BIOTRONIK-Safety and Clinical PerFormance of the Drug ELuting Orsiro Stent in the Treatment of Subjects With de Novo Coronary Artery Lesions-VI
Phase: NA
Conditions: Coronary Artery Disease
Sponsor: Biotronik (Beijing) Medical Device Ltd.

BIOFLOW-VI 
BIOTRONIK-Safety and Clinical PerFormance of the 
Drug ELuting Orsiro Stent in the Treatment of 
Subjects With de novo Coronary Artery Lesions – VI 
BIOTRONIK Orsiro Pre-Marketing Registration 
CLINICAL INVESTIGATION PLAN 
Version: V3.0 
CIP V 3.0, 15 Dec. 2015 
BIOTRONIK AG CONFIDENTIAL 
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REPRODUCTION, DISCLOSURE OR UNAUTHORIZED USE OF ANY PART OF THIS DOCUMENT IS STRICTLY 
PROHIBITED. 

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Clinical Investigational Plan 
 
 
 
 
 
 
 
 
Product Name: Sirolimus Eluting Coronary Artery Stent System 
Clinical Investigation Type: Medical Device Clinical Verification 
Implementer: BIOTRONIK (Beijing) Medical Device Limited 
 
Leading Organization Undertaking the Clinical Investigation: National 
Center For Cardiovascular Disease of Fuwai Hospital, CAMS & PUMC 
Principal of the Clinical Investigation: Yang Yuejin 
Unit of Statistic Analysis: Biostatistics Department of Cardiovascular 
Disease Prevention and Control Research Center, Ministry of Health 
Statistician: Li Wei 
Coronary Arteriography Core Lab: Medstar Research Health Angiographic 
Core Laboratory 
Date: Dec 15, 2015 

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National Clinical Study Manager 
 
Jing Wang                                                      ________________             ____________________ 
                                                                                 Date                                 Signature 
Biotronik (Beijing) Medical Device Limited 
1122 Interchina Commercial Building, 
33 DengShiKou Street, Dongcheng District 
100006 Bejing  
P.R. China 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .......................................................................................................................... 4 
2.1 
Sirolimus and DES ..................................................................................................................... 12 
2.2 
Investigational Device ................................................................................................................ 14 
2.2.2 
Carrier and Coating ............................................................................................................... 14 
2.3 
Control Device ............................................................................................................................ 14 
3 
INVESTIGATIONAL DEVICE DESCRIPTION ........................................................................... 16 
4 
INVESTIGATIONAL PLAN ........................................................................................................... 16 
4.2 
Study Design .............................................................................................................................. 17 
4.3 
Endpoints..................................................................................................................................... 17 
4.3.2 
Secondary Endpoints ............................................................................................................ 17 
4.4 
Inclusion Criteria ......................................................................................................................... 18 
4.5 
Exclusion Criteria ....................................................................................................................... 18 
5 
ENROLMENT AND PROCEDURES ........................................................................................... 19 
5.1 
Informed Consent ...................................................................................................................... 21 
5.2 
Enrolment .................................................................................................................................... 21 
5.3 
Baseline Examinations .............................................................................................................. 21 
5.4 
Medication ................................................................................................................................... 22 
5.5 
Interventional Procedure ........................................................................................................... 23 
5.6 
Process before Discharge ......................................................................................................... 25 
5.7 
Follow Up Visits .......................................................................................................................... 25 
5.8 
Unscheduled Coronary Angiogram Follow Up ....................................................................... 28 
5.9 
Treatment Failures ..................................................................................................................... 28 
5.10 
Additional Stent Treatment ....................................................................................................... 28 
5.11 
Bailout-Staged Procedure ......................................................................................................... 28 
6 
CLINICAL INVESTIGANTION PLAN DEVIATIONS ................................................................. 28 
7 
Study Participation Status ............................................................................................................. 29 
7.1 
Status Definitions ....................................................................................................................... 29 
7.2 
Subject Study Exit ...................................................................................................................... 29 
7.2.1 Subject Lost to Follow-up ............................................................................................................ 30 

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8 
DATA REPORTING AND STATISTICAL ANALYSIS ............................................................... 30 
8.2 
Statistical Analysis ..................................................................................................................... 31 
8.2.2 The statistical analysis method .................................................................................................. 32 
9 
DATA COLLECTION, MONITORING, INSPECTIONS AND AUDITS ................................... 32 
9.2 
Monitoring .................................................................................................................................... 32 
9.3 
Audits ........................................................................................................................................... 33 
9.4 
Source documentation .............................................................................................................. 33 
9.5 
Data Management ..................................................................................................................... 33 
9.6 
Record Retention ....................................................................................................................... 34 
10 
APPROVALS of Investigation .................................................................................................. 34 
10.2 
Competent Authority Approval ................................................................................................. 34 
10.3 
Investigator Responsibilities ..................................................................................................... 34 
10.4 
Investigational Device Accountability ...................................................................................... 35 
10.4.2 
Change of Device .................................................................................................................. 35 
10.5 
Non-CIP Research ..................................................................................................................... 35 
10.6 
Amendments to the CIP ............................................................................................................ 35 
10.7 
Subject Insurance ...................................................................................................................... 35 
11 
SAFETY ....................................................................................................................................... 35 
11.1 
Reporting to Sponsor (BIOTRONIK) ....................................................................................... 35 
11.2 
Adverse Events .......................................................................................................................... 36 
11.2.1 
List of Anticipated Adverse Events ...................................................................................... 36 
11.3 
Serious Adverse Events ............................................................................................................ 37 
11.4 
Adverse Device Effects (ADE) & Serious Adverse Device Effects (SADE) ....................... 37 
11.5 
Unanticipated Serious Adverse Device Effects (USADEs) .................................................. 38 
11.5.1 
CEC .......................................................................................................................................... 38 
12 
RISK ANALYSIS ........................................................................................................................ 38 
12.2 
Benefits ........................................................................................................................................ 38 
13 
STUDY TERMINATION ............................................................................................................ 38 
14 
FEASIBILITY ANALYSIS .......................................................................................................... 39 
15 
FINAL REPORT ......................................................................................................................... 39 
16 
PRINCIPLE OF CONFIDENTIALITY ...................................................................................... 39 
17 
PUBLICATION POLICY ............................................................................................................ 39 

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18 COMPLIANCE STATMENT ................................................................................................................. 39 
19 REFERENCES ................................................................................................................................. 40 
 
 
 
 

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1 
SYNOPSIS 
 
Study Title 
BIOTRONIK Orsiro Pre-Marketing Registration Clinical 
Investigation 
 
Study Objective 
To evaluate the effectiveness and safety of the BIOTRONIK 
Orsiro Sirolimus Eluting Stent (SES) with respect to in-stent Late Lumen 
Loss (LLL) in a non-inferiority study on de novo coronary lesions at 9 
months. 
Study Design 
The clinical investigation is a non-inferiority, multicenter, blinding 
evaluation, randomized, p a r a l l e l  controlled clinical study enrolling up 
to 440 subjects. All subjects will be randomized 1:1 to receive the 
BIOTRONIK Orsiro SES or the Abbott Xience Prime™ EES, in order to 
evaluate the efficacy and safety of the SES drug eluting stent in the 
treatment of coronary artery disease. Clinical follow up visits will take 
place at 1, 6, 12, 24, 36, 48 and 60 months post procedure. At 9 months 
(+ 30 days) all subjects will undergo a standard quantitative coronary 
angiography (QCA) follow up to assess the in-stent LLL as the main 
efficacious evaluation. Use the major adverse cardiac event (all-cause 
death, Q-wave, non-Q wave MI and clinically driven TLR) within one year 
post procedure as the main safety indicator to evaluate the investigational 
product’s safety. The clinical and angiographic data sorting, calculation 
and statistical analysis will be conducted by an independent data 
management center and angiographic core laboratory. 
 
Study Sites 
Up to 15 
sites 
 
Less than 15 sites 
 
Study Population 
Subjects with coronary artery disease due to de novo stenotic 
lesions in native coronary arteries, with a reference vessel diameter ≥ 
2.25 mm and ≤ 4.0 mm and a lesion lengths ≤ 36 mm. 
 
Study Device 
Investigational devices: BIOTRONIK Orsiro SES 
 
Control devices: Abbott Xience Prime™ EES 

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Inclusion Criteria 
-Clinical 
 
1. 
Subject who can understand the investigation’s goal has provided 
written informed consent, and is willing to comply with the study’s follow-
up requirements. 
2. 
Subject is ≥ 18 years and ≤ 75 years old, male or female without 
pregnant. 
3. 
Subject is an acceptable candidate for PCI. 
4. Subject has clinical evidence of asymptomatic ischemia, stable or 
unstable angina pectoris or old myocardial infarction. 
5. 
Subject has no contraindication for dual anti-platelet therapy treatment. 
 
 
Inclusion Criteria 
-Angiographic 
 
1. 
Target lesion must be in the major coronary artery or a branch (target 
vessel). 
2. 
Target lesion must have angiographic evidence of ≥ 70% and < 100% 
stenosis (by operator’s visual estimate).  
3. 
Subject has up to two target lesions (two target lesions in one target 
vessel, or for each target vessel, it has one target lesion). 
 
4. 
Target lesion is suitable for drug-eluting stent PCI treatment. 
5. 
Target lesion must be ≤ 36 mm in length by operator’s visual estimate, 
and can be completely covered by one stent.  
6. 
Target vessel must have a reference vessel diameter of 2.25–4.0 mm 
by operator’s visual estimate. 
7. 
Target vessel must have a Thrombolysis In Myocardial Infarction (TIMI) 
flow ≥ 2. 
 
 
Exclusion Criteria 
-Clinical 
 
1. 
Subject is pregnant and/or breastfeeding or intends to become 
pregnant during the duration of the study. 
2. 
 Subject has clinical symptoms and/or ECG changes consistent with 
acute ST elevation MI (STEMI) within 7 days prior to the index 
procedure, including hemodynamically unstable non-STEMI (NSTEMI) 
subjects. 
3. 
Subject is hemodynamically unstable. 
4. 
Subject is an unacceptable candidate for CABG. 

