant date.   
• 
Antiplatelet medical therapy. 
• 
Device- or procedure-related adverse events. 
• 
MI event rates utilizing alternative MI definitions, including Third Universal6 and 
the BIOFLOW-V protocol definition5. Alternative MI definitions will be specified in 
the CEC Charter. 
• 
TLF event rates at 1 year utilizing alternative MI definitions, including Third
Universal6 and the BIOFLOW-V protocol definition5. 
 Subject Status  
2.3
The definitions in Table 2 define subject statuses throughout the study.  Screen 
failure criteria are defined to target enrollment of a 100% on-label population. 
 
 
 
 
 

 
 
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Table 2: Subject Status Definitions 
Subject 
Status 
Definition 
Enrolled 
Subject who successfully meets all inclusion/exclusion criteria and provides 
written informed consent. 
Pre-Screen 
failure 
Subject in whom an Orsiro stent is deployed (or in whom an Orsiro stent 
implantation is attempted) and informed consent is not obtained due to subject 
not meeting inclusion/exclusion criteria or subject is not willing to participate in 
the study. 
Screen 
failure 
Subject who provides written informed consent but does not meet key 
inclusion/exclusion criteria and will be exited from the study. A subject is 
considered a screen failure if: 
• 
Subject did not receive at least one Orsiro stent within 24 hours prior to 
informed consent.  If more than one stent was implanted during the index 
procedure, not all stents were Orsiro stents (Clinical Inclusion criterion #3 is 
not met). 
• 
Subject is not eligible for dual antiplatelet therapy (Clinical Inclusion criterion 
#4 is not met or Clinical Exclusion criterion #6 is met). 
• 
Subject had a 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 or any PCI planned within the next 1 year 
(Clinical Exclusion criterion #4 is met). 
• 
Subject met any of the following Clinical Exclusion criteria: STEMI (#1), 
allergies to contrast and/or other specified medications or materials (#3), or 
significant renal disease (#9, #10).  
• 
Subject had greater than three target lesions in up to two separate target 
vessels (Angiographic Inclusion criterion #1 is not met). 
• 
Target lesion was >36 mm in length by operator visual estimate (Angiographic 
Inclusion criterion #6 is not met). 
• 
Target vessel has a reference vessel diameter outside of 2.25-4.0 mm by 
operator visual estimate (Angiographic Inclusion criterion #7 is not met). 
• 
Target lesion(s) met any of the following Angiographic Exclusion criteria: 
located within or treated through a graft (#1), was a restenotic lesion that 
was previously treated with a bare metal or drug-eluting stent (in-stent 
restenosis) (#2), location  within the left main coronary artery, or within 3 
mm of the origin of the left anterior descending (LAD) or left circumflex (LCX) 
(#3a), involves a side branch of > 2.0mm (#3b), total occlusion (#6). 
• 
Target vessel/lesion was excessively tortuous/angulated or is severely 
calcified, that would prevent complete inflation of an angioplasty balloon. 
Assessment based on visual estimation (Angiographic Exclusion criterion #4 is 
met). 
• 
Target vessel(s) meet any of the following Angiographic Exclusion Criteria: 
angiographic evidence of thrombus (#5), was treated with brachytherapy any 
time prior to the index procedure (#7). 
 
Premature 
study exit 
Enrolled subject who exits prior to completion of the 5-year follow-up.

 
 
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3 Protocol Requirements 
 Subject Population 
3.1
The investigator is responsible for screening all potential subjects and selecting 
those who are appropriate for study inclusion. The subjects selected for 
participation should be from the investigator's general patient population according 
to the inclusion and exclusion criteria described in Sections 3.1.3 through 3.1.6. 
 Indications 
3.1.1
Orsiro is indicated for improving coronary luminal diameter in patients, including 
those with diabetes mellitus, with symptomatic heart disease, stable angina, 
unstable angina, non-ST elevation myocardial infarction or documented silent 
ischemia due to atherosclerotic lesions in the native coronary arteries with a 
reference vessel diameter of 2.25 mm to 4.0 mm and a lesion length of ≤ 36 mm.  
 Contraindications 
3.1.2
Orsiro is contraindicated for use in patients with: 
• 
A known hypersensitivity or allergy to the stent and/or stent coating materials 
such as amorphous silicon carbide, PLLA polymer, L-605 cobalt chromium alloy 
(including the major elements cobalt, chromium, tungsten and nickel), 
sirolimus or its derivatives. 
Coronary artery stenting is contraindicated for use in the following patients: 
• 
Patients who have contraindications for antiplatelet and/or anticoagulation 
therapy. 
• 
Patients who are judged to have a lesion that would be likely to prevent 
complete inflation of an angioplasty balloon or proper placement of the stent or 
delivery device.  
  Clinical Inclusion Criteria 
3.1.3
Subjects must meet all of the following criteria to be eligible for the trial: 
1. 
Subject is ≥18 years of age. 
2. 
Subject was an acceptable candidate for treatment with a drug eluting 
stent at the qualifying index procedure, in accordance with the applicable 
guidelines on percutaneous coronary interventions and manufacturer's 
Instructions for Use. 
3. 
Subject received at least one Orsiro stent during an index procedure 
occurring within 24 hours prior to informed consent, as assessed by the 
end time of procedure. If more than one stent was implanted during the 
index procedure, all stents were Orsiro stents. 
4. 
Subject is eligible for dual antiplatelet therapy (DAPT) treatment with 
aspirin plus either clopidogrel, prasugrel, ticagrelor or ticlopidine. 

 
 
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5. 
Subject is willing to comply with study follow-up requirements. 
6. 
Subject has provided written informed consent as approved by the 
Institutional Review Board (IRB) of the respective clinical site.  Legally 
authorized representatives are not allowed to consent on a subject’s behalf.  
 Clinical Exclusion Criteria 
3.1.4
Subjects will be excluded from the trial if any of the following criteria are met: 
1. 
Subject had clinical symptoms and/or electrocardiogram (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 pregnant and/or breastfeeding or intends to become pregnant 
during the duration of the study. 
3. 
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), silicon carbide, 
PLLA, sirolimus.   
4. 
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 or any PCI planned within the next 1 year. 
5. 
Presence of an untreated clinically significant stenosis post-procedure 
whether treatment is planned or not. 
6. 
Planned surgery within 6 months of index procedure unless DAPT can be 
maintained throughout the peri-surgical period. 
7. 
History of a stroke or transient ischemic attack (TIA) within 6 months prior 
to the index procedure. 
8. 
Subject has documented LVEF < 30% prior to or during the index 
procedure. 
9. 
Subject is dialysis-dependent. 
10. Subject has impaired renal function (blood creatinine > 2.5 mg/dL or 221 
μmol/L prior to the index procedure). 
11. 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). 
12. Any significant concurrent medical diagnosis that would potentially impact 
DAPT effectiveness or increase thrombotic risk. 

 
 
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13. Subject is receiving chronic anticoagulation (e.g. coumadin, dabigatran, 
apixaban, rivaroxaban or any other agent). 
14. Subject has life expectancy of < 1 year. 
15. Subject is participating in an 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 follow-up requirements of this study or does not involve a 
drug that may confound the interpretation of any relevant clinical events of 
interest (e.g. investigational DAPT therapy). 
16. In the investigator’s opinion, subject will not be able to comply with the 
follow-up requirements. 
  Angiographic Inclusion Criteria 
3.1.5
Each target lesion/vessel must have met all of the following angiographic criteria 
from the index procedure 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. 
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 2.25–4.0 mm by 
operator visual estimate. 
8. 
Target lesion must have been treated with a maximum of two overlapping 
stents. 
 Angiographic Exclusion Criteria 
3.1.6
Subjects will be excluded from the trial if any of the target lesions/vessels met any 
of the following angiographic criteria during the index procedure: 
1. 
Target lesion was located within or treated through a saphenous vein graft 
or arterial graft. 

 
 
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2. 
Target lesion was a restenotic lesion that was previously treated with a 
bare metal or drug-eluting stent (in-stent restenosis). 
3. 
Target lesion had 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 was 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 had angiographic evidence of thrombus. 
6. 
Target lesion was totally occluded (100% stenosis). 
7. 
Target vessel was treated with brachytherapy any time prior to the index 
procedure. 
  Study Procedures and Visits 
3.2
Subjects will be followed for a period of 5 years post-index procedure.   
Table 3 provides an overview of the study schedule including required visits and 
associated follow-up windows.   

 
 
 
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Table 3: Visit Assessment Schedule / Schedule of Events 
 
Index 
Procedure 
Post-
Procedure 
Enrollment 
Visit 
1 Month
± 7 Days 
1 Year
± 30 Days 
2, 3, 4, 5 Years
±60 Days 
Unsched. 
Visit 
 
Telephone 
Interview or 
Office Visit 
Telephone 
Interview or 
Office Visit 
Telephone 
Interview or 
Office Visit 
Informed consent form1 
X1 
 
 
 
 
Demographics, clinical status, medical 
history, pre-procedure cardiac 
biomarkers (CK, CKMB or troponin), 
CBC, cardiovascular and 
antiplatelet/anticoagulant medications  
X2 
 
 
 
 
Index procedure information 
X3 
 
 
 
 
Post-procedure cardiac biomarkers 
(CK, CKMB or troponin) 
X4 
 
 
 
 
Ischemic/angina status 
 
X 
X 
X 
X 
 
12-lead ECG 
X  
X5 
X5 
X5 
 
Angiography to assess lesion 
characteristics and final stent location 
X6 
 
 
 
X6 
AEs and SAEs7 
 
X 
X 
X 
X 
X 
Antiplatelet medical therapy  
X 
X 
X 
X 
X 
AE = adverse event; CBC = complete blood count; CK = creatine kinase; CKMB = creatine kinase myocardial band; ECG = electrocardiogram; SAE = serious 
adverse event 
1 Informed consent must be obtained after the index procedure. The date of index procedure is considered day 0 and informed consent (enrollment) can occur as 
late as 24 hours post-index procedure.   
2 Retrospective collection of pre-procedure information. Laboratory results (including cardiac biomarkers and CBC) collected only if testing performed per 
standard of care. 
3 Retrospective collection of index procedure information. 
4 Cardiac biomarkers collected only if testing performed per standard of care. It is anticipated that cardiac biomarker testing per standard of care generally 
would include subjects with positive cardiac biomarkers prior to the procedure, subjects with procedural complications and subjects with signs or symptoms of 
possible coronary ischemia post procedure. 
5 ECG collected only if an office visit is performed and if ECG is performed per standard of care.  
6 Images from standard of care angiography during index procedure should be retained and may be requested for submission to Angiographic Core Lab if   
subject undergoes a repeat angiogram. 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 Lab. 
7 All SAEs, potential endpoint events, and AEs possibly related to the device and/or procedure will be reported for the entire study period.  

