Safety and Effectiveness of Edwards Lifesciences SAPIEN 3 Transcatheter Heart Valve (THV) in the Chinese Population
Phase: NA
Conditions: Aortic Stenosis, Symptomatic Aortic Stenosis, Aortic Regurgitation
Sponsor: Edwards Lifesciences

PROPRIETARY DATA: This document and the information contained herein may not be reproduced, used 
or disclosed without written permission from Edwards Lifesciences LLC 
Safety and Effectiveness of Edwards Lifesciences SAPIEN 3 Transcatheter 
Heart Valve (THV) in the Chinese Population 
NCT03466918 
June 22, 2017 

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Table of Contents 
Information of sponsors ......................................................................................................................... 5 
1.1 
Name of sponsors: ......................................................................................................................... 5 
1.2 
Address of sponsors: ...................................................................................................................... 5 
1.3 
Contact information of sponsors:................................................................................................... 5 
1.4 
Relevant qualification documents of sponsors: ............................................................................. 5 
1.5 
Name, address, contact information, and relevant qualification documents of agents: ................. 5 
List of all clinical trial institutions and investigators for multicenter clinical trials .............................. 5 
Purpose and contents of clinical trials ................................................................................................... 6 
3.1 
Purpose .......................................................................................................................................... 6 
3.2 
Contents ......................................................................................................................................... 6 
Background information of clinical trials .............................................................................................. 7 
Disease Process .......................................................................................................................................... 7 
Alternative Therapies/Techniques .............................................................................................................. 8 
Transcatheter Aortic Valve Implantation (TAVI) ....................................................................................... 8 
Characteristics, structure and composition, operating principle, mechanism of action, and test range 
of product........................................................................................................................................................... 8 
5.1 
Product characteristics ................................................................................................................... 9 
SAPIEN 3 Transcatheter Heart Valve ........................................................................................................ 9 
5.2 
Structure and composition, operating principle, mechanism of action of product ........................ 9 
Commander Delivery System .................................................................................................................. 10 
Expandable Introducer Sheath Set ........................................................................................................... 10 
Edwards Transfemoral Balloon Catheter ................................................................................................. 10 
Loader ...................................................................................................................................................... 10 
Crimper .................................................................................................................................................... 10 
Qualcrimp ................................................................................................................................................ 10 
5.3 
Trial range ..................................................................................................................................... 11 
Indications of products and contraindications, and matters needing attention .................................... 11 
Overall design ...................................................................................................................................... 11 
7.1 
Trial design ................................................................................................................................... 11 
7.1.1 
Trial purpose ................................................................................................................................. 11 
7.1.2 
Selection of test methods and reasons ......................................................................................... 12 
7.1.3 
Measures for reducing and avoiding bias .................................................................................... 12 
7.1.4 
Selection of subjects (including selection of control group if necessary) ................................... 12 
7.1.5 
Patient Screening and Data Collection ........................................................................................ 14 
Screening ................................................................................................................................................. 17 
Baseline .................................................................................................................................................... 17 
Procedure ................................................................................................................................................. 18 
Post-Procedure ......................................................................................................................................... 20 
Discharge Visit ......................................................................................................................................... 20 
Follow-Up Visits ...................................................................................................................................... 21 
30-Day Visit ............................................................................................................................................. 22 
6 Month Visit ........................................................................................................................................... 22 
1 Year Visit ............................................................................................................................................... 22 

 
 
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2-5 Year Annual Follow-up Visit ............................................................................................................. 23 
Missed Visits ............................................................................................................................................ 23 
Standard of Care ...................................................................................................................................... 23 
7.1.6 
Safety and Effectiveness evaluation methods .............................................................................. 24 
7.2 
Test process .................................................................................................................................. 25 
7.2.1 
Test flowchart .............................................................................................................................. 25 
7.2.2 
Specification for use of devices ................................................................................................... 25 
Study Device ........................................................................................................................................... 26 
Storage & Labeling .................................................................................................................................. 26 
Device Accountability ............................................................................................................................. 26 
7.3 
Monitoring Plan ........................................................................................................................... 26 
 
Statistical considerations ..................................................................................................................... 27 
8.1 
Statistical design, method, and analysis procedures .................................................................... 27 
8.2 
Sample Size ................................................................................................................................. 27 
8.3 
Expected expulsion rate ............................................................................................................... 28 
8.4 
Statistical method for all data, together with deficient, unused or fault data (including drop out 
and withdrawal) and method for treating unreasonable data ................................................................... 28 
8.5 
Procedures for reporting deviation from the original statistical plan .......................................... 28 
8.6 
Criteria and reasons for selection of subjects incorporated into analysis .................................... 28 
 
Data Management ................................................................................................................................ 29 
9.1 
Data Collection ............................................................................................................................ 29 
9.2 
Missing Data ................................................................................................................................ 29 
 
Feasibility Analysis ............................................................................................................................. 29 
10.1 
Successful possibility analysis ..................................................................................................... 29 
10.2 
Analysis of the possibility of failure ............................................................................................ 30 
 
Quality control of clinical trials ........................................................................................................... 30 
 
Ethical issues and informed consent for clinical trials ........................................................................ 30 
12.1 
Ethical considerations .................................................................................................................. 30 
12.2 
Examination and approval of clinical trial protocol .................................................................... 30 
12.3 
Informed consent process and text of informed consent ............................................................. 31 
 
Provisions on adverse event and device defect report ......................................................................... 31 
13.1 
Adverse events ............................................................................................................................. 31 
13.2 
Serious Adverse Events ............................................................................................................... 32 
13.3 
Reporting procedure and information of contact ......................................................................... 32 
Source Documents ................................................................................................................................... 32 
Investigator Assessment Responsibilities ................................................................................................ 32 
Sponsor Assessment Responsibilities ...................................................................................................... 32 
Medical Reviewer Responsibilities .......................................................................................................... 33 
Device Deficiency and Vigilance Reporting ........................................................................................... 33 
 
Provisions on deviation from clinical trial protocol and correction of clinical trial protocol .............. 33 
 
Direct access to source data and files .................................................................................................. 34 
Records .................................................................................................................................................... 34 
Record Retention Policy .......................................................................................................................... 34 
 
Finance and insurance ......................................................................................................................... 34 
Clinical Trial Funding .............................................................................................................................. 34 

 
 
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Clinical Trial Insurance ........................................................................................................................... 34 
 
Contents to be covered by clinical trial reports ................................................................................... 35 
 
Principle of medical confidentiality..................................................................................................... 35 
 
Provisions on publication of clinical trial results ................................................................................ 35 
 
Responsibilities of all parties ............................................................................................................... 35 
General Study Organization .................................................................................................................... 35 
Medical Reviewers .................................................................................................................................. 35 
Echocardiography Core Laboratory ........................................................................................................ 35 
Clinical Sites ............................................................................................................................................ 36 
Statement of Investigator ................................................................................................................................. 37 
Appendix A…………………………………………………………………………………Defnitions 
Appendix B………………………………………………………………………………...References 
Appendix C…………………………………………………...……………………..NIH Stroke Scale 
Appendix D……………………………………………….…………………..Modified Rankin Score 
Appendix E……………………………………………………...……………………….Frailty Index 
Appendix F…………………………………………………………...………………………..6MWT 
Appendix G…………………………………………………………………………………….KCCQ 
Appendix H………………………………..……………………………Clinical Trial Report Content 
 
 

 
 
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S-ZJ 
The Second Affiliated 
Hospital of Zhejiang 
University School of 
Medicine 
Jianan 
WANG 
Professor 
 
 
S-HX 
WestChina Hospital, 
Sichuan University 
Mao CHEN 
Professor 
 
 
 