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5. 
Subject has a known allergy to contrast medium that cannot be 
adequately pre-medicated, or any known allergy to thienopyridine, 
aspirin, both heparin and bivalirudin, L-605 cobalt-chromium (Co-Cr) 
alloy or one of its major elements (cobalt, chromium, tungsten and 
nickel), acrylic, fluoropolymers, silicon carbide, PLLA, sirolimus or 
everolimus. 
6. 
Previous revascularization of any target or non-target vessel 9 months 
prior to the index procedure. 
7. 
Planned surgery within 6 months of the index procedure. 
8. 
Planned staged treatment during the index procedure or within 30 
days after the index procedure. 
9. 
History of a stroke or transient ischemic attack (TIA) within 12 months 
prior to the index procedure. 
10. Subjects with active bleeding disorders, active coagulopathy, or any 
other reason, who are ineligible for DAPT. 
11. Subject will refuse blood transfusions. 
12. Subject has documented severe cardiac failure (over III level of NYHA) 
or left ventricular ejection fraction (LVEF) ≤ 40% as evaluated by 
echocardiogram, 
left 
ventricular 
angiography, 
radionuclide 
ventriculography or any non-invasive imaging method within 90 days 
prior to the index procedure. 
13. Subject is dialysis-dependent. 
14. Subject has impaired renal function (i.e., creatinine > 2.0 mg/dL or 175 
μmol/L determined) within 7 days prior to the index procedure. 
15. Subject has leukopenia (i.e. WBC < 3.5*10*9/L), thrombocytopenia 
(plt<100*10*9/L) or thrombocytosis (PLT>350*10*9/L). 
16. Subject is receiving chronic anticoagulation (e.g. coumadin, 
dabigatran, apixaban, rivaroxaban or any other agent). 
17. Subject is receiving oral or intravenous immunosuppressive therapy 
(inhaled steroids are excluded), or has known life-limiting 
immunosuppressive 
or 
autoimmune 
disease 
(e.g., 
human 
immunodeficiency virus, systemic lupus erythematosus; diabetes 
mellitus is excluded). 

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     18. Subject has a life expectancy of < 3 years. 
19. In the investigator’s opinion, subject will not be able to comply with the 
follow-up requirements. 
20. Subject is participating in another (medical device or drug) clinical 
study. Subjects may be concurrently enrolled in a post-market study, 
as long as the post-market study device, drug or protocol does not 
interfere with the investigational treatment or protocol of this study. 
 
Exclusion Criteria 
-Angiographic 
 
1. 
Target lesion is located within a saphenous vein graft or arterial graft. 
2. 
Target lesion has any of the following characteristics: 
a) 
Lesion location is within the left main coronary artery, or within 3 
mm of the origin of the left anterior descending (LAD) or left 
circumflex (LCX).  
b) 
Involves a side branch of > 2.5 mm in diameter. 
Note: Lesions within 3 mm of the origin of the right coronary artery 
may be treated. 
3. 
Target lesion is totally occluded (100% stenosis). 
4. 
Target vessel has angiographic evidence of thrombus. 
5. 
Target vessel/lesion is excessively tortuous/angulated or is severely 
calcified, preventing complete inflation of an angioplasty balloon. 
6. 
Target vessel was treated with brachytherapy at any time prior to the 
index procedure. 
Primary Endpoint 
 
In-stent LLL at 9 months post procedure by core laboratory QCA analysis 
Secondary Endpoints 
Treatment Success 
Indicators 
1. 
Device success, defined as attainment of ≤ 30% residual stenosis, 
TIMI=3, of the target lesion using the assigned study stent only. 
Note: Post-dilatation is allowed to achieve device success. 
2. 
Lesion success, defined as attainment of ≤ 30% residual stenosis, 
TIMI=3, of the target lesion using any percutaneous method. 
3. 
Procedure success, defined as attainment of ≤ 30% residual 
stenosis, TIMI=3, of the target lesion using the assigned study stent 
only, without occurrence of in-hospital major adverse cardiac events 
(MACE; composite of all-cause death, Q-wave or non–Q-wave MI, 
and any clinically-driven TLR). 

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Secondary Endpoints 
-Clinical 
The following endpoints were followed up at 1, 6, and 12 months post-
procedure, and once annually for up to 5 years. 
1. All-cause death  
2. Cardiac death 
3. Myocardial infarction 
4. MI of the target vessel 
5. Stent thrombosis 
6. All serious adverse device effects (SADEs) 
7. Target Lesion Revascularization, TLR 
8. Target Vessel Revascularization, TVR 
9. Target Lesion Failure (TLF), composite of cardiac death, target vessel 
Q-wave or non-Q wave Myocardial Infarction (MI), Coronary Artery 
Bypass Grafting (CABG), clinically driven TLR 
10. Target vessel failure (TVF), composite of cardiac death, target vessel Q-
wave or non-Q wave Myocardial Infarction (MI) and clinically driven TVR 
11. Major adverse cardiac event (all-cause death, Q-wave, non-Q wave MI 
and clinically driven TLR) 
 
  
Secondary Endpoints-
Angiographic 
 
In-stent and in-segment binary restenosis rate angiographically 
assessed (≥ 50% diameter stenosis) at 9 months post procedure, in-
segment Late Lumen Loss (LLL) at 9 months post-procedure, in-stent 
and in-segment percent diameter stenosis and minimum lumen 
diameter (MLD) at 9 months post-procedure. 
 
 
 
 
 
 
2 
INTRODUCTION 
 
Since the first Percutaneous Transluminal Coronary Angioplasty (PTCA) being successfully 
applied into human beings in 1977, this procedure has become a widely accepted treatment modality 

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for Coronary Artery Disease (CAD). However, all percutaneous techniques, regardless of the mode 
of intervention, have rather high rates of repeat interventions at t h e  long-term follow up, 
representing a limitation of the strategy. This limitation is attributable to the process of restenosis or 
angiographic re-narrowing of the vessel’s lumen following successful PTCA1. Being quite distinct from 
atherosclerotic lesions, restenosis following conventional angioplasty results from elastic recoil, vessel 
contraction, thrombus formation, smooth muscle cell proliferation and excessive production of extra 
cellular matrix. Depending on the subject population and angiographic diagnostic criteria, the 
reported incidence of restenosis after PTCA ranges from 30%-50%2. Such rates of recurrence have 
serious economic consequences. 
 
The first type of stent used in Percutaneous Coronary Intervention (PCI), were Bare Metal 
Stents (BMS), designed to address the limitations of PTCA1, 3, 4. BMS reduced the angiographic and 
clinical restenosis rates in de novo lesions compared to PTCA on its own and decreased the need for 
CABG. BMS substantially reduced the incidence of abrupt artery closure, but restenosis still occurred 
in about 20%-40% of cases5, 6, necessitating repeat procedures. The invention of Drug Eluting Stents 
(DES) significantly improved on the principle of BMS by adding an antiproliferative drug, which is 
either directly immobilized on the stent surface or released from a polymer matrix to inhibit neointimal 
hyperplasia. This allows for controlled release of the drug at the site of injury. The polymer drug 
carriers currently used on DES are either biodegradable or non-biodegradable. 
 
The introduction of DES greatly reduced the incidence of restenosis and resulted in a better 
safety profile as compared to BMS with systemic drug administration. These advantages, as well 
as a lower cost compared to surgical interventions, have made DES an attractive option for the 
treatment of coronary artery disease7. 
 
2.1 
Sirolimus and DES 
Sirolimus is a natural macrocyclic lactone, first isolated from Streptomyces 
Hygroscopicus in the mid-1970s. It was approved by the FDA for the prophylaxis of renal 
transplant rejection in 1999. Thus, sirolimus has potent antiproliferative, anti-inflammatory and 
immunosuppressive effects. It acts by inhibiting the activation of mammalian target or (mTOR), 
ultimately causing the  arrest of the cell cycle (progression from phase G1 to S). Thus sirolimus 
prevents cell proliferation that also includes T-cells and the proliferation and migration of smooth 
muscle cells, thereby, inhibiting the restenosis process8 
 
 
Reduction of neointimal hyperplasia with sirolimus DES compared with BMS have been shown 
in porcine models9. Re-endothelialization occurred at a similar degree in both DES and BMS groups. This 
has also been confirmed in human coronary arteries10, 11. Sirolimus DES have been shown to reduce 
neointimal thickening when compared to both bare metal and polymer coated stents in various animal 
models and clinical studies12-16. 
The very first DES to be approved for the market was the Cypher® SES. It received the CE mark 
in 2002 and FDA approval in 2003 and has since then been extensively studied in a number of 
clinical investigations. The efficacy of the Cypher® and the improved Cypher Select+® SES has 
been proven in populations ranging from highly selected subjects with single de novo lesions to 
unselected all-comers7,14,16-23. The Cypher® stent has shown significant improvements 
in 
angiographic outcomes, with reduced rates of restenosis and less need for revascularization 
compared to BMS 7, 23.

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Figure 1: Structural formula of Sirolimus 
 
 
 
Since the preliminary results from the first-in-
man feasibility    clinical    investigation    were 
presented, the Cypher® SES has now become 
available in more than 80 countries (Europe, 
Japan and US included) and has been used to 
treat +3 million subjects with CAD24. The Cypher® 
SES is one of the most studied DES today 
with 
a 
large 
body 
of 
clinical evidence 
demonstrating long-term safety and efficacy. 
 
For the indications that will be treated in 
the 
clinical 
investigation, 
single 
de novo 
coronary artery lesions, safety and efficacy have 
been demonstrated in the Cypher® First in Man 
feasibility 
clinical 
investigation16 
and 
four 
randomized controlled studies with the Cypher® 
stent, RAVEL20, SIRIUS14, E-SIRIUS25 and C-
SIRIUS21. Clinical data for up to 5 years after 
stent implantation are available for these 
studies11, 13, 26, 27. 
 
 

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2.2 
Investigational Device 
 
2.2.1 
Platform and Delivery System 
The Orsiro Sirolimus D E S , which received the CE mark in Feb 2011, is based off the design 
of the approved and successfully marketed PRO-Kinetic ENERGY™ stent system. The predecessor 
product, PRO-Kinetic™, has proven to be both safe and effective in the treatment of coronary lesions. 
 