 
 
 
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 Assessment Details 
3.2.1
Cardiac Biomarkers 
Cardiac biomarker testing [CK (creatine kinase), CKMB (creatine kinase myocardial 
band, or troponin)], should be performed according to standard of care.  Any 
cardiac biomarker testing performed per standard of care throughout the study 
duration should be collected and reported in the Electronic Data Capture (EDC) 
system. 
It is anticipated that cardiac biomarker testing per standard of care generally would 
include subjects with positive cardiac biomarkers prior to the procedure, subjects 
with procedural complications and subjects with signs or symptoms of possible 
coronary ischemia post procedure. 
Antiplatelet Regimen 
Subjects should receive dual antiplatelet (DAPT) therapy according to current 
guidelines.7 
All antiplatelet medications administered should be recorded in the medical record 
and reported in EDC from 72 hours prior to the index procedure (retrospectively 
collected) through the 5-year assessment.   
 Pre-Screening 
3.2.2
At each site, all patients in whom an Orsiro stent has been deployed should be 
screened for study eligibility and enrolled if they meet enrollment criteria and are 
willing to participate.  Reasons for subject non-eligibility for study enrollment (e.g. 
inclusion/exclusion criteria not met) or eligible for enrollment but not enrolled (e.g. 
patient unwilling to sign consent or death prior to being approached for consent) 
should be recorded on the electronic pre-screening log provided by BIOTRONIK. 
Additionally, all patients or in whom an Orsiro stent implantation was attempted, 
should also be recorded on the pre-screening log.  Pre-screening logs should be 
submitted to BIOTRONIK at monthly intervals during the enrollment phase.  
 Post-Procedure Enrollment Visit 
3.2.3
All clinical, angiographic, and other procedural inclusion and exclusion criteria 
should be confirmed post-procedure. After the patient has been determined to be 
eligible for the study, written informed consent must be obtained within 24 hours 
after the index procedure (as assessed by the end time of procedure) and prior to 
discharge for the patient to be enrolled in the study.  The end time of the procedure 
is defined as the time the guide catheter is removed from the subject.  Timing of 
consenting should be conducted in accordance with IRB requirements. 
After informed consent has been obtained, the following procedures/data are 
required at the Enrollment Visit: 
1. Retrospective collection of pre-procedure information from the medical record, 
including: 
• 
Demographics (e.g., age, sex at birth, race, and ethnicity).   

 
       
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• 
Clinical status (e.g., weight, height, blood pressure, ischemic/angina status 
assessment according to Canadian Cardiovascular Society Classification 
[CCSC] or Braunwald [refer to Section 17]). 
• 
Medical history: 
o General medical, cardiac, neurologic and renal history. 
o Cardiac 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. 
• 
Cardiovascular and antiplatelet/anticoagulant medications from 72 hours 
prior to the index procedure through enrollment. 
• 
Pre-procedure laboratory test results (if performed per standard of care): 
o CK, CKMB, and/or troponin prior to the procedure. If more than one 
draw was performed prior to the index procedure, the most recent 
value should be recorded.  
o Creatinine, Complete Blood Count, etc.  
2. Retrospective collection of index procedure and post-procedure information from 
the medical record, including: 
• 
Procedure information (e.g., lesion characteristics, device information, 
dilatation details, vessel preparation, residual stenosis.) 
• 
Adverse events occurring during or after the index procedure through the 
Enrollment Visit (refer to Section 5.3 for reporting requirements). 
• 
Collect post-procedure laboratory cardiac biomarker data (if testing 
performed per standard of care).  
3. Performance and/or collection of 12-lead ECG and ischemic/angina assessment 
per CCSC/Braunwald classification prior to discharge.  
4. Review of the study follow-up requirements with the subject, to help ensure 
compliance with the follow-up schedule and DAPT medication regimen.  
Confirmation of subject contact telephone numbers, including numbers for 
home, work, and primary physician, as applicable, should be completed.   
5. Reminder to subjects to contact site research personnel if approached by other 
clinical personnel about enrollment into another study.  Subjects should not be 
enrolled in any investigational drug or device clinical study during the BIOFLOW-
VII study. Co-enrollment in post-market studies may be allowed as long as the 
post-market study device, drug or protocol does not interfere with the follow-up 
requirements of this study or does not involve a drug that may confound the 
interpretation of any relevant clinical events of interest. The co-enrollment 

 
       
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study’s information should be reviewed with BIOTRONIK personnel and, if 
needed, the site’s IRB.   
Procedural angiograms from the index procedure should be archived for possible 
later evaluation by the Core Laboratory.  Two copies of the angiograms are 
suggested (one for the site, one for the Core Laboratory). 
  Follow-up Assessments 
3.3
All enrolled subjects will be followed through 5 years of follow-up, with assessments 
performed at 1 month, 1 year and annually thereafter. All visits should be 
performed by telephone interview with the subject, unless a standard of care 
routine office visit is planned within the applicable follow-up window. For each 
follow-up visit, all clinical assessments should be performed on the same date.  
Requirements of each follow-up evaluation are described below. 
Target windows for follow-up visits are provided on the subject’s record page in the 
EDC system and are based on the date of index procedure. It is recommended to 
schedule subjects early in the visit window, to allow for potential re-scheduling 
within the visit window, if necessary.  Visits completed outside of the target window 
will require completion of a Protocol Noncompliance electronic Case Report Form 
(eCRF). 
  One (1) Month Follow-up (30 ± 7 Days) 
3.3.1
Subjects will be evaluated at 1 month post-procedure by a telephone interview or 
an office visit.  The following assessments must be completed: 
• 
Ischemic/angina status (according to CCSC or Braunwald). 
• 
AEs and SAEs since the previous contact (refer to Section 5.2) 
• 
Antiplatelet medical therapy since the previous contact. 
• 
Any coronary intervention (e.g., repeat revascularization) that occurred since 
the Enrollment Visit. 
• 
12-lead ECG (collected only if an office visit is performed and if ECG is 
performed per standard of care). 
  One (1) Year Follow-up (360 ± 30 Days) 
3.3.2
Subjects will be evaluated at 1-year post-procedure by a telephone interview or an 
office visit.  
During the 1-Year follow-up visit, the following assessments must be completed: 
• 
Ischemic/angina status (according to CCSC or Braunwald). 
• 
AEs and SAEs since the previous contact. 
• 
Antiplatelet medical therapy since the previous contact. 
• 
Any coronary intervention (e.g., repeat revascularization) that occurred since 
the previous contact. 

 
       
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• 
12-lead ECG (collected only if an office visit is performed and if ECG is 
performed per standard of care). 
 Long-Term Clinical Follow-Up at 2, 3, 4 and 5 Years Post-Procedure 
3.3.3
(Annually ± 60 Days) 
Subjects will be evaluated at 2, 3, 4 and 5 years post-procedure by a telephone 
interview or an office visit.  
The following assessments must be completed: 
• 
Ischemic/angina status (according to CCSC or Braunwald). 
• 
AEs and SAEs since the previous contact. 
• 
Antiplatelet medical therapy since the previous contact. 
• 
Any coronary intervention (e.g., repeat revascularization) that occurred since 
the previous contact. 
• 
12-lead ECG (collected only if an office visit is performed and if ECG is 
performed per standard of care). 
 Reporting of Unscheduled Evaluations 
3.3.4
Subjects may present to the clinic outside of the scheduled follow-up windows.  
Such unscheduled study evaluation will be reported if the subject has experienced 
an AE.   
Subjects assessed at an unscheduled study evaluation may require diagnostic 
testing (e.g. ECG, angiogram, CKMB or troponin levels)and/or a revascularization 
procedure to further evaluate and treat ischemic symptoms.  Any repeat procedure 
must be reported on the relevant eCRFs, including any unscheduled evaluations 
prior to the repeat procedure and/or adverse events associated with the procedure, 
including separate AEs for each revascularization site if multiple sites were treated.   
Any repeat or unscheduled diagnostic or interventional coronary revascularization 
procedure performed should include a diagnostic assessment of the target lesion(s) 
and study 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 
Angiographic Core Laboratory for an independent review and assessment of the 
target lesion and study stent. 
 
  Study Exits 
3.4
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.   