 Purpose and contents of clinical trials  
3.1 
Purpose  
The purpose of this trial is to evaluate the safety and effectiveness of the SAPIEN 3 transcatheter 
heart valve implantation (TAVI) in Chinese patients with symptomatic severe calcific aortic 
stenosis who are considered at high risk for surgical valve replacement. Clinical data will be 
submitted for the purposes of obtaining Chinese regulatory approval.   
3.2 
Contents  
This is a prospective, single-arm, multi-center study to assess the safety and effectiveness of the 
SAPIEN 3 THV.  A minimum of 50 patients (maximum of 60 patients) with symptomatic severe 
calcific aortic stenosis requiring transcatheter aortic valve implantation (TAVI), who are considered 
high risk for surgical valve replacement and who receive a SAPIEN 3 THV.   
Study endpoints include: 
Primary Endpoint 
The primary endpoint is all-cause mortality at 30 days post-index procedure.   
Secondary Endpoints 
Safety Endpoints 
• Cardiovascular and non-cardiovascular mortality at 72 hours (peri-procedural) and 30 days 
• Stroke at 30 days 
• TIA at 30 days 
• All-cause mortality & disabling stroke at 30 days 
• Vascular complications (major) at 30 days 
• Bleeding complications (life threatening or disabling, and major) at 30 days 
• Myocardial infarction at 30 days 
• Acute kidney injury at 30 days (stages II and III) 
• Coronary obstruction requiring intervention at 30 days 
• Arrhythmia and conduction disturbance at 30 days 
• Permanent pacemaker implantation at 30 days 
• 
Valve-related dysfunction requiring repeat procedure (BAV, TAVI or SAVR) at 30 days 

 
 
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• Mitral valve apparatus damage or dysfunction at 30 days 
• Unplanned use of cardiopulmonary bypass (CPB) during TAVI implant procedure 
• Pericardial tamponade at 30 days 
• Endocarditis at 30 days 
• Valve thrombosis at 30 days 
• Valve malposition (migration, embolization, and ectopic deployment) at 30 days 
• Ventricular septal perforation at 30 days 
 
Device and Procedure Success Composite 
• Absence of procedural mortality AND 
• Correct positioning of a single prosthetic heart valve into the proper anatomic location AND 
• Intended performance of the prosthetic heart valve (no prosthesis-patient mismatch and mean 
aortic valve gradient <20mmHg or peak velocity <3m/s, AND no moderate or severe 
prosthetic valve regurgitation) at 30 Days 
Efficacy 
• New York Heart Association (NYHA) Classification at 30 days 
• Hemodynamic valve performance evaluation by echocardiography for aortic valve stenosis 
and aortic valve regurgitation (paravalvular & central) at 30 Days as determined by Echo core 
lab 
Quality of Life  
• 
KCCQ at 30 days 
 Background information of clinical trials  
Prolonged average life expectancy has resulted in an aging population and consequently, an increase 
in the number of patients with acquired, calcific, severe, symptomatic aortic stenosis (AS). The 
standard of care therapy for patients suffering from severe AS is aortic valve replacement surgery 
(AVR). In the aged population, many patients are too sick to be operated or have co-morbidities that 
preclude the option for surgery [1]. 
AS is a progressive, debilitating and life-threatening disease if left untreated. Affected individuals 
are typically > 65 years of age. The pathology involves progressive calcification of the leaflet 
bodies which limits normal cusp opening during systole. Cellular aging and degeneration have been 
implicated in this form of the disease and diabetes mellitus and hypercholesterolemia are risk 
factors. 
Disease Process 
The pathophysiology of AS includes an increase in afterload, progressive hypertrophy of the left 
ventricle, and a decrease in systemic and coronary blood flow as consequences of valve obstruction. 
Typically, patients with AS are free from cardiovascular symptoms (e.g. angina, syncope and/or 
heart failure) until late in the course of the disease. However, once symptoms manifest, the 
prognosis is poor, especially when associated with congestive heart failure. 

 
 
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Death in general, including sudden death, occurs primarily in symptomatic patients. Survival 
analyses have demonstrated that the interval from onset of symptoms to time of death is 
approximately two years in patients with heart failure, three years in those with syncope, and five 
years in those with angina [2]. Among symptomatic patients with moderate-to-severe AS treated 
medically, mortality rates after the onset of symptoms were approximately 25% at 1 year and 50% 
at 2 years and more than 50% of deaths were sudden [3]. 
Grading the severity of AS is based on a variety of hemodynamic and natural history data.  
According to the ACC/AHA guideline authors, AS is best described as a continuum. In patients with 
moderate-to-severe AS, valve area may decline up to 0.3 cm2 per year and the systolic pressure 
gradient across the valve can increase by as much as 15-19 mmHg per year, with a higher rate of 
progression observed in elderly patients with coronary artery disease 
(CAD) and chronic renal insufficiency [4]. Relief of aortic valve obstruction typically results in an 
improvement of symptoms, hemodynamic parameters, and global left ventricle systolic function, as 
well as reversal of left ventricular hypertrophy [4,5]. 
Alternative Therapies/Techniques 
Treatment options for patients suffering from symptomatic aortic stenosis, prior to the introduction 
of transcatheter aortic valve implant (TAVI), included palliation of symptoms without valve 
replacement (non-surgical standard therapy), or surgical aortic valve replacement (AVR). Treatment 
options were determined by patient risk for morbidity or mortality after surgery and patient choice. 
Non-surgical treatment options, including balloon aortic valvuloplasty, did not provide sustained 
hemodynamic improvement and have led to poor quality of life and shortened life expectancies [5-
7]. Patients considered poor candidates for AVR typically present with significant multiple 
morbidities or anatomical limitations [8].  
Patient frailty may also contribute to the decision to forego surgery. Surgical AVR has demonstrated 
excellent long term outcomes for patients with aortic valve stenosis, even in high risk populations 
(STS PROM > 10) [5-7, 9-11].  
Transcatheter Aortic Valve Implantation (TAVI) 
Transcatheter aortic valve implantation (TAVI) was first performed in man in 2002 [12], followed 
by clinical trials and approval for commercialization in Europe in 2007 [13, 14]. It is currently 
estimated that approximately 300,000 patients have undergone TAVI worldwide. The Edwards THV 
global clinical research program includes more than 30,000 patients enrolled in 18 clinical studies 
that include first-in-man, feasibility, and pivotal studies as well as randomized controlled trials and 
post market registries. Results and outcomes from these trials have been publically reported at 
medical congresses and in peer-reviewed scientific journals [15-22]. The randomized PARTNER I 
Trial produced the most conclusive evidence of safety and effectiveness of the Edwards SAPIEN 
THV in high surgical risk (Cohort A) and inoperable (Cohort B) patients with severe, symptomatic 
aortic stenosis [23,24]. The PARTNER II trial demonstrated safety and effectiveness of the second 
and third generation valves, the SAPIEN XT THV and SAPIEN 3, respectively, in intermediate risk, 
high risk and inoperable patients [25,26]. 
 Characteristics, structure and composition, operating principle, mechanism of action, and 
test range of product  

 
 
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Edwards 
Expandable 
Introducer Sheath 
Set (“eSheath”) 
9610ES14 
9610ES14 
9610ES14 
9610ES16 
Edwards 
Transfemoral 
Balloon Catheter 
9350BC16 
9350BC20 
9350BC23 
9350BC25 
Crimper 
9600CR 
9600CR 
9600CR 
9600CR 
Inflation Devices (x2) 
96402 
96402 
96402 
96406 
1Includes a Loader, Qualcrimp Crimping Accessory, and 2-piece Crimp Stopper 
 