The PRO-Kinetic ENERGY™ stent received the CFDA approval in Feb 2010. Its skeleton 
structure is made of a cobalt chromium alloy (Cobalt-Chromium L605), which is completely covered 
by a thin layer of amorphous silicon carbide (PROBIO®). This material has semiconducting properties 
that efficiently prevent the electron transfer from the fibrinogen to the metal surface in vitro. Thereby 
the conversion from fibrinogen to fibrin and it's deposition at the stent surface is reduced28. 
Additionally, t h e  aSiC:H-coated stent exhibits a lower adhesion and activation of blood platelets 
and leucocytes29. Finally, the release of potentially allergenic ions from a silicon carbide coated stent 
is substantially reduced in comparison to an uncoated metal stent. The PROBIO® coating is used on 
all BIOTRONIK coronary stents and has undergone extensive clinical testing30-34. 
 
The PTCA delivery system of Orsiro Sirolimus and PRO-Kinetic ENERGY are nearly identical, 
based on a fast-exchanging PTCA catheter. The stent is securely crimped on a Nylon 
balloon situated at the distal tip of the catheter between two radiopaque markers made of a 
Platinum-Iridium alloy. The proximal shaft of the delivery system is a hypotube made of 
polyamide-covered 304 or 304L stainless steel. It has a single luer port for connecting an 
inflation/deflation device to inflate/deflate the balloon. The distal section of the catheter 
comprises of the inflation/deflation (balloon) lumen and guide wire lumen which starts at the 
catheter tip and ends at the guide wire exit port. It accepts guide wires of 0.014" diameter. 
The stent delivery system is compatible with guiding catheters with a minimal inner diameter of 
≥ 0.056" (1.42 mm). Shaft exit markers are located on the hypotube 92 cm (brachial technique) 
and 102 cm (femoral technique) from the distal end of the catheter to indicate when the 
delivery system tip exits from the guiding catheter. 
2.2.2 
Carrier and Coating 
The polymer compound used as a carrier material for the supply and release of Sirolimus is a high 
molecular Poly-L-Lactidic Acid (PLLA). The stent body surface is completely coated by a matrix 
consisting of the carrier PLLA and the Sirolimus. The maximal thickness of the surface is 25 µm . The 
largest stent design has a maximal coating mass of 42.3 µg  per millimeter of stent length. PLLA 
is a highly biocompatible material. There is existing published experience with PLLA as a stent and 
stent coating material in humans32-34. 
 
2.3 
Control Device 
The Xience Prime™ Everolimus Eluting Stent (EES) is manufactured and marketed by Abbott 
Laboratories. Abbott received the CFDA approval and launched the Xience Prime™ EES in China in 
2014. The Xience Prime™ and Xience VTM adopt the same drug and coating technology. Xience VTM 
uses BMS MULTI-LINK®, while Xience PrimeTM adopts the BMS MULTI-LINK 8®, an updated version of 
the Xience V™ MULTI-LINK® Vision platform. Like Pro-Kinetic ENERGY™ the MULTI-LINK® family is 
made of a cobalt chromium alloy. Due to the technical similarity to Xience V™, the Xience Prime™ 
is expected to have a similar efficacy and safety profile. Thus, data known from the Xience V™ clinical 
program have been used for reference in the design of the current BIOFLOW-VI study. 
The SPIRIT FIRST study (N=60) was a multi-center, single blinded First In Man (FIM) study with 
the Xience V™ EES, conducted to assess the feasibility and efficacy in the treatment of subjects 
with de novo native coronary artery lesions, compared to the BMS MULTI-LINK VISION RX Coronary 
Stent System. This feasibility trial showed clinical safety and the angiographic in-stent LLL observed 
was 0.10±0.21 mm, a reduction of 88% relative to the bare metal stent at six months35, and a LLL of 
0.24±0.2 7 mm at 12 months36, which was a reduction of 71%. 

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The SPIRIT II, III, trials were a continuation of the assessment of the safety and 
performance of the Xience V™ EES. The in-stent LLL in the SPIRIT II and SPIRIT III clinical 
investigations were 0.11±0.27 mm37 and 0.16±0.4 1 mm38 respectively. Similar results were also 
shown in the Medtronic sponsored RESOLUTE III clinical investigation. The in stent late lumen loss in 
the Xience V™ group was 0.19±0.4 0 (N=182)39. 
 
2.4 Previous Evidence of the Investigational DES 
The Orsiro stent is investigational in China. However, the stent has received the CE Mark on 
February 23, 2011 and is currently approved for marketing in more than 55 countries worldwide with over 
200,000 units distributed as of March 2014. 
 
The development of the Orsiro stent system has been supported by an extensive clinical trial 
program designed to collect data on over 3,000 Orsiro-treated subjects in studies using the Xience 
Everolimus Eluting Stent System as a comparator. The Orsiro clinical trial program includes the BIOFLOW-
I First In Man study; the BIOFLOW-II international randomized study against the Xience Prime™ stent with 
intravascular ultrasound (IVUS) and optical coherence tomography (OCT) subsets, the BIOFLOW-III 
international all-comers registry, the BIOFLOW-IV international randomized study against the Xience 
Prime™/Xpedition™ stent with a pharmacokinetic subset, and the BIOSCIENCE international, randomized 
all-comers study against the Xience Prime™ stent.  Table 3-3 summarizes the key design elements of 
each Orsiro study. Currently, BIOFLOW I, BIOFLOW II, BIOFLOW III and BIOSCIENCE have been 
already completed.  
 
BIOFLOW-I was a 30-subject feasibility study conducted at two sites in Romania. The purpose of the 
trial was to evaluate the safety and efficacy of the Orsiro stent in the 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 primary endpoint of in-stent late lumen loss at 9 months was 0.05 ± 0.22 mm , the safety indicator 
included composite of cardiac death, target vessel MI and clinically-driven TLR was 6.7% (2/30)40 at 1 
year and 13.7% (4/30) at 2 years, and a composite rate of all-cause deaths, any MI and any 
revascularization of 16.7% (5/30) at 2 years. 
 
BIOFLOW-II was a prospective, multicenter, randomized (2:1）, controlled, non-inferiority trial that 
enrolled 458 patients. The purpose of this trial was to compare the efficacy and safety of Orsiro SES with 
the Xience Prime™ Everolimus Eluting Stent (EES) in subjects with single de novo coronary artery 
lesions in up to two coronary arteries. Follow-up angiography 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. At 12 months, there were no significant differences 
between the two arms in MACE.  
 
The BIOFLOW-III study was a prospective trial that enrolled a total of 1,356 subjects at 43 centers in 14 
countries. 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 primary endpoint is TLF rate at 12 months. The result was similar to 
BIOFLOW I and BIOFLOW II, with the rate of TLF at 5.1% at 12 months.  
 
The BIOSCIENCE study was 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. At 12 months, the TLF rate 
for the Orsiro stent (6.5%) was non-inferior to the Xience stent (6.6%). 
 
 

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3 
INVESTIGATIONAL DEVICE DESCRIPTION 
 
Investigational devices: BIOTRONIK Orsiro SES 
 
Control devices: Abbott Xience Prime™ EES 
 
The BIOTRONIK Orsiro SES is composed of four main components: 
 
• 
PRO-Kinetic ENERGY BMS platform 
• 
PLLA Biodegradable Polymer 
• 
Sirolimus Drug Substance 
• 
Stent Delivery System 
 
Both devices have received the CE mark. 
 
4 
INVESTIGATIONAL PLAN 
 
4.1 
Study Objectives and Methods 
In the present clinical investigation, the purpose is to evaluate the effectiveness and 
safety of the Orsiro SES in a prospective, multi-center, blinding evaluation, randomized, controlled 
setting, in subjects with de novo coronary artery lesions in one or a maximum of two coronary 
arteries. 
 
Angiography will be performed to assess the different procedural steps, the immediate post-
procedural success and the primary endpoint in-stent LLL at 9 months post procedure. All angiograms 
will be analyzed by an independent core laboratory, Medstar Research Health Angiographic Core 
Laboratory. 
The clinical investigation will commence approximately in QII 2015 and recruitment is expected to be 

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complete by 2016. 
 
4.2 
Study Design 
This is a prospective, multicenter, b l i n d i n g  e v a l u a t i o n , non-inferiority, randomized 
controlled clinical investigation. A population of up to 440 eligible subjects with single de novo 
coronary lesions up to 36 mm in length, in vessels with ≥2.25 and ≤4.0 mm reference 
diameter stenosis will be randomized, 1:1, to receive either the BIOTRONIK Orsiro SES or the 
Abbott Xience Prime™ EES. Planned follow-up investigations include clinical evaluation at 1, 6, 
12, 24, 36, 48 and 60 months post procedure. At the 9 months follow up visit all subjects will 
undergo angiographic evaluation. 
4.3 
Endpoints 
 
4.3.1 
Primary Endpoint 
The primary endpoint is the in-stent late lumen loss at 9 months, as assessed by t h e  core 
laboratory QCA analysis. 
 
4.3.2 
Secondary Endpoints 
 
4.3.2.1 
Treatment Success Indicator 
1) 
Device success, defined as attainment of ≤ 30% residual stenosis, TIMI=3, of the target lesion 
using the assigned study stent only. 
Note: Post-dilatation is allowed to achieve device success. 
2) 
Lesion success, defined as attainment of ≤ 30% residual stenosis, TIMI=3, of the target lesion 
using any percutaneous method. 
3) 
Procedure success, defined as attainment of ≤ 30% residual stenosis, TIMI=3, of the target lesion 
using the assigned study stent only without occurrence of in-hospital major adverse cardiac events 
(MACE; composite of all-cause death, Q-wave or non–Q-wave MI, and any clinically-driven TLR). 
 