 
       
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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  
In the event of major protocol noncompliance, 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.  Study exits are 
expected and will be taken into consideration during data analysis as described in 
Section 4.  Additionally, subject attrition has been calculated into the study sample 
size.  Investigators must document, in subject study records, the reasons and 
circumstances for all subject exits.  
 Withdrawal of Consent 
3.4.1
Subjects may withdraw their consent for study participation at any time without 
stating the reason and without any unfavorable consequences. A Study Termination 
eCRF will be completed and the reasons for withdrawal should be documented if 
willingly provided by the subject. 
The date of study exit is the date of withdrawal of consent.  
 Vital Status 
3.4.2
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 study site level.  Subjects have the right to discontinue from 
the study at any time or be discontinued at the investigator’s discretion. 
  Subject Death 
3.4.3
In the event of subject death during study participation, personnel at the study site 
are requested to notify BIOTRONIK promptly by completing an Adverse Event eCRF 
and a Study Termination eCRF. All actions taken, which were initiated to gain 
further information must be documented in writing and provided to BIOTRONIK. 
The date of study exit is the date of death.  
The following information will be required for any subject death:  
• Death certificate, death report signed by the investigator, or relevant medical 
records that include:  
• 
Date of death  
• 
Primary cause of death  

 
       
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• 
Any other circumstances surrounding the death  
• 
Investigator’s assessment of relatedness to device or procedure  
  Lost to Follow-up 
3.4.4
Subjects lost to follow-up are those for whom contact is lost despite the 
investigator’s best efforts to locate the subject. 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 attempt by certified mail and document 
the contact attempts.  
In the event the subject cannot be contacted using the above methods, the subject 
is terminated from the clinical investigation by completing a Study Termination 
eCRF.  Subjects are not eligible to be exited as lost to follow-up until after the 1-
Year Follow-up. If the 1-Year Follow-up was not completed and subject could not be 
contacted, and the required contact attempts (at a minimum) have been 
documented, then lost to follow-up may be an acceptable reason for exit. 
The date of exit in the Study Termination eCRF is the date that the site determines 
the subject to be lost to follow-up.  The date of last documented contact with the 
subject will also be collected.  Both dates should be clearly documented. 
  Study Completion 
3.4.5
All subjects are expected to be followed for 5-years. After a subject completes their 
final routine study follow-up, the subject’s study participation is complete and the 
subject should be exited from the study by completing a Study Termination eCRF. 
The date of exit is the date of the final study visit. 
 Screen Failures 
3.4.6
Subjects who provide informed consent and do not meet key inclusion and 
exclusion criteria as defined in Table 2 will be considered screen failures for the 
study and exited. These patients will continue to receive the same standard of care 
treatment.   

 
       
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4 Statistical Design and Analysis Plan 
Analysis of Study Endpoints
4.1
The BIOFLOW-VII study is a prospective, multicenter, single-arm study.  A total of 
556 subjects will be enrolled. 
 Primary Endpoint  
4.1.1
The purpose of the primary endpoint is to evaluate the rate of TLF of the Orsiro 
stent at 1 year compared to a performance goal of 6.9%. 
 
Ho: The TLF rate of the Orsiro stent at 1 year is greater than or equal to a 
performance goal of 6.9% 
Rate ≥ 6.9% 
Ha:The TLF rate of the Orsiro stent at 1 year is less than a performance 
goal of 6.9% 
Rate < 6.9% 
A rejection of the null hypothesis (Ho) would demonstrate that the primary endpoint 
is met. 
TLF is defined as a composite of cardiac death, target vessel-MI or clinically-driven 
TLR. Target vessel MI will utilize the SCAI definition4 for peri-procedural MI and the 
BIOFLOW-V protocol definition5 for spontaneous MI. 
 Secondary Endpoints 
4.1.2
There are no formal hypotheses for the secondary endpoints. 
  Sample-Size Analysis 
4.2
The study is designed to limit the number of subjects involved while still exposing 
the device to a sufficiently large patient population in order to ensure a 
representative and statistically meaningful sample. 
The estimated sample size for the study is based on TLF results from the BIOFLOW-
V study and in consideration of recent published relevant clinical TLF rates of other 
comparable stents that utilized the SCAI definition4 of peri-procedural MI. The 
BIONICS IDE study utilized the Third Universal definition6 of spontaneous MI, which 
is deemed to be similar to the spontaneous definition of MI used in the BIOFLOW-V 
study5.  
Comparable stents were evaluated in these two IDE studies involving a total of over 
2,000 subjects and had consistent TLF upper 95% confidence bounds in the range 
of 6.9% - 7.1% (Table 4).  A performance goal was derived considering this 
potential TLF rate range and was adjusted to account for the potential differences in 
the prospectively enrolled BIOFLOW-VII population enrolled under real world post-
approval conditions. 

 
       
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Differences in standard of care practices and patient population may impact the 
final TLF rate. Specifically, cardiac biomarkers are infrequently analyzed post-
procedure in asymptomatic patients as standard of care. Analysis of troponins is 
more frequent in clinical practice, whereas CKMB was measured more frequently as 
part of the protocol in the BIOFLOW-V study.  It is also anticipated that a post-
approval real-world population may have different frequencies of factors (e.g. 
diabetes, prior MI, etc.) and patient and lesion characteristics than those enrolled in 
IDE trials. These factors could result in a higher observed TLF rate than in 
BIOFLOW-V or other prior trials. 
Table 4: 1-Year TLF Rates for DES Utilizing SCAI Definition of Peri-
Procedural MI  
Study 
TLF Rate at 1 Year 
95% Confidence 
Interval 
BIOFLOW-V: Orsiro 
2.6% (22/833) 
(1.7%, 4.0%) 
BIOFLOW-V: Xience 
4.5% (19/426) 
(2.7%, 6.9%) 
BIONICS8,9,10 EluNIR 
5.4% (50/926) 
(4.0%, 7.1%) 
BIONICS: Resolute 
5.4% (50/930) 
(4.0%, 7.0%) 
 Assumptions for Primary Endpoint of TLF* at 1 Year 
4.2.1
The sample size required to evaluate the primary endpoint was estimated using the 
following design criteria: 
• 
Performance goal: 6.9% (upper 95% CI acceptability for BIOFLOW-VII) 
• 
Target Orsiro TLF rate: 4.0% 
• 
Statistical power: 80% 
• 
Significance level: one-sided 0.025 
Table 5: Primary Endpoint Sample Size 
 
Primary Safety 
Endpoint 1 
Sample Size of 
Evaluable Subjects 
495 subjects 
Sample Size Adjusted 
for Post-Approval Study 
Requirement 
500 subjects 
Total Adjusted for 
Attrition 
556 subjects 
 
*Peri-procedural MI based on SCAI definition4. Spontaneous MI based on BIOFLOW-V protocol 
definition5. 

 
       
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In order to collect additional data on the performance of the Orsiro stent, the 
sample size will increased to a target minimum of 500 evaluable subjects at 1-year 
post-index procedure as recommended by the FDA.  Assuming a 10% attrition rate 
through the first 1 year of subject follow-up, a total enrollment of 556 subjects has 
been estimated. 
 Maximum Number of Subjects per Site  
4.2.2
Enrollment at a single site will be limited to no more than 20% of the projected 
total study enrollment (approximately 111 subjects).  It is anticipated that a 
minimum of 20 sites will enroll subjects. 
  Data Analysis Plan 
4.3
Descriptive statistics will be used to present and summarize the data collected in 
the clinical study.  Frequency distributions and cross tabulations will be presented 
for discrete variables.  Means, standard errors, and ranges will be presented for 
continuous variables. 
Interim progress reports will be submitted to FDA every 6 months during the first 2 
years of the study and annually thereafter, unless otherwise specified by FDA. 
Summary and descriptive analyses of all endpoints will be included in the progress 
reports and may be posted on the FDA Post-Approval Studies webpage. Follow-up 
compliance rates will also be included in the progress reports. 
 Patient Demographics and Target Lesion Characteristics 
4.3.1
Patient demographics and target lesion characteristics will be compared with those 
of the BIOFLOW-V (IDE) study cohort at 25%, 50%, and 75% of the expected total 
enrollment to ensure that the enrolled patient population is comparable with the 
BIOFLOW-V (IDE) study population. 
 Analysis Population Definition(s) 
4.3.2
Table 6 provides definitions of the study analysis populations. 
Table 6: Study Analysis Populations 
Analysis Population 
Definition 
Intent-to-Treat (ITT) 
 
The ITT population is defined as all 
enrolled subjects who received at least 
one Orsiro stent and were not considered 
a screen failure. 
Per-Protocol (PP) 
The PP population is defined as all ITT 
subjects who have no major protocol 
eligibility violations that could impact the 
primary endpoint. Criteria defining the PP 
population will be pre-specified prior to 
any PP analyses being performed.  