Commander Delivery System 
The Edwards Commander Delivery System consists of a balloon catheter for deployment of the 
THV and a Flex Catheter to aid in valve alignment to the balloon, tracking and positioning of the 
THV. The delivery system includes a tapered tip to facilitate crossing of the aortic valve. The handle 
contains a FlexWheel to control flexing of the Flex Catheter, and a Balloon Lock and Fine 
Adjustment Wheel to facilitate valve alignment and positioning of the valve within the aortic 
annulus. A stylet is included within the guidewire lumen of the delivery system. The Balloon 
Catheter has radiopaque Valve Alignment Markers defining the working length of the balloon. A 
radiopaque Center Marker in the balloon is provided to help with valve positioning. A radiopaque 
Triple Marker proximal to the balloon indicates the Flex Catheter position during deployment.  
Expandable Introducer Sheath Set 
The Edwards eSheath Introducer Set is intended for introduction of interventional devices in the 
vascular system.  The product is intended for use by physicians trained and experienced in 
interventional techniques.  Standard techniques for placement of vascular access sheaths should be 
employed.   
Edwards Transfemoral Balloon Catheter 
The balloon catheter is indicated for dilation of stenotic native aortic valve leaflets. 
Loader 
The loader (packaged with the Edwards Commander delivery system) is used to aid insertion of the 
delivery system into the sheath, and may be removed to utilize the full working length of the 
inserted device 
Crimper 
The crimper reduces the diameter of the THV to mount it to the delivery system. The crimper is 
comprised of a compression mechanism that is closed with a handle located on the housing. The 
crimper is used with a 2-piece crimp stopper (packaged with the delivery system) to correctly crimp 
the THV.  
Qualcrimp 

 
 
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7.1.2 Selection of test methods and reasons  
This is a prospective, single-arm, multi-center study to assess the safety and effectiveness of the 
SAPIEN 3 THV.  Up to 60 patients will be enrolled and implanted with the device at four sites in 
China over an estimated six-month enrolment period with a follow-up period to 5 years.  The 
study is expected to last 5.5 years.   
An Echocardiography Core Lab will be established for standardizing echocardiographic secondary 
endpoints.  A Medical Reviewer will review all endpoint-related adverse events. 
7.1.3 Measures for reducing and avoiding bias  
An independent Echocardiography Core Lab will be established for standardizing echocardiographic 
secondary endpoints.  A Medical Reviewer will review all endpoint-related adverse events 
independently. 
7.1.4 Selection of subjects (including selection of control group if necessary) 
To ensure that a minimum of 50 patients are implanted with the SAPIEN 3 THV and complete the 
30 Day follow-up for Primary Endpoint, up to 60 patients will be enrolled and implanted with 
SAPIEN 3 THV.  Each site may not contribute more than 25 implanted patients to the study 
population.  All patients will be followed for 5 years. 
Enrolment will be closely monitored to ensure not more than 60 patients are implanted with 
SAPIEN 3 THV. 
7.1.4.1 Inclusion Criteria 
Patients must meet all of the Inclusion Criteria in order to participate in the study 
1. 
Subjects who are considered to be operable and high risk for surgical valve replacement: 
STS Score ≥ 8 and ≤ 15 or Logistic EuroSCORE ≥ 15 and ≤ 40.  If STS Score is below 
8 and Logistic EuroSCORE is below 15, patients should have other clinical or 
anatomical risk factors that would be considered high risk for surgery and documented 
by the heart team 
2. 
Severe symptomatic calcific aortic stenosis requiring aortic valve replacement 
characterized by one or more of the following within 60 days prior to the index 
procedure: AVA < 0.8 cm2, Indexed AVA <0.5 cm2/m2, mean gradient > 40mmHg, or 
peak aortic jet velocity > 4.0m/sec. 
3. 
NYHA Functional Class II or greater.  
4. 
The study patient or the study patient’s legal representative has been informed of the 
nature of the study, agrees to its provisions and has provided written informed consent 
as approved by the EC of the respective clinical site.  
5. 
The study patient agrees to comply with all required post-procedure follow-up visits. 
6. 
Native aortic valve annulus area between 273 mm2 - 683 mm2 as measured by CT.  
7. 
Native aortic annulus diameter between 18.6 mm – 29.5 mm as measured by CT. 
7.1.4.2 Exclusion Criteria 
Patients must not meet any of the Exclusion Criteria in order participate in the study 

 
 
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1. Evidence of an acute myocardial infarction ≤ 1 month (30 days) before the intended 
treatment [(defined as: Q wave MI, or non-Q wave MI with total CK elevation of CK-MB 
≥ twice normal in the presence of MB elevation and/or troponin level elevation (WHO 
definition)]. 
2. Aortic valve is a congenital unicuspid or is non-calcified. 
3. Aortic valve is bicuspid and the patient is less than 60 years old, or the aortic valve is 
bicuspid with no raphe (Sievers classification type 0) 
4. Anomalous coronary artery that would interfere with proper placement of the valve. 
5. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic 
regurgitation >3+). 
6. Pre-existing mechanical or bioprosthetic valve in any position.  
7. Any therapeutic invasive cardiac procedure resulting in a permanent implant that is 
performed within 30 days of the index procedure.  Implantation of a permanent 
pacemaker or ICD is not considered exclusion criteria. 
8. Any patient with a balloon valvuloplasty (BAV) within 30 days of the procedure (unless 
BAV is a bridge to procedure after a qualifying echocardiogram). 
9. Leukopenia (WBC < 3000 cell/mL), acute anemia (Hgb < 9 g/dL), Thrombocytopenia (Plt 
< 50,000 cell/mL).  
10. Renal insufficiency (creatinine > 3.0 mg/dL) and/or renal replacement therapy at the time 
of screening. 
11. Untreated clinically significant coronary artery disease requiring revascularization. 
12. Emergency interventional/surgical procedures within one month (30 days) prior to the 
TAVI procedure.  
13. Hypertrophic cardiomyopathy (HCM with myocardium more than 1.5cm without an 
identifiable cause) with or without obstruction (HOCM). 
14. Severe ventricular dysfunction with LVEF < 20%. 
15. Echocardiographic evidence of intracardiac mass, thrombus or vegetation. 
16. Active upper GI bleeding within 3 months (90 days) prior to procedure.  
17. A known contraindication or hypersensitivity to all anticoagulation regimens, or inability 
to be anticoagulated for the study procedure. 
18. Stroke or transient ischemic attack (TIA) within 3 months (90 days) of the procedure. 
19. Estimated life expectancy < 12 months (365 days) due to carcinomas, chronic liver disease, 
chronic renal disease or chronic end stage pulmonary disease. 
20. Significant aortic disease, including marked tortuosity (hyperacute bend), aortic arch 
atheroma [especially if thick (> 5 mm), protruding or ulcerated] or narrowing (especially 
with calcification and surface irregularities) of the abdominal or thoracic aorta, severe 
“unfolding” and tortuosity of the thoracic aorta. 
21. Iliofemoral vessel characteristics that would preclude safe placement of the introducer 
sheath. 
22. Currently participating in an investigational drug or another device study.  Note: Trials 
requiring extended follow-up for products that were investigational, but have since become 
commercially available, are not considered investigational trials. 
23. Active bacterial endocarditis within 6 months (180 days) of procedure, with our without 
treatment. 