4.3.2.2 
Clinical Endpoints 
The following endpoints were followed up at 1, 6, and 12 months post-procedure, and once annually for up 
to 5 years. 
1) 
All-cause death   
2) 
Cardiac death  
3) 
Myocardial infarction  
4) 
MI of the target vessel 
5) 
Stent thrombosis 
6) 
All serious adverse device effects (SADEs) 
7) 
Target Lesion Revascularization，TLR 
8) 
Target Vessel Revascularization，TVR 
9) 
Target Lesion Failure (TLF), composite of cardiac death, target vessel Q-wave or non-Q wave 
Myocardial Infarction (MI), Coronary Artery Bypass Grafting (CABG), clinically driven TLR 
10) 
Target vessel failure (TVF), composite of cardiac death, target vessel Q-wave or non-Q wave 
Myocardial Infarction (MI) and clinically driven TVR 
11) 
Major adverse cardiac event (all-cause death, Q-wave, non-Q wave MI and clinically driven 
TLR) 
 
4.3.2.3 
Angiographic Endpoints 
1) 
In-segment late lumen loss (LLL) at 9 months post-procedure 
2) 
In-stent and in-segment (proximal and distal) minimum lumen diameter (MLD) at 9 months post-
procedure 
3) 
In-stent and in-segment binary restenosis rate angiographically assessed (≥ 50% diameter 

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stenosis) at 9 months post procedure 
4) 
In-stent and in-segment percent diameter stenosis (% DS) 9 months after procedure. 
 
4.4 
Inclusion Criteria 
4.4.1 
Clinical Inclusion Criteria 
  Subjects must meet all of the following criteria to participate in the trial: 
 
1) Subject who can understand the investigation’s goal has provided written informed consent, and is 
willing to comply with the study’s follow-up requirements. 
     2) Subject is ≥ 18 years and ≤ 75 years old, male or female without pregnant. 
3) Subject is an acceptable candidate for PCI. 
4) Subject has clinical evidence of ischemic heart disease, stable or unstable angina pectoris or 
documented silent ischemia. 
5) Subject is eligible for dual anti-platelet therapy treatment with aspirin, plus either, clopidogrel, 
prasugrel, ticagrelor or ticlopidine. 
 
4.4.2 
Angiographic Inclusion Criteria 
 
Each target lesion/vessel must meet all of the following angiographic criteria for the subject to be eligible for 
the trial: 
 
1) 
Target lesion must be in major coronary artery or branch (target vessel). 
2) 
Target lesion must have angiographic evidence of ≥ 70% and < 100% stenosis (by operator visual 
estimate).  
3) 
Subject has up to two target lesions (two target lesions in one target vessel, or, for each target vessel, 
it has one target lesion). 
 
4) 
Target lesion is suitable for drug-eluting stent PCI treatment. 
5) 
Target lesion must be ≤ 36 mm in length by operator’s visual estimate, and can be completely 
covered by one stent.  
6) 
Target vessel must have a reference vessel diameter of 2.25–4.0 mm by operator’s visual estimate. 
7) 
Target vessel must have a Thrombolysis In Myocardial Infarction (TIMI) flow ≥2. 
 
4.5 
Exclusion Criteria 
4.5.1 
Clinical Exclusion Criteria 
 
Subjects will be excluded from the trial if any of the following criteria are met: 
 
1) 
Subject is pregnant and/or breastfeeding or intends to become pregnant during the duration of the 
study. 
2) 
Subject has clinical symptoms and/or ECG changes consistent with acute ST elevation MI (STEMI) 
within 7 days prior to the index procedure, hemodynamically unstable non-STEMI (NSTEMI) 
subjects included. 
3) 
Subject is hemodynamically unstable. 
4) 
Subject is an unacceptable candidate for CABG. 
5) 
Subject has a known allergy to contrast medium that cannot be adequately premedicated, or any 
known allergy to thienopyridine, aspirin, both heparin and bivalirudin, L-605 cobalt-chromium (Co-
Cr) alloy or one of its major elements(cobalt, chromium, tungsten and nickel), acrylic, fluoropolymers, 
silicon carbide, PLLA, sirolimus or everolimus. 

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6) 
Previous PCI of any target or non-target vessel 9 months prior to the index procedure. 
7) 
Planned surgery within 6 months of the index procedure. 
8) 
Planned staged treatment during the index procedure or within 30 days after the index procedure. 
9) 
History of a stroke or transient ischemic attack (TIA) within 12 months prior to the index procedure. 
10) Subjects with active bleeding disorders, active coagulopathy, or any other reason, who are ineligible 
for DAPT. 
11) Subject will refuse blood transfusions. 
12) Subject has documented left ventricular ejection fraction (LVEF) ≤ 40% as evaluated by 
angiography, echocardiogram, radionuclide ventriculography or any non-invasive imaging method 
within 90 days prior to the index procedure. 
13) Subject is dialysis-dependent. 
14) Subject has impaired renal function (i.e., creatinine > 2.0 mg/dL or 175 μmol/L determined within 7 
days prior to the index procedure). 
15) Subject has leukopenia (i.e. WBC < 3.5*10*9/L), thrombocytopenia (plt<100*10*9/L) or 
thrombocytosis (PLT>350*10*9/L). 
16) Subject is receiving chronic anticoagulation (e.g. coumadin, dabigatran, apixaban, rivaroxaban or 
any other agent). 
17) Subject is receiving oral or intravenous immunosuppressive therapy (inhaled steroids are permitted), 
or has known life-limiting immunosuppressive or autoimmune disease (e.g., human 
immunodeficiency virus, systemic lupus erythematosus; diabetes mellitus is permitted). 
18) Subject has life expectancy of < 3 years. 
19) In the investigator’s opinion, subject will not be able to comply with the follow-up requirements. 
20) Subject is participating in another (medical device or drug) clinical study. Subjects may be 
concurrently enrolled in a post-market study, as long as the post-market study device, drug or 
protocol does not interfere with the investigational treatment or protocol of this study. 
 
4.5.2 
Angiographic Exclusion Criteria     
 
Subjects will be excluded from the trial if any of the target lesions/vessels meet any of 
the following angiographic criteria: 
 
1) 
Target lesion is located within a saphenous vein graft or arterial graft. 
2) 
Target lesion has any of the following characteristics: 
a) 
Lesion location is within the left main coronary artery, or within 3 mm of the origin of the left 
anterior descending (LAD) or left circumflex (LCX).  
b) 
Involves a side branch of > 2.5 mm in diameter. 
Note: Lesions within 3 mm of the origin of the right coronary artery may be treated. 
3) 
Target lesion is totally occluded (100% stenosis). 
4) 
Target vessel has angiographic evidence of thrombus. 
5) 
Target vessel/lesion is excessively tortuous/ angulated or is severely calcified, preventing complete 
inflation of an angioplasty balloon. 
6) 
Target vessel was treated with brachytherapy any time prior to the index procedure. 
 
5 
ENROLMENT AND PROCEDURES 
The enrolment, randomization and follow up process are outlined in Figure 2. 
 

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Figure 2 Clinical investigation flowchart 

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5.1 
Informed Consent 
If the basic screening of a subject’s medical record meets the inclusion and no exclusion criteria, 
the subject should be given the clinical investigation informed consent information form and informed 
consent signature form (abbreviated as informed consent form). The informed consent form includes 
but is not limited to the following: 
 
 
Explanation of the clinical investigation 
 
Duration 
 
Expected benefits, risks or inconveniences 
 
Explanation of alternatives 
 
Medical record access and subject confidentiality 
 
Whether the data will be used for publications or submission for reimbursement support. 
 
No clinical investigation specific examination may be performed before the subject has signed 
the informed consent signature form. Informed consent should be singed in accordance with the 
applicable regulations, the Declaration of Helsinki, Good Clinical Practice and ISO 14155:2011(E). 
 
The person signing the informed consent shall: 
 
 
Avoid undue influence on subject’s willingness to participate 
 
 The subject’s legal rights should be protected 
 
Make the subject understand the trial a n d provide ample time for the subject to consider his/her 
participation. 
 
Assure that the informed consent form is fully completed i.e. Including dated signatures of 
the subject or the subject’s legal representative as well as the person obtaining the 
informed consent. 
 
The signed informed consent form will be retained by the investigator and made available (for review 
only) to the clinical investigation monitors, auditors and inspectors on request. A copy of the signed and 
dated informed consent form must be provided to the subject. 
5.2 
Enrolment 
Subjects are considered enrolled once they signed the informed consent signature 
form. However, the subjects are eligible for the clinical investigation only after fulfilling 
the in- and exclusion criteria The Intention to Treat (ITT) and the CIP population will 
only be based on eligible subjects.  
 
All target lesions must be treated in one procedure. Planned staged procedures are not allowed. 
Only Orsiro SES or Xience Prime™ EES may be implanted during the index procedure. There is 
no restriction in the enrolment of eligible subjects per site. 
 
5.3 
Baseline Examinations 
Subject clinical investigation eligibility must be confirmed prior to the intervention, through the following 
tests and examinations: 
 
 
Demographics 
 
For premenopausal women, a pregnancy test must be performed within 72 hours prior to 
angiography 
 
Review of in- and exclusion criteria 
 
Physical examination and relevant medical history including anginal status or myocardial 
ischemia 
 
A 12-lead electrocardiogram within 72 hours of the intervention 
 
Laboratory examination with 7 days of the intervention, including: 
 Infectious diseases screening (hepatitis B surface antigen,  hepatitis C antibody, syphilis 

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antibody (TPPA), and HIV antibody) 
 Blood routine (total WBC count, platelet count, hemoglobin, hematocrit, and RBC count) 
 Liver function test (ALT、AST) 
 Serum creatinine  
 Serum glucose 
 Serum lipid (triglyceride, cholesterol, high density lipoprotein, low density lipoprotein) 
 Cardiac biomarkers CK (optional), CK-MB and Troponin I and/or T 
 
5.4 
Medication 
Unless clinically contraindicated, all subjects should receive the medication regimen listed below 
(take each hospital and surgeon’s general use into consideration). The use of GPIIb/IIIa inhibitors is 
allowed but not mandatory. 
The generic name of all medications administered must be recorded in the subject’s medical record.  
 
Table 1 Medication List 
Timing 
Medication 
Procedure 
Prior to Procedure 
Heparin 
Left to the discretion of the interventionist 
Aspirin 
100 mg for 3 days prior to procedure or a  
300mg prior to procedure. 
Clopidogrel 
Loading dose < 6 hours prior or during 
the procedure of 300- 600 mg 
Subjects on Clopidogrel therapy (at least 
6 days): no loading dose required 
 
Ticagrelor2 
 
180mg prior to procedure. 
During Procedure 
Heparin(IV or LMWH) 
 
Per routine hospital practice, it is 
recommended to maintain an ACT > 250 
seconds. 