 
       
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  Analysis Methods 
4.3.3
All clinical data will be analyzed based upon the pre-defined analysis populations.  
The following methods will be used to evaluate the study endpoints. 
Primary Endpoint 
The primary analysis of the primary endpoint of the TLF rate of the Orsiro stent at 1 
year will be in the intent-to-treat (ITT) population.  The primary endpoint will be 
tested against a performance goal of 6.9% using a one-sided, exact test for one 
proportion with a Type I error level of 0.025. A supporting analysis will be 
performed in the PP population.  A Kaplan-Meier survival analysis (time-to-event) 
for the primary endpoint outcome will also be performed in the PP population. 
For each analysis population, subjects who have sufficient follow-up data (at least 
330 days of follow-up) or experienced the primary endpoint will be included in the 
primary endpoint analysis. 
Secondary Endpoints 
There are no formal hypotheses for the secondary endpoints. Secondary clinical 
endpoints 1 through 7 will be evaluated prior to discharge, at 1 month, 1 year, and 
annually thereafter through 5 years of follow-up.  Analyses of these secondary 
endpoints will be carried out on the ITT and PP analysis populations: 
1. All-cause death. 
2. MI. 
3. Cardiac death or MI. 
4. MACE and individual MACE components (MACE: composite of all-cause death,  
Q-wave or non–Q-wave MI, and clinically-driven TLR). 
5. TLF (evaluated at 2, 3, 4, and 5 years) and individual TLF components (TLF: 
composite of cardiac death, target vessel Q-wave or non–Q-wave MI, and 
clinically-driven TLR). 
6. TVF and individual TVF components (TVF: composite of cardiac death, target 
vessel Q-wave or non–Q-wave MI, and clinically-driven TVR). 
7. Stent thrombosis (definite, definite/probable, probable) according to 
Academic Research Consortium (ARC)-21 criteria for acute, subacute, late, 
very late and cumulative stent thrombosis. 
Analyses of the following additional secondary endpoints will be carried out on the 
ITT and PP analysis populations.   
1. Device success 
2. Lesion success
3. Procedure success 

 
       
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  Handling of Missing Data 
4.3.4
All reasonable methods will be taken to ensure a minimum of missing data, 
including site monitoring, training, and corrective actions, if required, ongoing 
review of collected data for accuracy and completeness, and repeated, documented 
attempts to contact subjects with missing study visits.   Any reasons for missing 
data or withdrawal from the study will be documented when possible. The impact of 
missing data on conclusions about the primary study endpoint will be examined in 
sensitivity analyses, which may include multiple imputation methods, if warranted.    
 Subgroup Analysis  
4.3.5
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. 
• 
Stent diameter ≤ 3.0 mm or > 3.0 mm. 
• 
Subjects with acute coronary syndrome versus non-acute coronary 
syndrome. 
There is no formal hypothesis for this subgroup analysis.  Subjects with an event 
and/or with appropriate follow-up will be included in this analysis. 
  Poolability Analysis  
4.3.6
The poolability of study results between clinical sites in the US will be analyzed and 
reported but there are no pre-specified tests of the statistical significance for site 
differences. 
  Sex Analysis 
4.3.7
Any differences between sexes in study results between clinical sites in the US will 
be analyzed and reported but there are no pre-specified tests of the statistical 
significance for sex differences.   

 
       
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5 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 Adverse Event eCRF. 
 General Definitions 
5.1
Table 7: Adverse Event Definitions 
Adverse Event (AE) 
ISO 14155:2011(E) 
Any untoward medical occurrence, unintended disease 
or injury, or untoward clinical signs (including 
abnormal laboratory findings) in subjects, users or 
other persons, whether or not related to the 
investigational medical device. 
 
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 – For users or other persons, this definition is 
restricted to events related to investigational medical 
devices. 
Adverse Device Effect 
(ADE)  
ISO 14155:2011(E) 
Adverse event related to the use of an investigational 
medical device.   
 
Note 1 - 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. 
 
Note 2 – This definition includes any event resulting 
from user error or from intentional misuse of the 
investigational medical device. 

 
       
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Serious Adverse Event 
(SAE) 
ISO 14155:2011(E) 
Adverse event that:  
1. led to death,  
2. led to serious deterioration in the health of a 
subject, that either resulted in 
a. a life threatening illness or injury, or  
b. a permanent impairment of a body 
structure or a body function, or  
c. an in-patient or prolonged hospitalization, 
or  
d. medical 
or 
surgical 
intervention 
to 
prevent life-threatening illness or injury 
or a permanent impairment to a body 
structure or a body function, 
3. led to fetal distress, fetal death or a congenital 
abnormality or birth defect.  
 
Note - Planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, 
without 
serious 
deterioration 
in 
health, 
is 
not 
considered a serious adverse event. 
Serious Adverse Device 
Effect (SADE) 
ISO 14155:2011(E) 
Adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse 
event. 

 
       
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  Protocol Defined Reportable Adverse Events 
5.2
The investigator shall report to the sponsor, by completing the appropriate eCRF, 
the following types of events experienced by the subject after enrollment 
(consent)*: 
• 
All serious adverse events. 
• 
All potential endpoint events, including death, MI, stent thrombosis, TLR, and 
TVR adverse events. 
• 
All adverse events possibly related to the device and/or procedure. 
• 
Abnormal laboratory findings will be considered AEs only if related to 
potential endpoint events (e.g., elevated cardiac biomarkers), or if 
determined by the investigator to be clinically significant. 
*Note: Adverse events occurring since the beginning of the initial index 
procedure (prior to consent), will be collected retrospectively.   
Other than adverse events occurring since the beginning of the initial index 
procedure, pre-existing conditions (underlying conditions present prior to obtaining 
subject consent) that are clearly documented in the subject’s medical record are 
not required to be reported as adverse events, unless there is an increase in 
severity or frequency or a change from the pre-enrollment baseline during the 
course of the study. 
All complaints will be reported through the standard market release product 
reporting process. 
  Reporting Adverse Events 
5.3
  Site Reporting 
5.3.1
The study site should report each reportable adverse event to BIOTRONIK via 
completion of an Adverse Event eCRF. Adverse events should be reported as soon 
as possible, even if this results in an incomplete eCRF.   
The investigator will be required to assess and characterize each protocol defined 
adverse event’s relatedness to the study device and procedure, seriousness, 
outcome, treatment or action taken. The investigator must ensure that all source 
documentation and relevant information is available. This also includes information 
from other parties such as family, other treatment facilities/hospitals, etc. Copies of 
all supporting documents, with identifying information redacted, should be 
submitted concurrently with the Adverse Event eCRF.   
The investigator must characterize each event by a single primary diagnosis. The 
primary diagnosis may describe an event consisting of several clinically 
recognizable features, symptoms or secondary diagnoses. Note: The observed 
symptoms and secondary diagnoses must be properly documented in the Adverse 
Event eCRF. 

 
       
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Multiple events may occur simultaneously in one subject. For each medically 
independent event with a primary diagnosis an individual report must be provided.   
The investigator must follow-up all ongoing reportable events either as long as the 
subject participates in the clinical study, the clinical study is terminated, or until the 
event has been resolved, whatever comes first.  
Investigators are required to adhere to applicable regulations and reviewing IRB 
reporting requirements for adverse events. Refer to Section 13.1 for further 
details on adverse event reporting timing requirements. 
The adverse events that an IRB considers reportable are dependent on the 
particular IRB. To avoid underreporting, BIOTRONIK recommends that, at a 
minimum, the investigator reports all deaths and serious device related events to 
the IRB. If the IRB is notified, provide a copy of the IRB adverse event notification 
to BIOTRONIK. 
Additionally, study sites may report adverse events through MedWatch FDA’s 
adverse event reporting tool for market-released devices.  
  Sponsor Reporting 
5.3.2
BIOTRONIK may determine that study adverse events meet the manufacturer’s 
reporting requirements through MedWatch reports. 

 
       
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6 Additional Study Conditions 
 Regulatory Compliance 
6.1
This study will be conducted according to local legal and regulatory requirements 
and applicable federal regulations. The study will be conducted in compliance with 
the international scientific and ethical quality standard for clinical trials known as 
Good Clinical Practice (GCP). This study will be publicly registered on 
https://clinicaltrials.gov/. 
  IRB Approval 
6.2
Institutional Review Board (IRB) approval is required from each institution prior to 
participation in this clinical study.  Subject enrollment may not begin until both the 
IRB and BIOTRONIK have granted approval for the study site.  IRB approval is also 
required throughout the duration of this clinical study.  If IRB approval is 
withdrawn, BIOTRONIK must be notified within 5 working days.  
 Other Institutions and Physicians 
6.2.1
This clinical study is not transferable to other institutions attended by the 
investigator unless prior approval is obtained from both BIOTRONIK and the 
appropriate IRB.   However, there are certain situations where an investigator 
might not be immediately available to provide the necessary medical care for a 
subject enrolled in the clinical study (such as a subject emergency room visit for 
medical treatment).  In these instances a protocol deviation will not be issued and 
all available data will be utilized. In any such situations, the IRB and the 
investigator must continue to provide oversight for that patient’s medical care and 
rights as a research subject.  
  Informed Consent 
6.3
All subjects must sign and date an IRB approved Informed Consent Form (ICF) 
prior to enrollment or any protocol related procedures. Legally authorized 
representatives are not allowed to consent on a subject’s behalf. Informed consent 
should be obtained in accordance with the FDA regulations (21CFR, Part 50), 
ICH/GCP Guidelines, the Declaration of Helsinki and any other national or local 
requirements. The consent process, including discussion of the study, should be 
documented within the subject’s medical record. A copy of the completed (signed) 
informed consent form should be given to the subject. 
This study does not include vulnerable patient populations.  The investigator is 
required to inform BIOTRONIK and the reviewing IRB within 5 days if any subject 
was not appropriately consented to participate in the study.   