 
 
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7.1.4.3 Standard and procedures for stopping tests/trial treatment 
The Sponsor has the right to discontinue a site or terminate the trial for the following reasons: 
• The Sponsor may terminate the study for safety reasons 
• A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product for any reason 
• The Sponsor may decide to close a study site when the Investigator fails to enroll patients 
during the enrolment period 
• Failure of the Investigator to comply with pertinent regulations of appropriate regulatory 
authorities 
• Insufficient adherence to protocol requirements 
• Submission of knowingly false information from the research facility to the Sponsor, the 
Sponsor’s representatives or appropriate regulatory authorities 
If the study is terminated early, all specified follow-up data on subjects enrolled prior to termination 
will be collected and reported 
7.1.4.4 Enrollment period and study duration 
Up to 60 patients will be enrolled and implanted with the device at four sites in China over an 
estimated six month enrolment period with a follow-up period to 5 years. The study is expected to 
last 5.5 years 
7.1.5 Patient Screening and Data Collection 
7.1.5.1 
Patient Screening and Enrolment 
The study site shall have a committed Heart Team involved in the screening process. The 
Heart Team will include at least two cardiac surgeon, one interventional cardiologist, one radiologist, and one 
anesthesiologist but could also include (without being limited to) the following specialties: 
• Echocardiography 
• Gerontology 
The screening of patients in cardiovascular and cardiac surgery departments will be conducted by one or more 
delegated study team members. The study team will be responsible for ensuring and reporting study patient 
screening for study eligibility. Cumulative screening and enrollment logs will be maintained by study sites. 
Reasons for screen failures will be documented in study logs. 
To accommodate the implant procedure learning curve, a roll-in strategy will be available.  Each study site 
will be allowed up to two roll-in patients.  Edwards Lifesciences will document if the patient is a roll-in 
patient before the implant procedure begins. Roll-in patients will complete all study visits and procedures, and 
not be counted toward the 60 implanted patients. 
In addition, the Heart Team will be required to assess all patients for study inclusion to ensure compliance to 
surgical risk criteria, screening procedures to assess valve size and delivery method, and other 
inclusion/exclusion criteria.  After heart team identifies a patient, the Sponsor will review and confirm 
eligibility during the case review process.  
All patients who sign a study informed consent will be entered into the database.  Subjects will be included 

 
 
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6Transesophogeal Echocardiogram (TEE) may be used if TTE is not available 
7For patients with abnormal findings related to valve integrity and position and patients with Adverse Events related to worsening valve 
function. 
Screening 
The following screening data will be collected for all study patients to assess eligibility as per 
standard of care: 
• Operability Risk Assessment 
• Medical history, pertinent physical examination [include blood pressure, height, weight and 
all major systems findings] 
• NYHA functional classification 
• CSS Angina classification 
• Risk assessment (STS Risk Score, Logistic EuroSCORE, and EuroSCORE II) 
• Non-Invasive Studies (must be completed within 60 days before procedure date) 
• Comprehensive transthoracic echocardiogram (TTE) (transesophageal echocardiogram 
(TEE) may be used as an alternative) 
Invasive Studies (must be completed before the procedure date) 
• Cardiac and abdominal CT angiogram of high quality with complete visualization to 
complete measurements of the aortic valve, aortic arch, both iliac and femoral arteries to the 
aorta.  In the situation where patients have compromised renal function that precludes the 
use of contrast agents, MR imaging may be used as an alternative to CT (≤180 days before 
procedure) 
• Left heart catheterization to assess the severity of aortic stenosis and severity of coronary 
artery disease (≤180 days before procedure) 
If any assessments need to be completed or repeated outside of standard of care, a patient will need 
to sign a Patient Informed Consent prior to completing assessments. 
Baseline 
Assessments and laboratory tests are required to be completed within 30 days prior to the procedure 
date.  Assessments and laboratory tests completed outside of the 30 days will need to be repeated.  
If completed outside of standard of care, then a Patient Informed Consent Form will need to be 
signed first. 
The following Baseline data will be collected for all study patients prior to procedure: 
• Current cardiac medications and all medications given for cardiovascular effect; 
• Neurological assessment  
o National Institutes of Health Stroke Scale (NIHSS) (Appendix C) 
o Modified Rankin Scale (mRS) (Appendix D) 
• Frailty Assessment (Appendix E) 

 
 
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• Six Minute Walk Test (Appendix F) 
• Kansas City Cardiomyopathy Questionnaire (KCCQ) (Appendix G) 
• Clinical Laboratory Tests 
o Blood count (hemoglobin, hematocrit, platelet count, white blood cells) 
o PTT or PT/INR 
o CK/CK-MB and/or Troponins 
o Creatinine 
o Liver Panel (ALT, AST) 
o Albumin 
• Non-invasive studies 
o 12-Lead ECG 
o Chest x-ray 
Procedure 
Transfemoral access technique will be used by the investigator in his/her normal practice of 
interventional cardiology and patient selection process. 
Recommended Antiplatelet/Anticoagulation Regimen  
Table 4 outlines the recommended antiplatelet regimen.  The categories were developed by The 
PARTNER II Trial Patient and Procedure Management Steering Committee. There are no current 
validated guidelines in this specific study population, however, the literature was surveyed and used 
as guidance for the following proposed guidelines. It is expected that specific agents and dosing 
regimens may vary from site to site. Patients will be assessed by the heart team for Category of 
Stroke Risk prior to prescribing treatment regimen. The Category and specific treatment regimen 
will be documented in the discharge case report form. Committee Categories are based on CHADS 
2 score for stroke risk [27]. 
NOTE: The CHADS 2 score only applies to patients in atrial fibrillation (AF) and has not been 
validated in non-AF patient populations; therefore the CHADS 2 score reference was used as one 
among many guidelines to establish the risk stratification for intensity of anticoagulation regimen. 
 Summary of Recommended Antiplatelet/Anticoagulation Therapy 
Pre procedure 
Aspirin 75-100 mg once daily 
• Patients with bare metal stent (BMS) within one month or 
drug eluting stent (DES) within 12 months should be 
continued on Clopidogrel/Prasugrel prior to their procedure 
• Patients in atrial fibrillation on warfarin should be bridged 
with LMW or UF heparin prior to the procedure 
• Patients with persistent or paroxysmal atrial fibrillation, not 
on anticoagulation, will not be required to have a TEE to 
rule out LA thrombus prior to procedure.  If intra-
procedural TEE during TAVI reveals thrombus, procedure 
will be aborted and delayed until patient has been on 

 
 
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warfarin or dabigatran for 30 days.   
• In patients under concomitant TAVI/PCI, Clopidogrel 
loading with either 300mg or 600mg prior to the procedure 
is recommended in addition to ASA:  
Intra procedure 
Heparin will be given to  achieve/ maintain ACT>250 sec. 
Post procedure 
 
Category I  for Stroke 
Risk 
No atrial fibrillation, 
No recent stents 
• ASA 75mg once daily 
• Clopidogrel 300mg load within 6 hours of procedure (either 
pre or post) 
• Clopidogrel 75mg once daily  for at least one month post 
procedure 
 
Category II for Stroke 
Risk 
No atrial fibrillation, 
recent stents 
• ASA 75mg once daily 
• Clopidogrel 75mg once daily should be continued prior to 
the procedure and after the procedure without interruption 
for at least one month after BMS and 12 months after DES 
Category III for Stroke 
Risk 
Atrial fibrillation, no 
recent stents 
 
• ASA 75mg once daily 
• Patients should be started on warfarin or dabigatran 24 
hours post TAVI if clinically safe and this should be 
continued for at least one month or indefinitely if possible.  
If clinically safe, patients started on warfarin should be 
bridged with unfractionated or low molecular weight 
heparin until INR therapeutic. 
• If patients are not a candidate for warfarin or dabigatran, 
Clopidogrel 75mg once daily can be considered as an 
alternative 
Category IV for Stroke 
Risk  
Atrial fibrillation, 
recent stents 
• ASA 75mg once daily 
• Clopidogrel 75mg once daily for at least one month post 
BMS or 12 months post DES 
• Patients should be started on warfarin or dabigatran 24 
hours post TAVI if clinically safe and continued 
indefinitely.  If clinically safe, patient’s being started on 
warfarin should be bridged with UF or LMW heparin until 
INR therapeutic. 
Note: Any changes to anticoagulation regimen from study visit to study visit will be noted on the 
CRF including reason for change. 
Antibiotic Prophylaxis 
Study subjects should be treated prophylactically with antibiotics for endocarditis per the 
recommendations of the American Heart Association [28]. 