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During Procedure 
GPIIb/IIIa Inhibitor 
Left to the discretion of the interventionist 
Intracoronary 
Nitroglycerin  
 
100-200 µg post angiography, prior to 
stent implantation, and post intervention 
angiograms 
 
Post-Procedure 
GPIIb/IIIa Inhibitor 
Per routine hospital practice 
Aspirin 
100 mg per day 
Clopidogrel1 
75 to 150 mg per day 
Left to the discretion of the interventionist 
 
Ticagrelor2 
  
90 mg twice per day 
 
Discharge 
Aspirin 
 
100 mg per day 
Clopidogrel1 
75 to 150 mg per day for a minimum of 12 
months. 
 
Dosage left to the discretion of the 
interventionist 
 
 
Ticagrelor2 
  
90 mg twice per day for, a minimum 
of 12 months.   
1Interventionist may substitute to Prasugrel, Ticlopidine or Ticagrelor for subjects who are allergic 
to Clopidogrel. Subjects on Ticlopidine must have CBC(s) performed per instructions for use. 
2 Interventionist may choose to use Aspirin together according to the haemorrhage risk other than 
Clopidogrel. 
 
 
 
5.5 
Interventional Procedure 

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All implanting interventionists must sign the clinical investigation site signature log and provide a 
signed and dated CV. All implanting interventionists must also receive adequate CIP training prior 
to clinical investigation procedure.  
 
Preparation and percutaneous access should be performed according to the standard hospital 
practice. Both femoral and radial accesses are accepted. The procedure begins once percutaneous 
access has been made. 
 
5.5.1 
Baseline Angiography 
Following intracoronary injection of nitroglycerin or isosorbide dinitrate, a baseline angiography 
of the target vessel must be performed according to the QCA corelab guidelines in at 
least 2 orthogonal views, presenting the target lesion free of foreshortening or vessel overlap. 
5.5.2 
Randomization 
After in- and exclusion criteria have been checked and written informed consent has been obtained 
prior to PCI, subjects will be randomized with the eCRF. 
 
 
• 
1/2 Treatment with Orsiro SES 
• 
1/2 Treatment with Xience Prime™ EES 
 
A randomization may only be done once. If by mistake a subject is randomized twice or more, the 
first assigned treatment arm will be used. 
 
5.5.3 
Puncture and Predilatation 
The target lesion should be crossed with a 0.014” guide wire. If predilatation is necessary it is 
recommended to choose following pre-dilation balloons. 
 
2.0 mm for a 2.25 mm vessel 
2.0 mm for a 2.5 mm vessel 
2.5 mm for a 3.0 mm vessel 
3.0 mm for a 3.5 mm vessel 
3.5 mm for a 4.0 mm vessel 
 
Furthermore, the selected pre-dilatation balloon must be a minimum o f  two millimeters shorter 
than the nominal length of the Orsiro stent that is planned to be implanted. 
 
 
5.5.4 
Stent Implantation 
Please note that a stent package may not be opened prior to randomization. 
 
The investigator is free to assess the artery diameter and the lesion length either visually or by 
online QCA during the procedure, always considering the instructions for use. The stent length should 
cover the target lesion from normal reference vessel proximal to normal reference vessel distal to 
assure full coverage of the lesion. 
 
Only one clinical investigation stent should be used per lesion. Overlapping is only allowed 
if the primary stent failed to completely cover the target lesion. In such case the second stent must be 
the same stent the subject was randomized to, unless clinically contraindicated. Please refer to the 
IFU of each stent for details of overlapping procedures.  
If the stents overlap, the overlapped part must at least be 2mm. 
 
 

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After stent implantation, an angiography must be performed. Following intracoronary injection 
of nitroglycerin or isosorbide dinitrate, angiograms should be made in the exact same 2 orthogonal 
views as pre-stenting according to the core lab instructions. 
 
. 
5.6 
 Process before Discharge 
Between the end of the procedure and hospital discharge, the following data has to be collected: 
 
 Cardiac biomarkers CK (optional), CK-MB and Troponin I and/or T must be taken within 6-24 
hours after procedure. 
 
 Liver function tes (ALT、AST) within 24 hours post-procedure 
 
 Serum creatinine within 24 hours post-procedure 
 
 After the index procedure a 12-lead ECG must be completed within 6-24 hours or at discharge 
(whichever comes first). 
 
A physical examination will be conducted to verify the anginal status according to CCS or 
Braunwald classification just prior to discharge. Adverse events and effects, concomitant medications, 
and any interventional treatment that occurred since the procedure must be recorded before discharge. 
 
Note: Every effort must be made to obtain myocardial enzymology values within the specified 
time ranges. Results of all  enzyme target, even measurements performed outside the time 
range must be documented on the CRFs. 
If CK, CKMB and/or Troponin I  and/or T elevation is a b n o r m a l  post-procedure, CK and Troponin 
measurements should be performed every 8 hours and documented in the eCRF until values have 
returned to normal. 
 
5.6.1 
Antiplatelet / Anticoagulation Regimen 
Forl medication please refer to Table 1 under section 5.4 
 
5.7 
Follow Up Visits 
All subjects will be followed through to hospital discharge and will undergo follow-up evaluations at 
following time points: 
 
5.7.1 
One Month Clinical Follow Up 
All subjects will be contacted for clinical evaluation at 30 days post-procedure (± 7 days), including: 
 
• 
Assessment of the anginal status (CCS or Braunwald), 
• 
Any adverse, or serious adverse events 
• 
Anti-platelet/anti-coagulant treatment plan 

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5.7.2 
6 Months Clinical Follow Up 
All subjects will be contacted for clinical evaluation at 180 days post-procedure (± 30 days), including: 
 
• 
Assessment of the anginal status (CCS or Braunwald), 
• 
Any adverse, or serious adverse events 
• 
Anti-platelet/anti-coagulant treatment plan 
 
5.7.3 
9 Months Clinical Follow Up 
All subjects will return to the clinic for an angiography at 270 days (+ 30 days) post- procedure 
including: 
 
• 
Ischemic/anginal status (CCS or Braunwald), 
• 
Any adverse, or serious adverse events/effects 
• 
Anti-platelet/anti-coagulant treatment plan 
• 
Blood routine (total WBC count, platelet count, hemoglobin, hematocrit, and RBC count) 
• 
Liver function test (ALT、AST) 
• 
Serum creatinine 
• 
12-Lead ECG 
• 
Angiographic assessment of the target lesion 
Catheter and imaging position applied by coronary angiogram should be with the same time of 
stent implanting. 
 
5.7.4 
12, 24, 36, 48, 60 Months Clinical Follow Up 
All subjects will be contacted for clinical evaluation at 12, 24, 36, 48, 60 months post-procedure (±30 
days), including: 
 
• 
Assessment of the anginal status (CCS or Braunwald), 
• 
Any adverse, or serious adverse events 
 
Anti-platelet/anti-coagulant treatment plan 

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Table 2: Schedule of treatments and assessments-baseline to 12-month follow up 
 
Baseline 
Procedure 
Discharge 
30 days 
± 7days 
180 days 
±30 days 
 
270days 
+30 days 
 
12, 24, 36, 
48, 60 
months 
± 30 days  
Signed informed 
consent 
X 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
Pregnancy 
Screening 
X1 
 
 
Medical and 
Cardiac History 
X 
 
 
Medication 
X2 
X3 
X3 
X3 
 
X3 
 
X3 
   
Blood Routine 
X4 
 
X 
 
 
 Infectious diseases 
screening 
X4 
 
 
 
Serum Creatinine 
X4 
X6 
 
X 
 
Liver function test 
X4 
X7 
      
X 
 
Serum glucose 
X4 
 
 
 
Serum lipid 
X4 
 
 
 
CK / CK-MB 
X4 
X8 
 
 
 
Troponin I or T 
     X4 
X8 
 
 
Physical examination 
and/or Ischemic status 
X 
X 
X 
X 
 
X 
 
X 
Intervention 
X 
 
 
Angiography 
X9 
X
10 
 
12-lead ECG 
X5 
X11 
X 
 
 
1. For premenopausal women, a pregnancy test must be performed within 72 hours prior to angiography 
2. Procedure Medication 
3. Anti-platelet/anti-coagulant medical therapy 
4. Within 7 days prior to procedure 
5. Within 72 hours prior to procedure 
6. Serum Creatinine within 24 hours post-procedure  
7. Liver function test(ALT、AST) within 24 hours post-procedure 
8. CK & CK-MB & Troponin within 6-24 hours post-procedure 
9. Angiography of all procedure steps and Pre- and Post- procedure in two orthogonal views 
10. Angiography in the same two orthogonal views as at index procedure 
11. ECG within 6- 24 hours or before discharge 
 
 

Page 28 of 45 
Clinical Investigational Plan 
 
 
 
 
5.8 
Unscheduled Coronary Angiogram 
Follow Up 
Any unplanned angiography and revascularization must be followed by a full clinical 
evaluation. The required data is to be entered into the eCRF. All films must be sent to the angiographic 
core laboratory for review. 
 
• 
If the subject undergoes a clinically driven angiography within 6 months post procedure, 
having no re-intervention of the target lesion(s), the subject must return 
for 
the 
angiographic follow up visit, 9months post procedure.  
 
• 
If the subject undergoes a clinically driven angiography between 6-9 months post procedure, 
this will be considered as the 9 months follow up angiography.  
 
• 
If the subject has a re-intervention for in-stent restenosis at any time prior to the 9 months 
follow up the subject will not have an additional angiography at the 9 months follow up visit.   
 
• 
However, if the subject has two treated target vessels with the study stent, whereof only 
one was re-intervened, the subject must return for the repeat angiography at the 9 months 
follow up visit. If one had revascularization and in-stent restenosis during 6-9 months, the 9 
months follow up visit is not needed.  
 
5.9 
Treatment Failures 
Failure to implant the study stent at the intended target lesion 
must be recorded on the Case Report Form as a treatment 
failure. If possible and feasible, another study stent will be 
chosen as first choice to treat this lesion.  
 