 
       
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7 Data Collection 
 Electronic Data Capture (EDC) 
7.1
MedNet Solutions, Inc. is a privately held company that specializes in web-based 
clinical data management technology. MedNet will host the EDC system and provide 
a secure environment that is accessible to authorized individuals through the 
internet. BIOTRONIK will implement a study specific configuration using this 
software to meet the data collection requirements of the protocol. The EDC system 
is 21 CFR Part 11 compliant and is the platform for eCRF data entry, clinical data 
discrepancy resolution, and access to reports for BIOTRONIK, specified study sites, 
and any other parties authorized by BIOTRONIK. 
  Electronic Case Report Forms (eCRFs) 
7.2
Original data will be collected from each study site and recorded into the EDC 
system, audited and monitored by BIOTRONIK, via completion of eCRFs. The 
investigator will be required to use an electronic signature to approve the content of 
the data reported in the eCRFs. 
The iMedNet EDC system incorporates the ability for sites to upload subjects’ signed 
and dated ICFs for the purposes of remote review of signed ICFs by Centralized 
Monitors to help identify any potential ICF compliance concerns early in the study 
prior to an on-site monitoring visit. As BIOTRONIK utilizes risk-based monitoring, 
the ability to upload unredacted informed consent forms is one of the factors taken 
into account when determining the need for a monitoring visit. An unredacted 
version of the subject’s signed and dated ICF allows the Centralized Monitor to 
verify that the ICF was signed and dated by the subject prior to study procedures 
being conducted and that the subject signature and date are legible, complete, and 
correlate with the subject initials entered into EDC.  
iMedNet is compliant with 21 CFR Part 11 Electronic Records; Electronic signatures. 
MedNet systems utilize industry standard methods for maintaining confidentiality 
and integrity of client data, and include (but are not limited to) SSL encryption, 
digital signatures, and secure technology policies and procedures. If additional 
information is required, iMedNet’s Traceability Matrix illustrating evidence of 
iMedNet's compliance with all 21 CFR Part 11 requirements can be provided upon 
request. 
If a site is not allowed to upload unredacted subject ICFs to the EDC system based 
on institutional policies, the site must provide to BIOTRONIK either a copy of the 
IRB or institutional policy or if a formal policy does not exist, a Note to File 
documenting this policy signed and dated by the Principal Investigator.  
  Data Quality Control 
7.3
BIOTRONIK will review study data. At any time, reports may be generated on data 
completion and missing data for each study site. The EDC system will be used to 
track received and expected follow-up data and eCRFs for each participant. This 

 
       
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system provides the capability to monitor the status, volume, and disposition of 
data. In addition, study data will undergo automatic edit and plausibility checks 
which provide information to the study sites to help improve and maintain data 
quality control procedures designed to detect inaccuracies and inconsistencies.  
To ensure protocol compliance at all participating study sites, BIOTRONIK monitors 
will conduct monitoring visits and/or centralized monitoring throughout the course 
of the study (refer to Section 11).  
  Subject Data Confidentiality 
7.4
All information and data collected for the BIOFLOW-VII study concerning subjects 
or their participation in this investigation will be considered confidential by 
personnel at BIOTRONIK, BIOTRONIK’s parent company, its subsidiaries and 
affiliates, as well as contracted designees, such as the CEC, Core Laboratory, EDC 
vendor and any other authorized third parties. Only authorized BIOTRONIK 
personnel or an authorized BIOTRONIK representative will have access to these 
confidential files. All data will be handled in accordance with applicable 
international, national and local laws, including the Health Insurance Portability and 
Accountability Act (HIPAA) of 1996. In order to verify the study data and ensure 
study integrity, monitors from BIOTRONIK, the FDA, other national regulatory 
and/or public health authorities and the reviewing IRB, if applicable, may review 
and/or copy the study records. Source documents supplied to the CEC or Core 
Laboratory will have confidential subject identifiers redacted. All data used in the 
analysis and reporting of this study will not include subject names or other 
identifiable references. 

 
       
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8 Protocol Compliance 
The investigator is required to conduct this study in accordance with the signed 
Investigator Agreement and clinical protocol.  The investigator shall notify 
BIOTRONIK and the reviewing IRB in writing no later than 5 working days after any 
significant deviation from the clinical protocol 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 clinical protocol.   
The site is responsible for reporting noncompliance via Protocol Noncompliance 
eCRFs. BIOTRONIK categorizes protocol noncompliance instances as either 
violations or deviations.  Both protocol violations and deviations will be reported in 
the interim and final clinical progress reports to FDA.  
BIOTRONIK will evaluate the noncompliance and issue corrective actions, as 
necessary, which may include but are not limited to, re-training, discontinuing 
enrollment at the study site, or closing the study site. 
  Protocol Violations 
8.1
Protocol violations are defined as instances where the protocol requirements and/or 
regulatory guidelines were not followed and are generally more serious in nature 
than deviations.  Protocol violations are considered to potentially affect the 
subject’s rights, safety, or well-being, and/or the scientific soundness/data 
reliability, accuracy, or completeness of the primary study endpoint data.   
Protocol violations include, but are not limited to: 
• 
Failure to obtain consent or other instances in which the subject did not 
provide consent. 
• 
Subject inclusion/exclusion violations. 
• 
Protocol requirement violations that affect the primary endpoint of the study 
design.  
Protocol Deviations
8.2
Protocol deviations are defined as instances where protocol requirements or 
regulatory guidelines were not followed but are generally less serious in nature than 
violations.  Protocol deviations generally do not affect the subject's rights, safety, or 
well-being and/or the completeness, accuracy and reliability of the study primary 
endpoint data. Instances of noncompliance should be considered a deviation if it 
does not meet the criteria for being considered a violation. 
Protocol deviations include, but are not limited to: 
• 
Informed Consent documentation issues such as incomplete ICF, missing 
dates for signature(s), missing initials or illegible information, subject 
signature date completed by someone other than subject, utilization of an 
outdated or non-IRB approved ICF, incomplete associated forms required at 
time of consent, etc. This is not an exclusive list. 

 
       
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• 
Procedure not performed within the allowed timeframe. 
• 
Required data not obtained. 
  IRB Reporting of Noncompliance 
8.3
The investigator must notify the reviewing IRB of all noncompliance issues per the 
IRB and protocol reporting requirements. At a minimum, all violations and 
noncompliance issues related to informed consent and informed consent 
documentation should be reported to the IRB.  
In some instances, such as failure to obtain consent, the investigator should also 
seek guidance from the IRB to ensure the subject received appropriate information 
to consider their participation in the study. 
The site should provide a copy of the IRB protocol noncompliance notification (as 
applicable) to BIOTRONIK.  
  Follow-up Compliance 
8.4
Sites are expected to ensure follow-up visit compliance over the duration of the 
study. 
Although the study sample size has been calculated with a 10% subject attrition 
rate over the first year, subject retention in a 5 year study may pose additional, 
unforeseen challenges. The EDC system includes an overview of each subject’s 
follow-up schedule, including the windows for each follow-up. BIOTRONIK will 
provide additional tools to the sites in an effort to minimize the number of subjects 
that are lost to follow-up. 
In addition, BIOTRONIK monitors will review subjects, including those that may be 
lost to follow-up, to ensure protocol and study visit compliance. 
  Audits/Inspections 
8.5
Study centers may be audited during the course of and after completion of the 
clinical study by BIOTRONIK or BIOTRONIK designees, the FDA, IRB, or other 
applicable regulatory authorities.  
The investigator must provide the auditor with all clinical study documents including 
the medical records for all enrolled subjects.  

 
       
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9 Risk Analysis 
This is a post-approval study conducted using legally marketed devices implanted 
according to their approved labeling. BIOTRONIK foresees no additional risks 
associated with this study beyond those stated in the IFU for the Orsiro stent. The 
only research related risk is the potential loss of confidentiality that is minimized by 
PHI redaction in the study.  

 
       
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10 Study Organization 
 Sponsor 
10.1
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. The 
sponsor, and/or other designees will ensure adherence to the sponsor general 
duties, 
selection 
of 
investigators, 
monitoring, 
supplemental 
applications, 
maintaining records and submitting reports. 
BIOTRONIK’s general duties include submitting the application to appropriate 
regulatory authorities and obtaining overall regulatory approval. 
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 deviations from the 
protocol, as appropriate. 
BIOTRONIK or its designee will prepare written reports and a final report as 
directed. 
 Clinical Events Committee 
10.2
A Clinical Events Committee (CEC) will be established consisting of independent 
physicians familiar with the treatment of coronary artery disease who are not 
participants in the study.  The CEC will review and adjudicate all potential endpoint 
events reported by study sites. Source documents supplied to the CEC will have 
confidential subject identifiers and site identifiers redacted. To minimize bias, 
members will not participate as investigators. 
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.  The CEC will 
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.  
 Angiographic Core Laboratory 
10.3
An Angiographic Core Laboratory (Core Lab) will independently assess repeat 
and/or unscheduled angiograms submitted by clinical sites for a suspected 
restenosis of a target vessel during the study follow-up period.  The Core Lab will 
provide independent review of angiographic follow-up of the treated target lesion, 
quantitative target lesion characteristics, and quantitative study stent results, to 
support the evaluation by the CEC. 
Sites should obtain angiographic images in accordance with standard of hospital 
practice but should make efforts to ensure the final stent location is documented at 
the initial index procedure and that any re-evaluation includes the study stent. 

 
       
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Initial index procedure, staged procedure (if applicable), and repeat procedure 
angiograms for all subjects will be kept on file at the study sites.  If coronary 
angiograms are performed during the trial follow-up period due to suspicion of 
restenosis of the target vessel, a revascularization of the target vessel, stent 
thrombosis or in follow-up to a myocardial infarction, sites should submit both the 
index procedure and follow-up angiography to the Core Lab for analysis.   
The Core Lab will provide sites with a written procedural manual describing the 
procedures for submitting angiograms.  Submission documentation of images to the 
Core Lab (i.e. Core Lab submission worksheet), as well as, a copy of the images 
submitted (via CD/DVD), should also be kept on file at the site. 
 Role of BIOTRONIK Personnel 
10.4
BIOTRONIK Clinical Studies personnel will: 
• 
Provide information, assistance, and training needed to conduct the study. 
• 
Ensure proper monitoring throughout the study. 
• 
Maintain proper records during and after the study. 
• 
Compile and submit reports in accordance with regulations and requirements. 
Please contact BIOTRONIK Clinical Studies personnel with any study related 
questions or concerns. 
BIOTRONIK field personnel (including sales representatives and field clinical 
specialists) are allowed to: 
• 
Review collected data for completeness and accuracy. 
• 
Discuss general study progress with investigators and RCs. 
• 
Answer technical questions on BIOTRONIK devices. 
BIOTRONIK Personnel are NOT allowed to: 
• 
Recruit subjects to participate in the study.  
• 
Participate in the informed consent process with subjects or sign the subject 
informed consent forms as a witness. 
• 
Assist with translation for non-English speaking subjects. 
• 
Sign study worksheets on behalf of the site 
• 
Perform data entry into the study Electronic Data Capture (EDC) systems. 
• 
Request or retrieve subject medical records. 
• 
Perform responsibilities of site study personnel such as completing or 
submitting IRB or other regulatory paperwork. 
• 
Serve as a communication liaison between the site and IRB or FDA.  
• 
Participate in any IRB or FDA inspections on behalf of the site. 