 
 
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Procedure Assessments 
Procedural information, findings, results, and SAPIEN 3 delivery system and device identification 
will be recorded on the Case Report Form and are listed below: 
• Duration of the procedure, defined as the time from skin incision to access closure; 
• All cardiac medications and all medications given for cardiovascular effect; 
• A supra-aortic angiogram or TEE to assess valve performance and coronary patency 
• Fluoroscopic imaging of implanted valve to assess acute deployment (e.g. proper annular 
placement, fully vs. under deployed, circularity/ovality) 
• Contrast media quantity 
• Total fluoroscopy time and dose 
• Adverse Events 
Subjects will be continuously monitored clinically, hemodynamically, and electrocardiographically 
during the index procedure for all local and systemic side-effects. 
It is recommended subjects are monitored in the operating room for at least 15 minutes after 
completion of the procedure, with special attention to hemodynamic condition and cardiac rhythm. 
The sheaths may be removed when ACTs reach <150 sec after implantation of the study valve (for 
non-surgical closures). 
Post-Procedure 
Post-procedure clinical evaluations should be performed within 48 hours of the index procedure.  
Specific assessments include the following: 
• Current cardiac medications and all medications given for cardiovascular effect 
• Adverse events 
• Neurological assessment 
o NIHSS 
o mRS  
• Clinical Laboratory Test 
o Blood count (hemoglobin, hematocrit, platelet count, white blood cells) 
o PTT or PT/INR 
o CK/CK-MB and/or Troponins 
o Creatinine 
• 12-Lead ECG 
Discharge Visit 
The following data will be collected for all study patients before discharge from the index 
hospitalization.  If patient is discharged over a weekend, the discharge tests may be completed on 
the last weekday prior to discharge.  For patients that are discharged within the 48 hours of exiting 
the cath lab / operating room, it is not required to repeat tests collected during the Post Procedure 
period that are also required for the Discharge visit. 

 
 
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valve is explanted, the patient needs to be followed up until resolution of any AE for safety 
purposes. These patients should then be exited from the study. 
30-Day Visit 
All patients will undergo the following assessments within the 30-Day follow-up period +14 days): 
• Pertinent physical examination [include blood pressure, weight and all major systems 
findings] 
• Adverse events 
• Current cardiac medications and all medications given for cardiovascular effect 
• NYHA functional classification 
• CSS Angina Classification 
• Neurological assessments 
o NIHSS 
o mRS  
• 6 Minute Walk Test (6MWT) 
• KCCQ 
• Clinical Laboratory Test 
o Blood count (hemoglobin, hematocrit, platelet count, white blood cells) 
o Creatinine 
o CK/CK-MB and/or troponins 
o Albumin 
• 12-Lead ECG 
• Comprehensive TTE.  If not adequate, a TEE will be performed 
For patients with abnormal findings related to valve integrity and position and patients with adverse 
events related to worsening valve function, fluoroscopic imaging of the implanted valve will be 
completed.   
6 Month Visit 
All patients will undergo the following assessments within the 6 Month follow-up period: 
• Adverse events 
• Current cardiac medications and all medications given for cardiovascular effect 
The 6 month visit may be completed via a telephone conversation with a delegated study team 
member.  The telephone call must be documented in the patient’s study records.  
1 Year Visit 
All patients will undergo the following assessments within the 12 Month follow-up period: 
• Pertinent physical examination [include blood pressure, weight and all major systems 
findings] 
• Adverse events 

 
 
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• Current cardiac medications and all medications given for cardiovascular effect 
• NYHA functional classification 
• CSS Angina Classification 
• 12-Lead ECG 
• Comprehensive TTE.  If not adequate, a TEE will be performed 
For patients with abnormal findings related to valve integrity and position and patients with adverse 
events related to worsening valve function, fluoroscopic imaging of the implanted valve will be 
completed. 
2-5 Year Annual Follow-up Visit 
All patients will undergo the following assessments within the 2-5 Year annual follow-up period: 
• Pertinent physical examination [include blood pressure, weight and all major systems 
findings] 
• Adverse events 
• Current cardiac medications and all medications given for cardiovascular effect 
• NYHA functional classification 
• CSS Angina Classification 
• Comprehensive TTE.  If not adequate, a TEE will be performed 
For patients with abnormal findings related to valve integrity and position and patients with adverse 
events related to worsening valve function, fluoroscopic imaging of the implanted valve will be 
completed. 
Missed Visits 
Every patient should be encouraged to remain in the study until they have completed the protocol-
required follow-up period. If the patient discontinues prematurely from the study, the reason for 
discontinuation must be documented on the appropriate case report form (CRF). Possible reasons 
for premature discontinuation may include, but are not limited to the following: 
• Withdrawal of consent: Patient decides to withdraw from the study. If a subject withdraws 
from the clinical investigation, the reason(s) should be recorded. If such withdrawal is due to 
problems related to the investigational device safety or performance, the investigator shall 
ask for the subject’s permission to follow his/her status/condition outside the investigation. 
• Lost to follow-up: All patients should be encouraged to return to the clinic for evaluation 
during follow-up (excluding 6 Month telephone visit).  If a patient is unable to return to the 
clinic, 3 separate telephone calls should be made to attempt to bring the patient back into the 
clinic or obtain safety information. All attempts should be documented in the source 
documents. If the patient does not respond to the 3 telephone calls then the Investigator 
should send a certified letter to the subject.  
Standard of Care 
All enrolled patients will receive the standard of care during the clinical trial as well as following 

 
 
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the conclusion of their participation.  Any patients with symptoms of valve failure at any time 
throughout the study duration should undergo standard diagnostic imaging (e.g. (TTE)) to assess 
valve function. Each patient will be provided with an implant card. This implant card can be carried 
by the patient to be shown to any clinician to inform a treating physician of the implanted SAPIEN 
3 THV. Subjects that are enrolled, but not treated with the SAPIEN 3 THV will likely be screened 
for alternative treatments (when available) or continue with the care they have been receiving to 
date. 
7.1.6 Safety and Effectiveness evaluation methods 
Primary Endpoint 
The primary endpoint is all-cause mortality at 30 days post-index procedure.   
Secondary Endpoints 
Safety Endpoints 
• 
Cardiovascular and non-cardiovascular mortality at 72 hours (peri-procedural) and 30 days 
• 
Stroke at 30 days 
• 
TIA at 30 days 
• 
All-cause mortality & disabling stroke at 30 days 
• 
Vascular complications (major) at 30 days 
• 
Bleeding complications (life threatening or disabling, and major) at 30 days 
• 
Myocardial infarction at 30 days 
• 
Acute kidney injury at 30 days (stages II and III) 
• 
Coronary obstruction requiring intervention at 30 days 
• 
Arrhythmia and conduction disturbance at 30 days 
• 
Permanent pacemaker implantation at 30 days 
• 
Valve-related dysfunction requiring repeat procedure (BAV, TAVI or SAVR) at 30 days 
• 
Mitral valve apparatus damage or dysfunction at 30 days 
• 
Unplanned use of cardiopulmonary bypass (CPB) during TAVI implant procedure 
• 
Pericardial tamponade at 30 days 
• 
Endocarditis at 30 days 
• 
Valve thrombosis at 30 days 
• 
Valve malposition (migration, embolization, and ectopic deployment) at 30 days 
• 
Ventricular septal perforation at 30 days 
Device and Procedure Success Composite 
• 
Absence of procedural mortality AND 
• 
Correct positioning of a single prosthetic heart valve into the proper anatomic location AND 
• 
Intended performance of the prosthetic heart valve (no prosthesis-patient mismatch and mean aortic 
valve gradient <20mmHg or peak velocity <3m/s, AND no moderate or severe prosthetic valve 
regurgitation) at 30 Days 
Efficacy 
• 
New York Heart Association (NYHA) Classification at 30 days 
• 
Hemodynamic valve performance evaluation by echocardiography for aortic valve stenosis and aortic 
valve regurgitation (paravalvular & central) at 30 Days as determined by Echo core lab 

 
 