5.10 Additional Stent Treatment 
In the event of a major dissection or an occlusive complication manifested as decreased target vessel 
flow, chest pain, or ischemic ECG changes after the index procedure, which do not respond to repeat 
balloon inflations or intracoronary  vasodilators  (nitroglycerin, verapamil, diltiazem, nitroprusside), other 
bailout procedures may be performed which may include additional stenting. Should a second stent be 
used, it must be a study stent unless clinically contraindicated.Multiple stenting with the Orsiro stent 
requires a 2 mm overlap. If the Xience Prime stent has to be used, the overlap placement should be 
done according to its IFU. Such procedures have to be documented accordingly in the eCRF. 
 
 
5.11 Bailout-Staged Procedure 
Planned staged procedures are not allowed in this clinical investigation. If during the 
intervention it becomes clinically necessary to postpone the treatment, this is regarded as a staged 
procedure and must be documented in CRF. 
 
6 
CLINICAL INVESTIGANTION PLAN DEVIATIONS 
 
A Clinical Investigational Plan (CIP) deviation is defined as an instance(s) of failure to follow, 
intentionally or unintentionally, the requirements of the clinical investigation. 
 
All measures must be undertaken to avoid deviations from the CIP. Deviations from the CIP must 

Page 29 of 45 
Clinical Investigational Plan 
 
 
be documented in the Case Report Form. Original clinical information should be reserved to report 
the reasons of plan deviations. 
 
Investigators must also adhere to procedures for reporting CIP deviations to their Ethic 
Committee (EC) in accordance with their specific EC reporting guidelines and procedures. Under 
emergency circumstances, deviations from the CIP to protect the rights, safety and well-being of 
human subjects may proceed without prior approval of the sponsor and the EC. Such deviations shall 
be documented and reported to the sponsor and the EC as soon as possible. 
 
 
7 
Study Participation Status 
7.1 
Status Definitions 
 
Provisionally enrolled- A subject who is fully informed about the specifics of the study by the authorized 
site personnel and provides informed consent by properly signing an informed consent form after 
confirmation of the initial enrollment criteria. 
  
 
Screen failure- Provisionally enrolled subject who withdraws consent prior to randomization or is 
unsuitable for randomization following laboratory assessments, pre-procedure electrocardiogram (ECG) 
or diagnostic angiogram at the index procedure. These subjects will be exited from the study once screen 
failure is confirmed. Subject informed consent forms will be kept in the site’s administrative files. 
 
Enrolled- A provisionally enrolled subject who meets all clinical and angiographic eligibility criteria, and has 
been randomized. These subjects will be followed in accordance with the protocol requirements. 
 
Study exit- Early termination of study participation applicable to subjects that have signed an informed 
consent form. 
 
Study completion- A subject who completes all protocol-required study procedures. 
 
7.2 
Subject Study Exit 
 
Investigators should make every effort to ensure subjects complete all protocol-required procedures, 
including study follow-up visits. However, subjects may be required to exit the study, despite an 
investigator’s best efforts. Good Clinical Practice (GCP) guidelines describe the need for clear subject exit 
procedures, to include when and how to exit subjects from the study, as well as to outline the type and 
timing of the follow-up and data collection for these subjects. 
 
Subjects may be exited from this study in the following limited situations: 
• 
Subject death 
• 
Subject withdrawal of informed consent  
• 
Investigator believes it is in the best medical interest of the subject to discontinue 
study participation due to safety reasons 
• 
Subject is considered a screen failure or a procedure failure 
 
 In any of the situations noted above, data collected up to and including the exit of the subject will be 
used in data analysis. No data will be collected after the exit of the subject from the study. Study exits are 
expected and will be taken into consideration during data analysis as described. Additionally, subject 
attrition has been calculated into the study sample size. Therefore, all subjects exited from the study will be 
counted toward the randomization goal and will not be replaced. Investigators must document, in subject 
medical records, the reasons and circumstances for all subject exits. 
 
In cases where further participation in the study poses potential risk to the subject, study exit should 

Page 30 of 45 
Clinical Investigational Plan 
 
 
be considered. In addition to subject safety, consideration should be given to the scientific validity of the 
primary endpoints when making decisions concerning subject exit. Study follow-up options and 
requirements for subjects exiting from the study should be determined and applied to all subjects exiting for 
similar reasons. Deviations in subject eligibility, as defined in the protocol, should be considered protocol 
violations and reported to the Institutional Review Board (IRB) or Ethics Committee (EC) immediately upon 
discovery, in accordance with local regulations. 
 
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. Identification of vital status will be handled at the investigational site level. Subjects have the right 
to discontinue from the study at any time or be discontinued at the investigator’s discretion. 
 
7.2.1 Subject Lost to Follow-up 
 
Subjects may be unable to adhere to the regularly scheduled study visits. Study sites should attempt 
to contact these subjects in order to maintain study visit compliance and all contact attempts should be 
documented. At a minimum, the site should make two attempts to contact the subject by phone and one by 
certified mail. 
 
If the subject is able to be contacted, all efforts should be made to perform the required study visit 
and complete the relevant case report forms. However, if a subject is contacted and a study visit cannot be 
performed, the study site should complete the relevant case report forms with any relevant data obtained 
from the subject contact by phone. If a subject is unable to be contacted at any of the remaining study visits, 
either a missed visit will be entered for each visit or the subject may be exited as lost to follow-up, using the 
date of last actual contact as the study exit date. 
 
Likewise, due to unforeseen circumstances, subjects may relocate during the course of the study and 
may no longer be able to return for study follow-up visits. Attempts to collect data from these subjects should 
be made by the investigator in collaboration with the subject’s new provider. All data that is obtained may 
be utilized in data analysis, but it should be documented that it was collected by an unapproved investigator. 
If no data can be collected from the subjectas collected by an unapproved investigator. If or study follow-up 
visits. Attempts to collect data from these subjects should be made by the invest 
 
The investigative site should make an attempt to verify the vital status of subjects that are lost to follow 
up through means including, but not limited to, the relative ornizations, as applicable. BIOTRONIK and/or 
its designee may provide assistance to investigative sites to obtain vital status information, as permitted, for 
lost to follow up subjects. 
 
8 
DATA REPORTING AND STATISTICAL ANALYSIS 
 
8.1 
Determination of Sample Size 
The calculation of the sample size is based on the primary endpoint only: In-stent late lumen (LLL). 
The trial is based on a non-inferiority hypothesis test, with 2 groups (Orsiro and Xience stents), with a sample 
allocation ratio 1:1 
 
Since Late Lumen Loss is a quantitative variable and the sample size will be larger enough (at least 
200 subjects per group) to invoke the Central Limit Theorem, a student’s t-test for independent samples 
will be used. And since it is a non-inferiority hypothesis, only 1-tail will be tested.  
 
In order to put forward a reasonable LLL hypothesis, data from three different studies is considered. The 
values are related to in-stent Late Lumen Loss and are displayed in the Table 3. 
 

Page 31 of 45 
Clinical Investigational Plan 
 
 
In-stent Late Lumen Loss (Table 3) 
Product 
Study 
N 
Fup 
mean 
std. dev. 
95% CI 
%CV 
Xience 
Resolute Vs Xience 
220 
13 mths 
0.19 
0.40 
[0.14,0.24] 
211% 
Bioflow II 
172 
9 mths 
0.11 
0.29 
[0.07,0.15] 
264% 
Xience VS Paclitaxel 
772 
8 mths 
0.14 
0.41 
[0.11,0.17] 
293% 
Orsiro 
Bioflow II 
332 
9 mths 
0.10 
0.32 
[0.07,0.13] 
320% 
 
According to the above data, we first calculate the weighted mean of the control group Xience: 
Table 4 
               
 
               
                  
 
 
 
The final weighted mean is 0.14 and assum that both Orsiro and Xience can achieve tha same LLL level. 
About non-inferiority study: . 
 
 
H0:μOrsiro - μXience > Δ 
HA:μOrsiro - μXience ≤ Δ 
 
 
μOrsiro is the LLL level of Orsiro stent at 9 month, and μXience is the LLL level of Xience stent at 9 month. 
 
 
It was assumed μorsiro = μXience = 0.14; standard deviation for the Late Lumen Loss mean at 9 months 
is equal for both stents; σXience = σPaclitaxel = 0.41 (the max value for all tests in table 3);  Δ =0.41/3= 
0.137; power of 85%; α = 0.025; test: one-sided student’s t-test for independent samples; 25% loss for 
follow-up. Each group of 162 subjects per group, needs to confirm the hypothesis, as well as 216 
subjects per group considering a 25% loss for follow-up.. 
 
The calculation formula of sample size: 
 
 
 
8.2 
Statistical Analysis 
   8.2.1 The study population is divided into the following categories 
 
Full analysis set (FAS): The subjects set determined by the intention to treat (ITT) principle refers 
to the data set constituted by all the subjects participating randomly, using investigational devices 
and having a baseline curative effect evaluation. 
 
Per protocol analysis (PPS): Refer to the treatment subpopulation eliminating the serious violation 
Product 
n 
Mean 
N*Mean 
Xience 
220 
0.19 
41.80 
172 
0.11 
18.92 
772 
0.14 
108.08 
Orsiro 
332 
0.10 
33.20 
Total 
1496 
 
202.00 

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Clinical Investigational Plan 
 
 
cases. 
 
Safety analysis set (SS): Refer to the subjects set receiving randomization and minimal one safety 
evaluation post baseline. 
The curative effect evaluation is on the basis of FAS and PPS. All the baseline demographic statistical 
analysis is on the basis of FAS, and the safety evaluation is on the basis of SS. 
 
8.2.2 The statistical analysis method 
Descriptive analysis: Count data is described by proportion, meterage data is described by mean, standard 
deviation, maximum, minimum description, median, the 25th and 75th percentile. 
 
Baseline demographic statistical analysis: Comparison between groups of count data adopts continuous 
correction of the χ2 test. When a cell theory frequency is exceeding 25% is less than 5, use the Fisher 
exact test. Comparison between groups of normal distribution meterage data adopts the group t-test (two 
groups) or variance analysis (multigroup). Comparison between groups adopts the Wilcoxon Rank Sum 
test. 
 
Curative effect evaluation: After the test of homogeneity of variance in each center for the primary endpoint 
of in-stent LLL, comparison between groups uses covariance analysis of adjustment center and baseline 
effect, and provides the minimum mean square of dependent variable (LLL), minimum variance between 
groups and 95% confidence interval. For other curative effect indexes, group comparison of normal 
distribution meterage data adopts the paired t-test. Group comparison of abnormal distribution meterage 
data adopts the Wilcoxon Sign Rank test. The method of comparison between groups is the same as a 
baseline analysis. 
 