 
       
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11 Monitoring 
 Summary 
11.1
The responsibility of BIOTRONIK as sponsor is to ensure protocol and regulatory 
compliance through proper monitoring of the clinical study at sites. BIOTRONIK 
utilizes a risk-based monitoring strategy consistent with FDA’s Guidance for 
Industry:  Oversight of Clinical Investigations – A Risk-Based Approach to 
Monitoring, August 2013. Risk-based monitoring starts with performing a study risk 
assessment of the identified critical data and processes. The resulting monitoring 
plan focuses on targeted source data verification and trend analyses to improve 
oversight and data quality, while integrating predefined triggers for monitoring 
visits. The detailed study risk-based monitoring plan developed by BIOTRONIK 
focuses on a combination of monitoring visits and centralized monitoring.  
Monitors may periodically conduct on-site or remote monitoring visits during the 
clinical study in accordance with the monitoring plan. Sites are required to support 
monitoring visits and the study monitoring effort, including either direct monitor or 
site-assisted access to the applicable medical record systems. The principal 
investigator (PI) is encouraged to be available during monitoring visits. Monitoring 
visits will also provide an assessment of the continued acceptability of the facilities 
to continue participation in the study.    
Centralized monitoring may be conducted throughout the course of the study in 
accordance with the monitoring plan.  Centralized monitoring is conducted via 
investigator locked eCRFs through the source data verification of source documents 
uploaded to the eCRF. Some examples of data that may be monitored remotely 
include: informed consent forms, enrollment, eligibility, implant, study termination, 
and adverse events reported in the EDC system. Sites are required to support 
centralized monitoring by providing signed, dated, final source documents to 
BIOTRONIK in order to source data verify data reported in the EDC system and 
resolving queries in a timely manner.  
The E6(R2) Good Clinical Practice: Integrated Addendum to International Council 
for Harmonisation (ICH) E6 (R1) Guidance for Industry dated March 2018 outlines 
the ALCOA-C guidelines for source documentation. All source documentation and 
study records should meet these ALCOA-C guidelines of attributable, legible, 
contemporaneous, original, accurate and complete. This guidance ensures the 
confidentiality, credibility, accuracy and validation of research records. All pages of 
source documents should be labelled with the subject ID.  It is critical that the fully 
executed and unredacted informed consent form and all necessary source 
documentation are uploaded to the EDC in a timely manner. 
Through centralized monitoring or monitoring visits, BIOTRONIK will assess the 
site’s performance in the following areas: 
• 
Verification that informed consent was obtained and documented properly 
• 
Adherence to protocol eligibility criteria and requirements 
• 
Conduct and documentation of procedures and assessments related to: 

 
       
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o Study objectives 
o Protocol required data collection and procedures 
o Evaluating, 
documenting, 
and 
reporting 
adverse events, and 
withdrawals, especially when a withdrawal may be related to an 
adverse event  
• 
Investigator oversight and delegation of authority to site personnel 
• 
Verification of study-specific required documentation 
• 
Conduct and documentation of procedures essential to trial integrity 
• 
Adherence to applicable requirements regarding the obligations of the 
investigator and maintenance of records. 
Entries in eCRFs will be reviewed and source data verified by monitors (authorized 
BIOTRONIK personnel, or by authorized BIOTRONIK designees) to ensure that the 
investigator and the study team conducts the study in accordance with the protocol 
and applicable FDA and local laws and regulations to ensure adequate protection of 
the rights, safety and well-being of subjects and the quality and integrity of the 
resulting data.  
If a monitor becomes aware that an investigator is not complying with the signed 
Investigator Agreement, the study protocol, applicable laws, and FDA and/or local 
regulations and any conditions of approval imposed by the reviewing IRB, the 
monitor is obliged to notify BIOTRONIK study management. BIOTRONIK will 
evaluate the noncompliance and issue corrective actions, as necessary, which may 
include but are not limited to, re-training, discontinuing enrollment at the study 
site, or closing the study site. 
  Monitors 
11.2
Monitors are trained, qualified, and designated by BIOTRONIK management to 
oversee the progress of an investigation at the clinical site.  Additional monitors 
may be appointed as necessary. 

 
       
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12  Study Completion or Early Termination 
BIOTRONIK will notify the study site upon completion or termination of the clinical 
study or of the investigator’s participation.  At BIOTRONIK’s request, an 
investigator will return any pertinent materials in their possession.  Whenever 
possible, BIOTRONIK will provide a final report and a copy of the site’s eCRFs to 
each study site as required by FDA regulations.  BIOTRONIK will determine which 
sites will have an on-site close out visit and provide details on closure activities to 
all investigators to ensure the investigator understands any applicable regulatory 
requirements, including those related to record retention. All participating 
investigators are required to promptly notify BIOTRONIK if their financial disclosure 
information has any relevant changes during the course of the study or for 1 year 
following completion of the study, in accordance with 21CFR54.4.  

 
       
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13 Records and Reports 
Investigator Records
13.1
Investigators are required to maintain on file the following accurate, complete and 
current records relating to this investigation: 
• 
All correspondence relating to the study with another investigator, an IRB, 
BIOTRONIK, a monitor, or any other regulatory agency (e.g., a letter sent from 
the investigator to the IRB). 
• 
A copy of the clinical study protocol. 
• 
Signed investigator or research agreement. 
• 
Signed Financial Disclosure Form. 
• 
A copy of the IRB approval for the research study. 
• 
A copy of the IRB approved subject Informed Consent Form. 
• 
All documentation, including: 
− 
A copy of all signed Informed Consent Forms. 
− 
All supporting documentation for data entered into the EDC system. 
− 
Records of any adverse events, including supporting documentation. 
− 
Records pertaining to subject deaths during the study. 
− 
Documentation and rationale for any deviations from the clinical protocol. 
− 
Documentation of training. 
− 
Any other records required by BIOTRONIK. 
The investigator must retain records related to the study for a minimum period of 2 
years after the investigation is completed consistent with FDA regulations, IRB 
requirements, and institutional policies. Please ensure that BIOTRONIK is notified of 
any transfer of records, including changes to your site’s address or Principal 
Investigator status during the required 2-year period.  
 Investigator Reporting Responsibilities 
13.2
Investigators are required to prepare and submit to BIOTRONIK the following 
complete, accurate, and timely reports on this investigation as identified in the 
table below which outlines the responsibilities, including time constraints, for 
submitting required reports.  Additionally, investigators are required to provide any 
other information upon the request of an IRB, regulatory authority, or BIOTRONIK. 
 

 
       
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Table 8: Investigator Reporting Responsibilities 
Type of Report 
Prepared by 
Investigator for: 
Time Constraints of Notification 
Subject death during 
investigation 
BIOTRONIK, IRB 
BIOTRONIK as soon as possible 
and as required by reviewing IRB 
Withdrawal of IRB 
approval 
BIOTRONIK
Within 5 working days of receipt of 
notice of withdrawal of approval 
Progress Report(s)  
BIOTRONIK, the 
monitor, IRB 
Submitted no less than yearly 
Significant deviations 
from study plan  
BIOTRONIK, IRB 
Within 5 working days after 
emergency to protect life or 
physical well-being of subject, 
otherwise prior approval by 
BIOTRONIK is required 
Final report 
BIOTRONIK, IRB 
Within 3 months after termination
or completion of the study or 
investigator’s part of the study 
 Sponsor Records 
13.3
BIOTRONIK will maintain the following records: 
• 
All correspondence with the investigator(s), IRB, and FDA that pertains to the 
study  
• 
Investigator agreements, financial disclosures, and curriculum vitae 
• 
Name and address of each investigator and each IRB that is involved with the 
investigation 
• 
Adverse events  
• 
Adverse device effects  
• 
Complaints  
• 
Electronic Case Report Form data 
• 
Confirmation of completed subject informed consent forms 
• 
Clinical study protocol Screening visit reports 
• 
Monitoring visit reports 
• 
Clinical progress reports 
 
 

 
       
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  Sponsor Reporting Responsibilities 
13.4
BIOTRONIK is responsible for preparing the following reports, when necessary:
Table 9: Sponsor Reporting Requirements 
Type of Report 
Prepared by 
BIOTRONIK for 
Time Constraints of 
Notification 
Withdrawal of IRB 
approval 
FDA, all reviewing IRBs 
and participating 
investigators 
Within 5 working days after 
receipt of notice of withdrawal 
of approval 
Withdrawal of FDA 
approval  
Reviewing IRBs and 
participating 
investigators 
Within 5 working days after 
receipt of notice of withdrawal 
of approval 
Progress report 
FDA, all reviewing IRBs 
Submitted every 6 months 
during the first 2 years of the 
study and annually thereafter 
Final report
FDA, all reviewing IRBs 
and participating 
investigators 
A final report will be submitted 
within 6 months after 
completion or termination of the 
study. 
Study closure 
FDA, all reviewing 
IRBs, and participating 
investigators 
Within 30 working days of 
completion or decision to 
terminate the study. 

 
       
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14 Publication Policy 
BIOTRONIK intends to publish the results of this clinical study.  BIOTRONIK 
reserves the right to include the report of this clinical study 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 study Principal Investigator reserve the right for the first 
publication of the clinical study 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.  
The institution and the investigator have the right to publish the results of data 
obtained solely at their investigational site for the study.  Before publishing, 
however, the institution and 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.  
BIOTRONIK 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, BIOTRONIK may extend such review period to file 
patent applications or take other steps to protect its intellectual property interests 
or to remove from the paper or presentation any language that may impact 
BIOTRONIK’s intellectual property interests. 