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Study Device 
The SAPIEN 3 and its delivery components will have a unique product identifier.  This 
information will be recorded in the study subject’s medical file.  The Instructions for Use for the 
SAPIEN 3 THV System are provided with the device.  
Storage & Labeling 
The SAPIEN 3 THV System is to be stored as specified on the unit labels.  All investigational 
stock will be stored in a secure and controlled area. 
Device Accountability 
The Investigator shall maintain accurate records of the receipt and disposition of the investigational 
devices. A device disposition log supplied by Edwards will be used to record device receipt, uses, 
discards, or returns. Device disposition will be verified by the Sponsor periodically throughout the 
study. All unused devices shall return to Edwards, along with the completed device disposition log 
at completion of the enrolment period. The Investigator’s copy of the device disposition log must 
document the devices used in study subjects as well as unused devices that are returned to Edwards. 
Use of the SAPIEN 3 THV System is prohibited outside of this protocol. 
7.3 
Monitoring Plan 
Edwards Lifesciences will contract with a Contract Research Organization (CRO) to provide a 
Clinical Research Associate(s) (CRA) to monitor the study sites to ensure that all investigators are 
in compliance with the protocol and the Investigator’s Agreement, and that all study subjects have 
been properly consented with the current version of the informed consent document. Edwards 
Lifesciences will evaluate circumstances where an investigator deviates from the clinical protocol 
and will retain the right to remove either the investigator or the investigational site from the study. 
Routine on-site monitoring visits shall include verification of the following: 
• Compliance with the protocol, any subsequent amendment(s), GCP and maintenance of 
regulatory and EC requirements.  Deviations shall be discussed with the Investigator(s) or 
delegated personnel, documented and reported 
• Only authorized and delegated individuals are participating in the study 
• The SAPIEN 3 THV System is being used according to the protocol and IFU 
• Study Site resources, equipment and study personnel, remain adequate throughout the 
duration of the study 
• Patient Informed Consent is completed in accordance to the protocol and regulations 
• Only Patient Informed Consents Forms approved by the EC are used appropriately 
• Source documents and other clinical records are accurate, complete up to date, stored and 
maintained properly 
• CRFs and queries are complete, recorded in a timely manner, and consistent with source 
documents  
• All adverse events and device deficiencies are reported to Edwards without unjustified delay 
• All serious adverse events and deviations are reported to the EC, if required 

 
 
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• All other required reports, notifications, applications, submissions and correspondence are 
maintained in the investigator's files and are accurate, complete, timely, legible, dated and 
identify the clinical investigation 
• Current laboratory normal values, laboratory certifications, accreditations, or other 
validations are present in the investigator's file 
• Subject withdrawal has been documented; the monitor shall discuss this with the principal 
investigator or his/her authorized designee 
• Subject non-compliance with the requirements stated in the informed consent has been 
documented; the monitor shall discuss this with the principal investigator or his/her 
authorized designee 
• Suitability of the attempts to contact lost to follow-up patients and any intermediaries 
• The principal investigator and investigation site team are informed and knowledgeable of all 
relevant document updates concerning the clinical investigation 
• Any corrective and preventive actions, as needed, have been implemented and are effective. 
Monitors shall be appropriately qualified per the following requirements: 
• Qualified in the field of the applicable regulations and GCP through training and experience 
as well as scientific or clinical knowledge; 
• Knowledgeable on the use of the investigational device(s) and relevant requirements, 
protocol and informed consent process; 
• All monitoring activities shall be documented in a written report. The frequency of 
monitoring visits will depend on enrollment and center compliance, but each center will at 
least be visited once per year. Further details are laid out in the monitoring plan. 
Edwards Lifesciences will review significant new information, including unanticipated adverse 
events and ensure that such information is provided to the study investigators and to all reviewing 
ECs and regulatory agencies as necessary.  Efforts will be made to ensure that data collection 
compliance is monitored and communicated to the Investigators in a timely manner throughout the 
trial. 
 Statistical considerations  
8.1 
Statistical design, method, and analysis procedures  
The clinical study is a single-arm prospective study intended to demonstrate the safety and 
performance of the SAPIEN 3 THV in the Chinese population. 
8.2 
Sample Size 
The sample size of 50-60 patients is determined per Chinese regulatory requirements and agreement 
for a regional study of a medical device already approved in other regions based on a well-designed 
prospective study. 
8.2.1.1 Minimum and maximum number of subjects for each clinical trial institution and reasons 
To ensure that a minimum of 50 patients are implanted with the SAPIEN 3 THV and complete the 
30 Day follow-up for Primary Endpoint, up to 60 patients will be enrolled and implanted with 

 
 
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SAPIEN 3 THV. Each site may not contribute more than 25 implanted patients to the study 
population. 
8.3 
Expected expulsion rate 
The Chinese regulatory requirements determine 50 patients should meet the primary endpoint.  If a 
minimum of 50 patients complete 30 Day visit and upto 60 patients have the procedure, the expected 
drop-out rate is <17%. 
8.4 
Statistical method for all data, together with deficient, unused or fault data (including drop out 
and withdrawal) and method for treating unreasonable data  
The primary and secondary endpoints will be reported based on the AT Population. Descriptive and 
summary statistical analysis will be performed on all endpoints. Patient listings for adverse events, 
deaths, and reinterventions will include all enrolled patients.  
All clinically relevant baseline and follow-up variables will be tabulated. Descriptive statistics for 
continuous variables include mean, standard deviation, sample size, median, minimum, and 
maximum) and frequency tables or proportions for discrete variables. 
Kaplan Meier estimates will be performed at the pre-specified follow-up times to project the 
estimates for time-related endpoints such as the 30-day mortality rate, the primary endpoint; the 
standard error and confidence limits will be computed using Greenwood’s algorithm. Based on 50 
patients as point estimate and length of estimate on the primary endpoint, the 30 days death rate and 
95% confidence interval will be summarized. 
Echocardiographic data will be analyzed by an Echo core laboratory with respect to the degree of 
total aortic valve regurgitation (TVR) and paravalvular aortic valve regurgitation (PAR) according 
to the VARC-2 definitions [29]. 
These data and other categorical data (e.g., NYHA class) will also be presented as shift from 
baseline for each of the pre-specified follow-up periods. 
8.5 
Procedures for reporting deviation from the original statistical plan 
More detailed information regarding the statistical methods and analysis will be presented in the 
Statistical Analysis Plan (SAP). Statistical method changes and/or deviation from the original 
statistical analyses plan will be documented in the section of amendment of the versioned SAP 
which requires re-approval before the performance of analyses and to be included in the final study 
report.  
8.6 
Criteria and reasons for selection of subjects incorporated into analysis  
All patients documented as part of the roll-in patient strategy will not be included in analysis 
population and will be evaluated separately.  
Analysis Sets 
• As Treated (AT) Population: all patients that were enrolled in the trial for whom the 
SAPIEN 3 valve implant procedure was begun, defined as the time in which the first 
Edwards’ investigational device is inserted into the patient. 