Safety evaluation: According to the investigational and control group, describe the normal number and 
proportion pre-procedure, and the abnormal number and proportion post procedure respectively. Use the 
number and incidence of cases to describe the adverse event, and use the continuous correction of χ2 
test or the Fisher exact test for this ratio. Meanwhile, describe in detail the relationship between the 
specific performance, extent of all the adverse events in each group and the stent implantation. 
 
All the statistical analyses will be conducted at the bilateral, 0.05 significant level. Use SAS 9.13 
statistical software for statistical analysis, and EPIDATA 3.0 entry software for data management. 
 
9 
DATA COLLECTION, MONITORING, INSPECTIONS AND AUDITS 
 
9.1 
Data collection- eCRF 
All required data for this clinical investigation will be collected on eCRF. All site staff must be 
trained on the correct completion of eCRF before they are given access for data entry.  
 
Subjects will only be identified in eCRFs by a unique reference number, month and year of birth. 
eCRFs are confidential documents and will only be available to BIOTRONIK, the investigator, the 
clinical investigation statistician, and c om p et e n t au t h or it y.  Each site should keep all subjects’ 
document for follow-up. 
 
Appropriate internet access is required for data entry. 
. 
 
 
 
9.2 
Monitoring 

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Clinical Investigational Plan 
 
 
Monitoring will be performed by BIOTRONIK or by BIOTRONIK designees, to ensure that the 
investigator and the clinical investigation team conducts the clinical investigation in accordance with 
the CIP, Declaration of Helsinki, I S O  1 4 1 5 5 : 2 0 1 1 ( E )  and GCP, to ensure adequate 
protection of the rights, safety and wellbeing of subjects and the quality and integrity of the resulting data. 
 
During monitoring visits, the clinical monitor will perform source data verification as defined 
in the monitoring plan. For this purpose, the investigator must permit access to medical/subject records 
(source data) throughout the clinical investigation. In the case of electronic medical/subject records, 
the Investigator has to ensure that the monitor receives appropriate access or that print outs of all 
clinical investigation or relevant source documents is given. 
 
9.3 
Audits 
Study centers may be audited during a n d  a f t e r  the course of the clinical investigation by 
BIOTRONIK, ethic committees and other applicable regulatory authorities, and provide all subjects’ 
medical data. 
 
If an auditor becomes aware that i n v e s t i g a t i o n  is not complying with the requirements 
mentioned above, the auditor is obliged to notify BIOTRONIK. BIOTRONIK will evaluate the non-
compliance and issue corrective actions, discontinue enrolment or, as a last measure, close the 
clinical investigation site. In such a case, the investigator must return all unused devices to BIOTRONIK. 
 
 
9.4 
Source documentation 
All clinical record must be recorded and maintained in the medical files and saved in each 
investigational center’s National Drug Clinical Trial Institution. All the source data and CRF should be 
saved for ten years after the investigational product appears on the market. The c l i n i c a l  
i n f o r m a t i o n  must contain, but is not limited to, the following information: 
 
 
Date of informed consent 
 
Subject participation in the clinical investigation 
 
Demographics 
 
Date of the discharge 
 
Documentation of medical/surgical history and previous medication 
 
Vessel and lesion sizes and characteristics 
 
All angiographies, ECGs 
 
Cardiac ischemia/anginal status 
 
Description of interventional procedure (material used, drugs administered during the 
procedure, date, time, complications etc.) 
 
All adverse event(s): Diagnosis and symptom(s), onset and end date, severity, action taken, 
outcome 
 
 
Concomitant medication 
 
Date of clinical investigation completion or withdrawal 
 
The following additional documents are considered a s  source 
 
 
Subject’s contact information 
 
SAE reports 
 
9.5 
Data Management 
The data manager is responsible for providing a clean data set at the end of the clinical 
investigation. Queries should be resolved by the investigator or a person designated by the investigator 

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Clinical Investigational Plan 
 
 
in a timely manner. When all data is complete the database will be locked and the data analyzed. 
 
9.6 
Record Retention 
All clinical investigation records and reports must remain on file at the clinical investigation centers by the 
national legislation. The investigator must contact BIOTRONIK before destruction of any records and reports 
related to the clinical investigation. BIOTRONIK must be informed if the investigator plans to leave 
the clinical investigation site. In such case the site must name a new contact person before the 
investigator parts from the clinical investigation site.  
BIOTRONIK is responsible for retaining the Trial Master File (TMF) according to national legislation and 
BIOTRONIK Standard Operating Procedure (SOPs).. 
 
 
10 
APPROVALS of Investigation 
 
10.1 Ethics Committee Approval 
Prior to the clinical investigation, the investigator is responsible for submitting the clinical 
investigational plan, informed consent form and relative files to Medical Ethics Committee of the hospital. 
Approval f r o m  t h e  E C  must b e  a c q u i r e d  prior to initiating the clinical investigation. Any 
modification of the study plan must be approved by the EC before initiating. Any severe adverse event 
that happened during investigation must be reported to the EC in written form. 
The investigator has the obligation to submit the applicable document for ethical approval to the 
EC, and meanwhile, a copy of this document should be provided to BIOTRONIK. A copy of the EC opinion, 
approval and EC voting members list should also be provided to BIOTRONIK. If further information is 
needed by the EC, the investigator should submit these in time. 
 
The investigator must report to the EC any new information that may affect the safety of the 
subjects or the conduct of the clinical investigation. 
 
Upon completion of the clinical investigation, the investigator shall provide the EC with a brief 
report on the outcome of the clinical investigation as required by the local EC. 
 
10.2 Competent Authority Approval 
BIOTRONIK is responsible for obtaining approval from the Competent Authority (CA), if applicable, prior to 
any site initiation. BIOTRONIK must report to the CA any new information that may affect the safety of the 
subjects or the conduct of the clinical investigation. 
 
10.3 Investigator Responsibilities 
Prior to shipment of the first clinical investigation device and first implantation, the 
investigator must read and sign this CIP as well as the Investigator’s Agreement 
prior to enrolling any subjects  national and local regulatory requirements must be fulfilled. 
 
Each clinical investigation site must have, but is not limited to, the following documents: 
 
 
Competent authority approval (GCP Certification) 
 
Ethics committee approval 
 
Signed investigator’s agreement 
 
Signed and dated 
CVs 
for 
all investigators 
participating 
in 
the 
clinical 
investigation. 
 
Laboratory Accreditation and the normal ranges 
 

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Clinical Investigational Plan 
 
 
10.4 Investigational Device Accountability 
 
10.4.1 Traceability Records 
A device accountability system will be maintained during the clinical investigation at each site; 
documenting device use at the site. Date of use, size, reference and lot numbers of the BIOTRONIK 
Orsiro will be documented in the eCRF system.  
 
 
10.4.2  Change of Device 
All device failures and malfunctions should be reported in the e-CRF and t h e  s t e n t  should be 
returned to BIOTRONIK. 
 
 
10.5 Non-CIP Research 
BIOTRONIK has a legal responsibility to the regulatory authorities to fully report all the results 
of sponsored clinical studies. No investigative procedures other than those stated in this CIP shall be 
undertaken on the enrolled clinical investigation subjects without the agreement of the EC and 
BIOTRONIK 
 
10.6 Amendments to the CIP 
Amendments to the CIP should be confirmed by BIOTRONIK. All changes must be documented 
in a signed CIP amendment. All amendments must be submitted to the EC for approval prior to 
implementation. 
 
 
10.7 Subject Insurance 
Subjects who participate in this study will be insured against study related injury. BIOTRONIK 
has issued clinical trial liability insurance with appropriate coverage for the continuation of the entire 
study. 
 
11 
SAFETY 
During the course of this clinical investigation, adverse events may occur. Adverse event information 
will be collected throughout the clinical investigation in the eCRF by the investigator or by the 
investigator delegated person. Any adverse event should be followed until it is resolved or resolved with 
sequelae. Based on the nature and/or the severity of the event it is categorized as either: 
 
 
• 
Adverse Event 
• 
Serious Adverse Event 
• 
Adverse Device Effect 
• 
Serious Adverse Device Effect 
• 
Unanticipated Serious Adverse Device Effect 
 
11.1 Reporting to Sponsor (BIOTRONIK) 
Adverse events classified to be 'serious' will be reported to BIOTRONIK within 24 hours after awareness 
by the investigator.  Reporting should be done using the 'Adverse Event Form' in the EDC, email or 

Page 36 of 45 
Clinical Investigational Plan 
 
 
the fax number indicated in the investigator file. A c c o r d i n g  t o  t h e  C l i n i c a l  E v e n t  
C o m m i t t e e  ( C E C ) ’ s  r e q u i r m e n t ,  t h e  i n v e s t i g a t o r  i s  o b l i g e d  t o  
p r o v i d e  a l l  k i n d s  o f  s o u r c e  d a t a  a b o u t  t h e  s e r i o u s  a d v e r s e  
e v e n t ,  a n d  t h e n  s c a n  a n d  u p l o a d  t h e s e  t o  t h e  E D C  s y s t e m  .  If 
additional information or documentation is needed the clinical project manager or a designee will 
contact the investigator to retrieve the necessary information. 
 
Primary Contact for Serious Adverse Events Reporting at BIOTRONIK is:  
 
Jing Wang 
National Clinical Study Manager 
Phone: 021-65223851-852 
Fax: 021-65223852 
 
 
11.2 Adverse Events 
An adverse event (AE) is any untoward medical occurrence (including abnormal laboratory 
findings) in subjects, whether or not related to the investigational medical device 
 
Any current condition that is recorded as a pre-existing condition either in the medical history 
of physical examination section, unless there is a change in nature, severity, or degree of incidence, 
is not an AE. 
 
Relation to the clinical investigation device a n d  p r o c e d u r e  will be assessed 
 
 
11.2.1  List of Anticipated Adverse Events 
The anticipated adverse events are those related to regular percutaneous interventions, including 
drug and polymer. 
 