 
       
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15 Prior Orsiro Clinical Trials 
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 year11 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.  The purpose of this trial was to compare the Orsiro 
sirolimus-eluting stent with the Xience Prime everolimus-eluting stent 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.  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.  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).12 
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).12 
Long-term 5 year clinical event rates were low and showed no significant 
differences between the two arms.  The TLF rate was 10.4% in the Orsiro group 
compared to 12.7% in the Xience Prime group at 60 months (p=0.4728).  No 
definite or probable stent thrombosis occurred in the Orsiro arm through 5 years.13   
 

 
       
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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.14  The purpose of 
the registry was to evaluate safety and performance of the Orsiro sirolimus-eluting 
stent 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 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%. 
BIOFLOW-III did not include mandatory angiographic follow-up and the rate of 12-
month TLR was 3.0%.  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. 
At 5 years, the TLF rate was 9.3% overall with definite or probably stent thrombosis 
rate of 0.7%.  Among subgroups, the TLF rate for diabetic subjects was  13.0% and 
for subjects that had presented with acute MI was 10.6%.15 
BIOFLOW-IV 
BIOFLOW-IV is a prospective, international, multicenter, randomized controlled trial 
designed to assess the safety and effectiveness of the Orsiro stent in the treatment 
of subjects with up to two de novo coronary artery lesions.  A total of 579 subjects 
were enrolled at 46 sites in Japan and Europe. 138 subjects were enrolled in Japan 
and 441 subjects were enrolled at sites in Europe. The BIOFLOW-IV clinical trial 
consists of a randomized control trial and a pharmacokinetic sub-trial.  The 
BIOFLOW-IV randomized controlled trial (RCT) enrolled 579 subjects with up to two 
de novo lesions ≤ 26 mm in length in native coronary arteries 2.5–3.75 mm in 
diameter.  Subjects were randomized in a 2:1 fashion to receive the Orsiro stent or 
the 
Xience 
Prime/Xpedition 
stent. 
 
The 
concurrent, 
non-randomized 
pharmacokinetic (PK) sub-trial at sites in Japan, enrolled 21 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 was 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 from September 2013 to January 25, 2015.  The primary 
endpoint results of TVF at 12 months were 5.1% (19/374) for Orsiro and 6.6% 
(12/183) for Xience. The noninferiority hypothesis was confirmed with p=0.0003 in 

 
       
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the ITT population (absolute difference -1.48%, 95% CI of -5.70 to 2.74). There 
were no significant differences in the TVF sub-components of clinically- driven TVR, 
TV-MI, or cardiac death.  The BIOFLOW-IV study supported the safety and efficacy 
of the Orsiro drug eluting stent as noninferior to the Xience drug eluting stent in 
treatment of subjects with coronary artery disease.  
Clinical event rates at 3 years showed no significant differences between the two 
arms.  The TVF rate was 10.4% in the Orsiro group compared to 9.7% in the Xience 
group at 36 months (p=0.8382).  Definite or probable stent thrombosis rates were 
0.8% in the Orsiro group compared to 0% in the Xience group at 36 months 
(p=0.5544). There were no late stent thrombosis events in either group.16 
BIOFLOW-V 
BIOTRONIK completed the BIOFLOW-V study as the pivotal US IDE trial for the 
Orsiro stent system. 
BIOFLOW-V is a prospective, multicenter, randomized, controlled trial designed to 
assess the safety and efficacy of the Orsiro Sirolimus Eluting Coronary Stent 
System compared with the Xience Everolimus Eluting Coronary Stent System in 
subjects with up to three native de novo or restenotic (after standard PTCA only) 
coronary artery lesions.2 A total of 1,334 subjects were) randomized at 90 clinical 
sites in 13 countries in North America, Europe, Israel and the Asia-Pacific regions 
between May 8, 2015 and March 31, 2016. 
The primary endpoint was TLF at 1 year, defined as the composite of cardiac death, 
target vessel MI or clinically-driven TLR. For the analysis of the primary endpoint, 
the trial combined data on the randomized subjects with data from two prior 
studies (BIOFLOW-II and BIOFLOW-IV) by employing a Bayesian approach.  
The 1-year TLF rate in the BIOFLOW-V study3 was 6.2% for Orsiro and 9.6% for 
Xience utilizing the protocol-definition for peri-procedural MI and 2.6% for Orsiro 
and 4.5% for Xience utilizing the Society for Cardiovascular Angiography and 
Interventions (SCAI) definition4 for peri-procedural MI.  
In analyses of additional clinical endpoints, including MI, target vessel MI and the 
composite of cardiac-death or MI, significantly lower rates in the Orsiro group 
compared to the Xience group were observed (p=0.0129 for MI at 12 months, 
p=0.0155 for target-vessel MI at 12 months and p=0.0072 for cardiac death or MI 
at 12 months). The rates of death, cardiac death. clinically-driven TLR and stent 
thrombosis were comparable in the Orsiro and Xience groups.  
The trial demonstrated the non-inferiority of Orsiro versus Xience with regards to 1-
year TLF. These results support the safety and efficacy of the Orsiro stent compared 
to the Xience stent in a complex subject population undergoing percutaneous 
coronary intervention. 
At 2 years, the significant differences observed at 1 year favoring Orsiro regarding 
composite endpoints of TLF, TVF, and MACE were maintained. The TLF rate was 
7.5% in the Orsiro group compared to 11.9% in the Xience group at 24 months 
(p=0.015). The difference in TLF was driven principally by a significant difference in 
target vessel- MI (5.3% Orsiro vs. 9.5% Xience, p=0.01) in addition to significantly 

 
       
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lower clinically-driven TLR (2.6% Orsiro vs. 4.9% Xience, p=0.04). In a landmark 
analysis  between 1 and 2 years, a significant difference in clinically-driven TLR 
emerged (0.7% Orsiro vs. 2.6% Xience, p=0.01). Definite and definite/probable 
stent thrombosis were numerically, but not statistically, lower with Orsiro (0.5% 
Orsiro vs. 1.2% Xience, p=0.17). However, combined late and very late rates of 
both definite and definite/probable stent thrombosis were significantly lower in the 
Orsiro cohort (0.1% Orsiro vs. 1.0% Xience, p=0.045 for both comparisons).17 
BIOSCIENCE 
The BIOSCIENCE study is a prospective, multicenter, randomized controlled trial 
that enrolled 2,119 subjects at 13 clinical sites in Switzerland.  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.18 
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.  
At 2 years the TLF rate for the Orsiro stent was 10.5% vs. 10.4% for the Xience 
stent (risk ratio [RR] 1.00, 95% CI 0.77–1.31, P=0.979).   There was no significant 
difference in rates of cardiac death, target-vessel MI, TLR, and definite stent 
thrombosis. In the pre-specified subgroup of patients with ST-segment elevation 
myocardial infarction, Orsiro was associated with a lower risk of target-lesion failure 
compared with Xience (RR 0.48, 95% CI 0.23–0.99, P=0.043, Pinteraction=0.026).19 
At 5 years the TLF rate was not significantly different between the groups (20.2% 
Orsiro vs. 18.8% Xience; risk ratio [RR] 1.07, 95% CI 0.88–1.31, p=0.487).  All-
cause mortality was significantly higher in patients treated with Orsiro than in those 
treated with Xience (14.1% vs. 10.3%; RR 1.36, 95% CI 1.06-1.75; p=0.017), 
driven by a difference in non-cardiovascular deaths.  There was no difference in 
cumulative incidence of definite stent thrombosis at 5 years (1.6% in both 
groups).20 
BIO-RESORT 
The BIO-RESORT study is a large-scale, investigator-initiated, multicenter, assessor 
and patient blinded, three-arm, randomized, non-inferiority trial conducted at four 
clinical sites in the Netherlands. The purpose of the study was to examine three 
drug eluting stents, each with a different drug coating (everolimus, sirolimus, and 
zotarolimus), with interest in performance of the stents and potential differences in 

 
       
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biodegradable vs durable polymers. The primary endpoint (TVF) was a composite of 
safety (cardiac death or target vessel-related MI) and efficacy (TVR) at 12 months 
of follow up, with analysis by intention to treat (non-inferiority margin 3.5%). 
Enrollment began on 21 December 2012, concluded on 24 August 2015, with 
results reported by von Birgelen et al. in The Lancet in October, 2016.21 
The all-comers trial enrolled 3514 patients, of which 2449 (70%) had acute 
coronary syndrome, including 1073 (31%) presenting with ST-elevated myocardial 
infarction. Subjects were randomized with 1172 receiving everolimus-eluting stents, 
1169 receiving sirolimus-eluting stents, and 1173 receiving zotarolimus-eluting 
stents. A total of 3490 patients (99%) completed 12-month follow-up. The primary 
endpoint of TVF was met by 55 (5%) of patients with everolimus-eluting stents, 55 
(5%) of the 1169 patients with sirolimus-eluting stents, and 63 (5%) of the 1173 
patients with zotarolimus-eluting stents. There were no significant differences in 
any outcome measures, including stent thrombosis, among the treatment arms. 
At 2 years, the TVF rate for Orsiro was 6.6% vs. 6.8% for Synergy and 8.3% for 
Resolute Integrity.  There were no statistical differences in the components of 
TVF.22 At 3 years, the TVF rate for Orsiro was 8.5% vs. 8.8% for Synergy and 
10.0% for Resolute Integrity.  There were no statistical differences in the 
components of TVF.23   
 

 
       