 
 
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• Valve Implant (VI) Population: all AT patient who received and retained the SAPIEN 3 
valve upon leaving the procedure room 
 Data Management 
9.1 
Data Collection 
Data will be captured and managed through an electronic data capture (EDC) system. Passwords will be issued 
to appropriate data management personnel to ensure confidentiality and protection of the data by allowing 
variable levels of access to the computer system. 
Electronic CRFs (eCRFs) will be used to collect all patient data during the trial. eCRFs must be 
fully completed for each patient, and signed electronically by the investigator and/or designee. 
The investigator, or an individual designated by him/her, is responsible for recording all data from 
the trial onto the eCRFs on a dedicated website. The investigator is required to provide an electronic 
signature on the appropriate eCRF pages to verify that he/she has reviewed the recorded data. 
Completed eCRFs will be reviewed at the investigational site and remotely by authorized Edwards 
Lifesciences personnel at regular intervals throughout the trial. All eCRFs will be tracked at 
Edwards Lifesciences and missing or unclear data will be requested as necessary throughout the 
trial. 
9.2 
Missing Data 
All possible steps will be taken to minimize missing data in the study, including monitoring of data forms for 
completeness and efforts to track and maintain contact with study subjects during the follow-up period. 
 Feasibility Analysis  
10.1 Successful possibility analysis  
Product handling and procedure guidance are provided in the Training Materials and IFU and will 
be used for device training to minimize risks associated with device use. 
Additionally, efforts will be made to minimize these possible risks though site/investigator selection 
and management. First, site and investigator selection criteria are established to ensure that the 
study personnel and their institutions are qualified to screen, perform and manage the study 
procedures as well as support the associated requirements for research. 
Second, the trial management structure is designed to provide disciplined oversight of the trial 
activities including close monitoring of site and personnel performance and also support 
opportunities for investigators and study personnel to share best practices through investigator 
meetings, ongoing education and case reviews. 
Site and investigator criteria include the following: 
• Interventional cardiologists must be experienced and skilled in percutaneous balloon 
valvuloplasty. 
• Strong interdepartmental collaboration between cardiac surgery and interventional 
cardiology operators will be assessed by an experienced trial study team. The study site 

 
 
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team must be trained in the use of the investigational devices prior to enrollment of study 
patients. 
• The procedure setting must include a fixed C-arm angiography and PCI imaging capability 
in the catheterization lab or operative suite and/or a hybrid catheterization/operating room 
suite. 
• The study site must have an operating room. 
The study site must have an adequately staffed research department with a minimum of one dedicated 
study coordinator 
10.2 Analysis of the possibility of failure 
For the purposes of this study, adverse events that may be anticipated are associated with the use of 
the SAPIEN 3 THV System as well as the anesthesia and interventional procedures used to deliver 
and deploy the SAPIEN 3 THV. 
Anticipated risks have been minimized to the furthest extent possible, but the nature of the procedure 
and the severity of the patient’s disease state has inherent risks. Exposure to ionizing radiation 
associated with fluoroscopy, x-rays and CT is no more than is associated with routine clinical practice 
for transcatheter aortic heart valve replacement. 
Risks are outlined in the SAPIEN 3 THV System Instructions for Use (IFU)   
 Quality control of clinical trials  
Clinical sites will be chosen that have proper facilities in place to complete THV procedures. 
Additional training of appropriate clinical site personnel will be the responsibility of the Sponsor. 
To ensure proper device usage, uniform data collection, and protocol compliance, the Sponsor will 
present a formal training session to study site personnel which will review the instructions for use of 
the device, the Investigational Plan, techniques for the identification of eligible patients, instructions 
on in-hospital data collection, CT recommendations, echocardiography data collection for core 
laboratory analysis, methods for soliciting data from alternative sources, schedules for follow-up 
with the study site coordinators, and regulatory requirements. Detailed feedback regarding 
completion of forms will be provided by the Sponsor, and through regular site monitoring. Edwards 
Lifesciences reserves the right to enforce retraining for sites who have demonstrated study or 
procedure compliance issues. 
 Ethical issues and informed consent for clinical trials  
12.1 Ethical considerations 
The SAPIEN 3 THV System is not commercially available in China.  The clinical investigation 
shall be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki (as updated in Fortaleza Brazil in 2013) and in compliance with China’s Good Clinical 
Practice (GCP) for Medical Devices and any national regulations.  
12.2 Examination and approval of clinical trial protocol 
The clinical investigation plan and Patient Informed Consent form used to study the SAPIEN 3 
THV System must be reviewed and approved by the appropriate national authority and local or 
regional Ethics Committee (EC) where the clinical investigation is to be conducted before 

 
 
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enrolment of patients may begin. Any additional requirements imposed by the EC or regulatory 
authority shall be followed. 
Changes to the investigational plan that may increase the risk or present new risks to the patient 
must be approved in writing by Edwards Lifesciences and the EC before the change is 
implemented. 
12.3 Informed consent process and text of informed consent 
The Patient Informed Consent Form must be approved by Edwards Lifesciences and the site’s EC. 
The study investigator(s) and support staff will approach patients with symptomatic aortic stenosis 
to assess their interest in participating in the study.  They will provide an overview of the study 
and device, including the background, benefits, risks, and study procedures.  If patients are 
interested in participating in the study, then they will be provided with the full Patient Informed 
Consent Form document.  Patients will be allowed to read the document in its entirety, and then 
delegated study personnel will answer all of their questions. If the patient is comfortable with 
proceeding, then they will be asked to sign and date the Patient Informed Consent Form.  Informed 
consent must be obtained prior to the screening procedures or baseline tests that are specific to this 
study.  
During the course of the study, if new information becomes available that can affect a patient’s 
future health and medical care, then the information will be provided to the patient and the process 
documented.  If relevant, all affected patients will be asked to confirm their continuing informed 
consent in writing. 
All patients who sign a Patient Informed Consent Form should be entered in the database.  Data 
should not be entered until a Patient Informed Consent Form is signed.  Patients that are screened 
and do sign a Patient Informed Consent Form should be documented on the Screening Log. 
 Provisions on adverse event and device defect report 
13.1 Adverse events 
Adverse events may be volunteered by patients, elicited from questioning by Investigator or 
delegated study personnel, or collected via observation by the Investigator.  In addition, patients 
will be instructed to contact the investigator, and/or study coordinator if any significant adverse 
events (e.g., expanded safety composite events) occur between study evaluation visits. 
All adverse events are reported from the start of the procedure, which is defined as when anesthesia 
is first administered, and are reported until subject participation has ended (i.e. completion of the 
study or withdrawal of consent).  Adverse events must be reviewed at every follow-up visit until 
resolution, AE has stabilized (according to Investigator), or the study has been completed.  Should 
the adverse event be ongoing at time of study completion, the database should be updated to reflect 
status. 
Reporting guidelines for adverse events: 
• Record the number of units of blood needed for any transfusion associated with any overt 
bleeding event 

 
 
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• Failure of a percutaneous closure device shall be reported as an access site vascular closure 
device complication 
• Vascular complications shall be designated as access or non-access related; 
13.2 Serious Adverse Events 
All Serious Adverse Events (SAE) and Unanticipated Serious Adverse Device Effect (USADE) 
must be reported to Edwards Lifesciences within 24 hours of the Investigator or delegated study 
personnel becoming aware of the event or according to local regulations (whatever is most 
stringent).  SAEs and USADEs will be reported to the EC and regulatory authorities as required by 
national regulations or by the EC itself. 
Information may be entered into the Case Report Form or reported directly to the Edwards 
Lifesciences, with documentation of such notification being recorded and filed.  Notifications and 
source documents will be provided to Safety Officer. 
At the time of initial notification, the following minimal information should be provided: 
• Identifiable patient: subject number 
• Identifiable reporter: study site 
• Adverse event summary 
• Causal relationship to device and procedure 
• Awareness date 
The USADE Case Report Forms should be completed within five working days.  All USADEs 
must be followed until resolution or until a stable clinical endpoint is reached.  All required 
treatments and outcomes of the USADE must be recorded.  
Edwards will notify all participating clinical Investigators, ECs, and regulatory bodies as necessary 
of all USADEs that occur during the study within the specified reporting time frame following 
event notification.  Investigators are responsible for reviewing information received about 
USADEs. 
13.3 Reporting procedure and information of contact 
Source Documents 
The site will provide to Edwards Lifesciences a copy of anonymized supporting documentation 
(such as hospital record, laboratory results, autopsy results) of all SAEs and safety related 
composite events.  
Investigator Assessment Responsibilities 
The Investigator will determine if an adverse event is serious and not related, possibly related, or 
related to the device or procedure. 
Pre-existing medical conditions or symptoms reported prior enrolment will be recorded in medical 
history form and will not be recorded as an adverse event.  In the event there is a worsening in the 
pre-existing medical condition or symptoms after enrolment, then an adverse event will be 
recorded.  
Sponsor Assessment Responsibilities 

 
 