The following adverse events may be associated with the use of coronary stenting devices, 
PTCA: 
 
• 
Cardiac events: including MI (determine whether or not it is related to PCI’s acute MI, the troponin 
should > 5 times of the normal upper limit) or unstable angina, coronary artery occlusion, coronary 
artery rupture, coronary artery spasm, restenosis of the treated coronary artery (restenosis >= 
50%), cardiogenic shock, cardiac tamponade, puncture or tear of coronary artery or aorta, cardiac 
perforation, emergency surgery (peripheral vessel or CABG), pericarditis, pericardial effusion. 
• 
Arrhythmia events: VT, VF, atrial fibrillation, atrio ventricular block. 
• 
Stent system events: no stent delivered to the target lesion, dislocation from the delivery system, 
stent dislocation, stent deformation, thrombosis in stent, thrombogenesis in stent, stent fracture, 
stent migration, stent compression, balloon filling shortage, balloon rupture, catheter withdrawal 
difficulties. 
• 
Disease of the respiratory system: acute pulmonary edema, respiratory failure 
• 
Vessel events: pain in the pucture position, bleeding or hematoma, high/low blood pressure, 
aneurysm, pseudoaneurysm, arteriovenous fistula, retroperitoneal hematoma, acute vascular 
occlusion, vascular tear or perforation, vascular stenosis, thrombosis or occlusion, vasospasm, 
peripheral ischemia, distal embolization (air, fat). 
• 
Nervous system: stroke or TIA, periphery or femoral nerve injury. 
• 
Bleeding events: bleeding or hematoma at the position of puncture, bleeding events which need a 
blood transfusion or other treatment. 

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Clinical Investigational Plan 
 
 
• 
Allergic reaction to contrast agent, antiplatelet medicine, stent coating, anticoagulant drug, cobalt-
chromium alloy, sirolimus and everolimus. 
• 
Death 
 
The occurrence of the above listed adverse events may lead to repeat revascularization, MI, 
emergency bypass surgery, or death. 
 
The side effects/adverse events of the PLLA polymer are no different than those of other stent coatings 
and may include but are not limited to the following: 
 
• 
Allergic reaction 
• 
Focal inflammation at the site of stent implantation 
• 
Restenosis of the stented artery 
 
Potential adverse events related to s i r o l i m u s  drugs (following oral administration) include but are 
not limited to: 
 
• 
Abnormal liver function test 
• 
Anemia 
• 
Asthralgias 
• 
Diarrhea 
• 
Hypercholesterolemia 
• 
Hypersensitivity, including anaphylactic/anaphylactic type reactions 
• 
Hypertriglyceridemia 
• 
Hypokalemia 
• 
Infections 
• 
Interstitial lung disease 
• 
Lymphoma and other malignancies 
• 
Thrombocytopenia 
 
11.3 Serious Adverse Events 
In case any of the following criteria is applicable to the Adverse Event it classifies as Serious 
Adverse Event. 
 
• 
Led to in-patient or prolonged hospitalization 
• 
Led to injury 
• 
Led to operational capability affected 
• 
Led to serious deterioration in the health of the subject 
• 
Led to permanent impairment of a body structure or a body function 
• 
Led to the injury need intervention treatment 
• 
Led to fetal distress, fetal death or a congenital abnormality or birth defect 
 
 
11.4 Adverse Device Effects (ADE) & Serious Adverse Device Effects (SADE) 
An adverse device effect is an adverse event related to the use of an investigational medical 
device. This definition includes adverse events resulting from m i s u s e  a n d  t h e  a d v e r s e  
e v e n t s  b e c a u s e  o f  t h e  d e v i c e  i t s e l f .  
 
 
If an ADE or SADE has occurred, any retrievable part of the Orsiro Stent System should be returned 
to BIOTRONIK AG o r  a u d i t  c o m p a n y  for analysis.  

Page 38 of 45 
Clinical Investigational Plan 
 
 
 
 
11.5 Unanticipated Serious Adverse Device Effects (USADEs) 
USADE is any serious adverse device effect which by its nature, incidence, severity or outcome 
has not been identified in the current version of the risk analysis report. 
 
11.5.1  CEC 
The CEC is composed of three independent physicians with excellent experience in the targeted 
indication. The CEC will adjudicate all reportable SAEs, ADEs, SADEs, and UADEs in the clinical 
investigation. 
 
BIOTRONIK will supervise a n d  e n s u r e  that the centers p r o v i d e  source documents for 
the CEC to analysis. Final adjudication of the event will be done by the CEC. The adjudication by the 
CEC will overrule the one of the investigator, should the investigator and CEC disagree. 
 
 
12 RISK ANALYSIS 
 
12.1 Risks 
For more detailed information on the risks of implantation of both stents, including a complete 
list of warning, precautions and potential adverse events, please refer to the Instructions for Use of both 
devices, which are provided with the products. 
 
Anticipated adverse events for the BIOTRONIK Orsiro SES, including events related to regular 
PCI, as well as risks related to angiography are listed in section 11.3  
 
This study will collect data prospectively on subjects that are randomly assigned to be implanted 
with either the Orsiro SES or the Xience Prime™ EES. Both investigation devices have received 
the CE mark. Implantation of the devices will therefore not bring additional risk to the subjects. 
 
However, the study will put some additional risk to the subjects compared to routine procedures: 
 
 
All subjects will undergo repeat angiography at 9 months. 
 
 
ECG’s will be required at screening and prior to discharge. Clopidogrel will be administered 
for a minimum of 12 months in all subjects unless medically contraindicated. 
 
12.2 Benefits 
In this clinical investigation all subjects will have a more intense medical follow ups then in 
standard practice, which can be beneficial to the long term clinical outcome for the individual. 
 
In addition, two CE marked drug eluting stents will be used which are developed with the latest 
technology of medicine coating.  
General benefits include that data will be used to retrieve more information on the safety and 
efficacy of the Orsiro SES or the Xience Prime™ EES. 
 
13 STUDY TERMINATION 
 
BIOTRONIK will monitor the progression of the clinical investigation. The clinical investigation 

Page 39 of 45 
Clinical Investigational Plan 
 
 
may be suspended or discontinued early if there is an observation of serious adverse e v e n t .  
 
BIOTRONIK may terminate investigator and site participation in the clinical investigation if there is 
evidence of failure to maintain adequate clinical standards, failure to comply with the CIP, fraud or any 
other form of misconduct. In the event of clinical investigation termination or suspension, BIOTRONIK 
will send a report outlining the circumstances to the EC, CA if applicable, and all investigators. A 
suspended or terminated clinical investigation may not be re-initiated without approval of the reviewing EC 
and CA. 
 
 
 
 
14 FEASIBILITY ANALYSIS 
 
14.1 Feasibility analysis of success 
 
The Orsiro Sirolimus Eluting Stent (SES) is based on the design of PRO-Kinetic ENERGY™ 
stent system. The predecessor product, PRO-Kinetic™, has been proven to be both safe and effective 
in the treatment of coronary lesions. The PTCA delivery system of Orsiro and PRO-Kinetic ENERGY 
are nearly identical, based on a fast-exchange PTCA catheter. This product is supposed to be safe 
and efficacious. 
 
14.2 Feasibility analysis of failure 
 
 
The main reasons leading to procedure failure or adverse effects may be related to the following 
factors: 1) procedure proficiency; 2) post-procedure nursing level; 3) uncertainty of the pre-procedure 
disease progression of the patient.  
 
15 FINAL REPORT 
 
 
The clinical trial report should be consistent with the study protocol, which shall be signed and dated 
by the investigators, then be audited, sealed and dated by the clinical trial institution of medical device. The 
final report shall ensure the authenticity and confidentiality of the clinical data. 
 
16 PRINCIPLE OF CONFIDENTIALITY 
 
 
All the ancillary data of this agreement and clinical study are confidential and belong to the sponsor. 
Investigators should take the duty of confidentiality, including patent applications, manufacturing process 
and the unpublished data which the sponsor has provided to the researchers, and shall not disclose to any 
third party unless they get the sponsor’s agreement. The obligation of confidentiality is still effective after 
the termination or closure of the study. 
 
17 PUBLICATION POLICY        
 
The investigator has the right to write a thesis and report about this investigation. However, the 
investigator should notice the sponsor in writing before publishing and should not violate the agreed duty 
of confidentiality. 
 
18 
COMPLIANCE STATMENT 
 
The execution of clinical investigation shall comply with the applicable human clinical trials 
and regulations, especially the followings: 
 
Declaration of Helsinki (Fortaleza 2013 version) 

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Clinical Investigational Plan 
 
 
 
ISO 14155 (2011 version) 
 
ICH/GCP (2002 version) 
 
Related requirements applicable to the country and local 
 
 
 
 
The clinical investigation shall only be implemented when approved by the Ethics 
Committee and relative monitoring organizations. Meanwhile, the investigation must meet any related 
requirements from the EC and monitoring organizations. 
 
19 REFERENCES 
 
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Ref Type: Journal 
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Ref Type: Journal 
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Ref Type: Journal 
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Ref Type: Journal 
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Clinical Investigational Plan 
 
 
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Ref Type: Journal 
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study. EuroIntervention. 2013;8:1006–1011 
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Declaration of investigator: 
I agree that: 
1. Implement the clinical investigation strictly according to the Declaration of Helsinki, Chinese existing 
laws and regulations, and the investigation plan. 
2. Record all the needed data correctly in the CRF, and finish the clinical investigation final report on time. 
3. Only use the investigational product in the clinical investigation. During the process, record and save 
the received and useful information of the investigational product completely and correctly. 
4. Allow the auditor and supervision department authorized or delegated by the sponsor to audit and 
inspect the clinical investigation. 
5. Strictly comply to the clinical investigation contract and terms of relative agreement signed by both 
parties. 
 
I have read all contents of the clinical investigation plan and the above declaration. I agree with all the 
requirements listed above. 
 
Clinical Investigator      Department         Duty                   Title 
Illegible                       Cardiology (5)   Chief Physician      Chief Physician 
Wang Lin                     Cardiology (5)        Illegible              Associate Chief Physician 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Opinion from the EC:  
(seal: illegible) 
                                      Sep 14, 2015 
 
Opinion from the medical institution undertaking the clinical investigation: 
(seal: illegible) 
                                      Sep 24, 2015 
 
Opinion from the implementer: 
(seal: illegible) 
                                      July 3, 2015 
 
 
Appendix – Enterprise Qualification Files