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16 Abbreviations and Acronyms 
Abbreviation / 
Acronym 
Complete Term 
ADE 
adverse device effect 
AE 
adverse event 
AMI 
acute myocardial infarction 
ARC 
Academic Research Consortium 
CABG 
coronary artery bypass graft 
CAD 
coronary artery disease 
CCSC 
Canadian Cardiovascular Society Classification 
CEC 
clinical events committee 
CK 
creatine kinase 
CKMB 
creatine kinase myoglobin band 
cm 
centimeter 
Co-Cr 
cobalt-chromium 
DAPT 
dual antiplatelet therapy 
DES 
drug-eluting stent 
dl 
deciliter 
ECG 
electrocardiogram 
eCRF
electronic Case Report Form
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
h 
hour 
ICF 
Informed Consent Form 
IDE 
investigational device exemption 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IVUS 
intravascular ultrasound 

 
       
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Abbreviation / 
Acronym 
Complete Term 
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 
OCT 
optical coherence tomography 
PCI 
percutaneous coronary 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 
SES 
sirolimus-eluting stent 
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 

 
       
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Abbreviation / 
Acronym 
Complete Term 
TVR
target vessel revascularization
ULN
upper limit of normal
URL 
upper range limit 

 
       
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17 Glossary 
ANTICOAGULATION THERAPY
Anticoagulation therapy is the use of agents which thin the blood by binding or 
reducing production of clotting factors, or antithrombin III, i.e. warfarin, heparin, 
heparin derivatives, dabigatran, rivaroxaban, apixaban, and edoxaban. 
BRAUNWALD CLASSIFICATION OF UNSTABLE ANGINA24 
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 
precipitated 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. 
CANADIAN 
CARDIOVASCULAR 
SOCIETY CLASSIFICATION 
(CCSC) 
OF 
ANGINA25,26 
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. 

 
       
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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. 
CARDIAC DEATH 
See Deaths 
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 quantitative coronary angiography (QCA), or revascularization of a target 
lesion with diameter stenosis ≥70% by QCA without either angina or a positive 
functional study. 
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. 
CORONARY ARTERY 
Coronary artery includes entire territory of left anterior descending artery, left 
circumflex artery or right coronary artery and any major side branch of the specific 
artery; the ramus artery will be considered a branch of the left circumflex artery. 
DAPT 
Dual antiplatelet therapy (DAPT) refers to treatment of patients being treated with 
two types of antiplatelet medications to prevent clotting.  These medications include 
aspirin plus a P2Y12 inhibitor (clopidogrel, prasugrel, ticagrelor, or ticlopidine).  
DE NOVO LESION 
A native coronary artery lesion not previously treated. 
DEATHS 
All deaths reported during study will be 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. 

 
       
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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. 
ENROLLED SUBJECT  
Subject who meets all clinical and angiographic eligibility criteria and has provided 
informed consent by properly signing an informed consent form.  
Enrolled subjects will be followed in accordance with the protocol requirements. 
EVALUABLE SUBJECT 
Enrolled subject who meets all inclusion/exclusion criteria.  Subject is part of the 
Intent-to-Treat analysis population. 
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. 
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.  

 
       
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MYOCARDIAL INFARCTION – PROTOCOL DEFINITION 
Different criteria for spontaneous and peri-procedural MI will be utilized for the primary 
adjudication for endpoints for MI.   
Peri-procedural < 48 hours post PCI 
Society for Cardiovascular Angiography and Interventions (SCAI) definition4 
1.  In patients with normal baseline CKMB  
• 
The peak CKMB measured within 48 hours of the procedure rises to ≥10 x the local laboratory 
ULN, or to ≥5 x ULN with new pathologic Q-waves in ≥2 contiguous leads or new persistent 
LBBB,  
• 
OR in the absence of CKMB measurements and a normal baseline cTn, a cTn (I or T) level 
measured within 48 hours of the PCI rises to ≥70 x the local laboratory ULN, or ≥35 x ULN 
with new pathologic Q-waves in ≥2 contiguous leads or new persistent LBBB. 
2.  In patients with elevated baseline CKMB (or cTn) in whom the biomarker levels are 
stable or falling 
• 
The CKMB (or cTn) rises by an absolute increment equal to those levels recommended above 
from the most recent pre-procedure level. 
3.  In patients with elevated CKMB (or cTn) in whom the biomarker levels have not been 
shown to be stable or falling
• 
The CKMB (or cTn) rises by an absolute increment equal to those levels recommended above 
plus new ST-segment elevation or depression plus signs consistent with a clinically relevant 
MI, such as new onset or worsening heart failure or sustained hypotension. 
Spontaneous MI > 48 hours(PCI)  
Vranckx P et al5
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. 
PERCENT DIAMETER STENOSIS 

 
       
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The value calculated as 100 x (RVD – MLD)/RVD using the mean values from two 
orthogonal views (when possible) by quantitative coronary angiography or visual 
estimate.  (RVD: reference vessel diameter; MLD: minimal lumen diameter.) 
PERCUTANEOUS CORONARY INTERVENTION (PCI) 
All interventional cardiology methods for treatment of coronary artery disease. 
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. 
STENT THROMBOSIS – ACADEMIC RESEARCH CONSORTIUM-2 (ARC-2) 
DEFINITION1 
Classification 
Criteria 
Definite stent 
thrombosis 
Angiographic confirmation of stent thrombosis* 
The presence of a thrombus† that originates in the stent or in the segment 5 
mm proximal or distal to the stent or in a side branch originating from the 
stented segment and the presence of at least 1 of the following criteria: 
Acute onset of ischemic symptoms at rest 
New electrocardiographic changes suggestive of acute ischemia 
Typical rise and fall in cardiac biomarkers (refer to definition of 
spontaneous myocardial infarction) 
Or 
Pathological confirmation of stent thrombosis 
Evidence of recent thrombus within the stent determined at autopsy 
Examination of tissue retrieved following thrombectomy (visual/histology) 
Probable stent 
thrombosis 
Regardless of the time after the index procedure, any myocardial infarction that is 
related to documented acute ischemia in the territory of the implanted 
stent/scaffold without angiographic confirmation of stent/ scaffold thrombosis and 
in the absence of any other obvious cause.‡ 
Silent stent 
occlusion 
The incidental angiographic documentation of stent occlusion in the absence of 
clinical signs or symptoms is not considered stent thrombosis. 
Timing of ST (duration after stent implantation) 
Acute 
0§–24 h
Subacute 
>24 h–30 d 
Late 
>30 d–1 y 
Very Late 
>1 y 
Early stent thrombosis is 0 to 30 days (acute plus subacute stent thrombosis). 

 
       
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*Definite stent thrombosis is considered to have occurred by either angiographic or pathological 
confirmation. 
†Occlusive thrombus: Thrombolysis in Myocardial Infarction grade 0 or 1 flow within or proximal to a 
stent/scaffold segment. Nonocclusive thrombus: intracoronary thrombus is defined as a (spherical, 
ovoid, or irregular) noncalcified filling defect or lucency surrounded by contrast material (on 3 sides or 
within a coronary stenosis) seen in multiple projections, persistence of contrast material within the 
lumen, or visible embolization of intraluminal material downstream. 
‡When the stented segment is in the left circumflex coronary artery or in the presence of preexisting 
electrocardiographic abnormalities (e.g., left bundle branch block, paced rhythms), definitive evidence 
of localization may be absent and Clinical Events Committee adjudication is based on review of all 
available evidence). 
§Defined as the moment the patient is undraped and taken off the catheterization table. 
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) 
Repeat percutaneous intervention of the target lesion or bypass surgery of the 
target vessel performed for restenosis or other complication of target the lesion. 
The target lesion is defined as the treated segment including the 5 mm margin 
proximal and 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)  
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. 

 
       
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THROMBOLYSIS IN MYOCARDIAL INFARCTION (TIMI) CLASSIFICATION27 
System developed during Thrombolysis in Myocardial Infarction (TIMI) trials for 
grading severity of stenosis and extent of blood flow through coronary arteries. 
TIMI 0: No perfusion. 
TIMI 1: Penetration with minimal perfusion.  Contrast fails to opacify entire bed 
distal to stenosis for duration of cine run. 
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). 
 

 
       
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18 Study Milestones / Timeline 
The timeline of the BIOFLOW-VII study is dependent on the date of FDA approval of 
the study protocol, the ability to recruit a sufficient number of interested sites, and 
the ability to enroll subjects.  
Progress reports will be submitted every 6 months during the first 2 years of the 
study and annually thereafter, unless otherwise specified by FDA. 
Milestone 
Window 
Estimated Date 
FDA Approval of Orsiro (P170030) 
--- 
February 22, 2019 
FDA approval of PAS protocol 
Approval 
November 2019 
First IRB approval and first site 
opened to enrollment  
Approval + 3 months 
February 2020 
First subject enrolled 
Approval + 3 months 
February 2020 
Enrollment of 10 subjects 
Approval + 5 months 
April 2020 
Enrollment of 100 subjects 
Approval + 9 months 
August 2020 
All sites opened 
Approval + 18 months 
May 2021 
Enrollment completion 
Approval + 18 months 
May 2021 
Final 12-month follow-up visit 
(Primary Endpoint) 
Enrollment Completion + 
12 months + Visit 
Window 
(Approval + 31 months) 
June 2022 
Final 5-year follow-up visit 
(Study Completion) 
Enrollment Completion + 
60 months + Visit 
Window 
(Approval + 81 months) 
July 2026 
Final report submitted to FDA 
Study Completion +  
6 months  
(Approval + 87 months)
January 2027 

 
       
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19 References 
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9  Medinol LTD. Summary of Safety and Effectiveness Information (SSED). EluNIR™ 
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12 Windecker S, Haude M, Neumann FJ et al. Comparison of a Novel Biodegradable 
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19 Zbinden R, Piccolo R, Heg D, et al. Ultrathin Strut Biodegradable Polymer 
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