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All adverse events will be reviewed by the Study Safety Officer who will determine if the adverse 
event is serious; anticipated or unanticipated; and not related, possibly related, or related to the 
device or procedure.  
Medical Reviewer Responsibilities 
All endpoint related adverse events will be reviewed by a Medical Reviewer who will determine if 
the adverse event is serious; and not related, possibly related, or related to the device or procedure. 
1.1. Device Deficiency 
Device deficiency is an inadequacy of a medical device with respect to its integrity, quality, 
durability, reliability, safety or performance. It includes malfunctions, user errors and inadequate 
labeling. 
Device deficiencies include those deficiencies that did not lead to an adverse event but could have 
led to a medical occurrence: 
a. If intervention had not been made, or 
b. If circumstances had been less fortunate. 
Reporting conventions for device deficiencies that could result in a Serious Adverse Event (SAE) 
are the same as those for an actual SAE. 
Device Deficiency and Vigilance Reporting 
Device deficiencies which could have led to a serious adverse device effect should undergo the 
same reporting as serious adverse events.  They should be reported to Edwards Lifesciences within 
24 hours of awareness and to the EC and regulatory authorities as required by regulations or the EC. 
Adverse device effects, device malfunctions and device failures must be reported to Edwards 
Lifesciences in accordance with the regulations and Edwards Lifesciences policies. 
The Edwards Lifesciences ‘Complaint Reporting Process’ form is available in the site study 
document file. 
 Provisions on deviation from clinical trial protocol and correction of clinical trial protocol 
The investigator will not deviate from the protocol without the prior written approval of Edwards 
Lifesciences except in medical emergencies or in unforeseen, isolated instances where minor 
changes are made that will not increase the patient’s risk or affect the validity of the trial.  In 
medical emergencies, prior approval for protocol deviations will not be required, but the Edwards 
Lifesciences clinical research personnel must be notified within 24 hours of the incident.  
All protocol deviations need to be recorded in the respective section of the eCRF and reported 
according national and ethics committee requirements. Periodic monitoring of protocol compliance 
will be performed for each site. The sponsor maintains the right to place a moratorium on 
enrollment in sites deemed to have excessive protocol compliance issues.  A major protocol 
violation is the instance where a deviation significantly affects the integrity of the study and 
guidelines for Good Clinical Practice, such as when there is failure to obtain informed consent or 
violation of inclusion/exclusion criteria. In cases of major protocol violation, the principal 
investigator is required to make a written statement attesting to retraining or other action(s) to be 

 
 
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taken at his/her site to avoid such violations in the future. 
 Direct access to source data and files 
Records 
All records related to the study and qualifications of site personnel must be kept on file and 
available for review.  These documents may include but are not limited to: 
• Clinical trial investigational plan and all amendments, all approved versions 
• Signed clinical trial agreement 
• EC approval letter, including final informed consent 
• EC membership list 
• Correspondence relating to the trial 
• CVs for all investigators and research coordinator 
• Site personnel signature list 
• Clinical monitor sign-in log 
• Patient screening/enrollment log 
• Lab certification and lab test normal ranges 
• Reports (includes reports from investigator and sponsor) 
All records related to the patients’ consent and study data must be maintained for each patient 
enrolled in the trial.  These records include and are not limited to: 
• Signed Patient Informed Consent Form (latest approved site version) 
• All completed eCRFs 
• Supporting documentation of any complications and/or safety events. 
Edwards Lifesciences requests that the investigator retain copies of procedure reports, procedure 
nursing notes and the results of any interventional procedures that occurs post trial procedure.  
Edwards Lifesciences reserves the right to secure data clarification and additional medical 
documentation on patients enrolled in this trial. 
Record Retention Policy 
All clinical sites will maintain study records for a minimum of 15 years after marketing approval is 
obtained.  After 15 years, clinical sites should follow hospital and regulatory guidelines for record 
retention.  Record retention dates will be provided to all parties concerned by Edwards 
Lifesciences. 
 Finance and insurance 
Clinical Trial Funding  
As the Sponsor, Edwards Lifesciences will fund the trial for its duration.   
Clinical Trial Insurance  
As required by local/country regulation, Edwards Lifesciences will obtain clinical trial insurance for 
the duration of the clinical trial and provide evidence of coverage. 

 
 
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 Contents to be covered by clinical trial reports 
The template of the Clinical Trial Report can be found in Appendix G. 
 Principle of medical confidentiality  
All information and data sent to the data management center concerning patients or their 
participation in this trial will be considered confidential.  Only authorized data management center 
personnel will have access to these confidential files.  Authorized personnel from Edwards 
Lifesciences and its contractors and regulatory authorities have the right to inspect and copy all 
records pertinent to this trial.  All data used in the analysis and reporting of this evaluation will be 
without identifiable reference to the patient. 
 Provisions on publication of clinical trial results  
Clinical sites have the right, consistent with academic standards, to publish their individual registry 
results provided such publication does not constitute a violation of the Study Agreement. The site 
agrees to submit any proposed submission for publication to Edwards Lifesciences for review and 
approval before any submission. Consent cannot be denied without a sensible reason.  
The results of the clinical investigation will be submitted, whether positive or negative for 
publication. The publication policy will be part of Study Agreement. 
 Responsibilities of all parties  
General Study Organization 
Edwards Lifesciences is the Study Sponsor, and has the overall responsibility for the conduct of the 
study, including assurance that the study meets the regulatory requirements of the appropriate 
regulatory bodies.  Edwards Lifesciences will have certain direct responsibilities and will 
coordinate other responsibilities to the specified committees, Echo core lab and other support 
services as necessary 
Edwards Lifesciences will be responsible for submitting the Clinical Investigation Plan and all 
changes to it to the regulatory body and local EC to obtain ongoing approvals as needed. 
Edwards Lifesciences will submit all reports required by the appropriate regulatory authorities as 
identified in this section of the regulation. This may include unanticipated and serious adverse 
device effects, withdrawal of EC approval, current investigators list, annual progress reports, recall 
information, final reports and protocol violations. 
Edwards Lifesciences and Core Laboratories will maintain copies of correspondence, data, 
shipment of devices, adverse device effects and other records related to the study as appropriate. 
Medical Reviewers 
Medical Reviewers will review and classify adverse events in accordance with the study protocol.   
Echocardiography Core Laboratory 
A Core laboratory will be established for Echocardiography endpoint analysis.  Standardized 
protocols for acquiring and transmitting electronic records will be developed and documented prior 
to study initiation.   

 
 
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Clinical Sites will upload a qualifying echocardiography prior to the enrolment of the first subject in 
accordance with the standardized protocol. 
Edwards Lifesciences will review echocardiography data for the duration of the study. 
Clinical Sites 
Edwards Lifesciences will select qualified investigators, ship devices only to participating 
investigators, obtain a signed Clinical Study Agreement and provide the investigators with the 
information and training necessary to conduct the study. Edwards Lifesciences will retain copies of 
all study-related correspondence with study sites. 
 
 

 
 
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 Statement of Investigator 
I hereby agree:  
1. Carry out this clinical trial strictly according to the requirements of the Declaration of Helsinki, 
current laws and regulations of China, and the protocol.  
2. Accurately record all data required into the case report form (CRF) and accomplish clinical trial 
report on time.  
3. The medical device for test is only used for this clinical trial. Completely and accurately record 
the receiving and the use of the medical device for the test during the clinical trial and maintain the 
record.  
4. Allow the sponsor to authorize or dispatch supervisor, inspector and supervisory department to 
conduct supervision, inspection, and check on the clinical trial.  
5. Strictly perform the clinical trial contract/agreement signed by all parties.  
I have carefully read the clinical trial protocol including above statement and I agree with all 
contents above.  
Opinions of sponsor  
                               Signature (seal)  
                     Date:  
 
Opinions of investigator  
                   Signature  
                      Date:  
 
Opinions of medical device clinical trial institution  
                                       
                 Signature (seal)  
                     Date: