A Prospective, Randomized, Controlled, Multi-Center Study to Establish the Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low Risk Patients Who Have Severe, Calcific, Aortic Stenosis Requiring Aortic Valve Replacement
Phase: NA
Conditions: Aortic Stenosis
Sponsor: Edwards Lifesciences

 
 
 
 
PARTNER 3: 
A Prospective, Randomized, Controlled, Multi-Center Study to 
Establish the Safety and Effectiveness of the SAPIEN 3 
Transcatheter Heart Valve in Low Risk Patients who have Severe, 
Calcific, Aortic Stenosis Requiring Aortic Valve Replacement 
 
 
 
NCT02675114 
 
 
 
Dec 2018 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 1 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 - Low Risk 
 
 
 
A Prospective, Randomized, Controlled, Multi-Center Study to 
Establish the Safety and Effectiveness of the SAPIEN 3 Transcatheter 
Heart Valve in Low Risk Patients who have Severe, Calcific, Aortic 
Stenosis Requiring Aortic Valve Replacement 
 
 
 
 
                                           Clinical Protocol Study Number - 2015-08 
Version 5.0 
DEC 2018 
 
 
 
 
 
 
Study Sponsor: 
Edwards Lifesciences LLC 
One Edwards Way 
Irvine, CA 92614 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROPRIETARY DATA: This document and the information contained herein may not be reproduced, used or disclosed without 
written permission from Edwards Lifesciences LLC. 
Edwards, Edwards Lifesciences, the stylized E logo, Certitude, Edwards Commander, Edwards SAPIEN, Edwards SAPIEN 3, SAPIEN, 
and SAPIEN 3 are trademarks of Edwards Lifesciences Corporation. 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 2 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................................................... 4 
1.0 
INTRODUCTION ................................................................................................................... 12 
2.0 
STUDY OBJECTIVE ............................................................................................................. 22 
3.0 
STUDY DESIGN .................................................................................................................... 22 
4.0 
ENROLLMENT ...................................................................................................................... 22 
5.0  
STUDY DEVICE .................................................................................................................... 22 
6.0 
STUDY ENDPOINTS ............................................................................................................. 26 
7.0 
STUDY POPULATION .......................................................................................................... 28 
8.0  
STUDY PROCEDURES ........................................................................................................ 31 
9.0 
ADVERSE EVENTS .............................................................................................................. 50 
10.0 
RISKS AND BENEFIT ANALYSIS ........................................................................................ 54 
11.0 
STATISTICAL ANALYSIS .................................................................................................... 56 
12.0 
STUDY ADMINISTRATION .................................................................................................. 67 
13.0 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................................... 72 
Appendix A        Abbreviations ................................................................................................................. 76 
Appendix B 
Definitions ...................................................................................................................... 78 
Appendix C 
Instructions For Use (IFU) ............................................................................................. 97 
Appendix D 
Physician and Support Staff Training ......................................................................... 98 
Appendix E 
Six Minute Walk Test ................................................................................................... 101 
Appendix F 
    Frailty Index .................................................................................................................. 108 
Appendix G 
Mini Mental State Examination (MMSE) ..................................................................... 110 
Appendix H 
NIH Stroke Scale (NIHSS) ............................................................................................ 111 
Appendix I 
    Modified Rankin Scale (mRS) ..................................................................................... 122 
Appendix J 
    Echocardiogram ........................................................................................................... 124 
Appendix K-1 
Computed Tomography (CT) ...................................................................................... 163 
Appendix K-2 
Sub-Study CT ............................................................................................................... 216 
Appendix L 
    Histopathology ............................................................................................................. 234 
Appendix M 
EQ-5D-5L ....................................................................................................................... 238 
Appendix N 
Kansas City Cardiomyopathy Questionnaire (KCCQ) ............................................. 241 
Appendix O 
SF-36 ............................................................................................................................. 245 
Appendix P 
References .................................................................................................................... 251 
Appendix Q 
Actigraphy/QOL Sub-Study QOL measures [Enrollment Closed] .......................... 254 
 
 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 3 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Tables 
Table 1.1-1: Criteria for Determining Severity of Aortic Stenosis ................................................................................... 12 
Table 1.2.1-1: Primary Endpoint Analysis – Non Inferiority Test SAPIEN 3 vs. SAPIEN .............................................. 16 
Table 1.2.1-2: Death and Stroke at 30 Days (SAPIEN 3 vs. SAPIEN VI Population) .................................................... 17 
Table 1.2.1-3: Aortic Insufficiency at 30 Days (SAPIEN 3 vs. SAPIEN VI Population) .................................................. 17 
Table 1.2.1-4: Major Vascular Complications at 30 Days (SAPIEN 3 vs. SAPIEN VI Population) ................................. 17 
Table 1.2.1-5: PIIS3 – Clinical Outcomes at 30 Days and 1 Year in Combined S3HR/INOP Cohort (AT Population) .. 18 
Table 1.2.2-1: PIIS3 - 30-Day Clinical Events in S3i (AT Population)………………………………………………………19 
Table 5.1.1-1: Device Sizing ............................................................................................................................................ 24 
Table 8.3.2-1: Recommended anticoagulation/antithrombotic regimen .......................................................................... 36 
 
 
Figures 
 
Figure 1.1.3-1 Edwards TAVR Technology .................................................................................................................... 14 
Figure 1.1.3-2: SAPIEN 3 THV .............................................................................................................................................. 15 
Figure 1.2.2-1: Moderate/Severe PVL at 30 Days of SAPIEN Valves…………………………………............................20 
Figure 5.1.1-1 Edwards SAPIEN 3 Model 9600TFX .......................................................................................................... 23 
 
 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 4 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PROTOCOL SYNOPSIS 
 
 
Title 
A prospective, randomized, controlled, multi-center study to 
establish the safety and effectiveness of the SAPIEN 3 
transcatheter heart valve in low risk patients who have 
severe, calcific, aortic stenosis requiring aortic valve 
replacement. 
 
Purpose 
To establish the safety and effectiveness of the Edwards 
SAPIEN 3 (Edwards Lifesciences, Irvine, California) 
Transcatheter Heart Valve (THV) in patients with severe, 
calcific aortic stenosis who are at low operative risk for 
standard aortic valve replacement (AVR). 
 
Study Device 
Edwards SAPIEN 3 THV system Model 9600 TFX (20, 23, 
26 and 29 mm) with the associated delivery systems. 
Control 
Commercially available surgical bioprosthetic aortic valve 
replacement 
 
Study Design 
Prospective, randomized, controlled, multi-center. 
 
Patients will be randomized 1:1 to receive either 
transcatheter heart valve replacement (TAVR) with the 
Edwards SAPIEN 3 or aortic valve replacement with a 
commercially available surgical bioprosthetic valve. A 
subset of eligible patients from each study arm will be 
enrolled in a computed tomography (CT) sub-study and/or 
an Actigraphy/QOL sub-study [enrollment closed] at select 
sites. 
Patient Population 
Patients with severe, calcific, aortic stenosis requiring aortic 
valve replacement who are at low operative risk  
 
Sample Size 
   PARTNER 3 Randomized Trial: 
Up to 1182 patients will be enrolled.  
 
PARTNER 3 Sub-studies:  
Of the 1182 patients, a subset of patients will be enrolled 
in the following sub-studies: 
• 
CT Sub-study (up to 440)  
• 
Actigraphy/QOL Sub-study  (up to 400) [Enrollment 
Closed] 
 
PARTNER 3 Single-Arm Registries: 
Additional patients will be enrolled in the following single-
arm registries:  
• 
Alternative Access Registry (100) [Enrollment Closed] 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 5 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
• 
Bicuspid Registry (up to 75) 
• 
Underrepresented Populations Registry (up 
to 100) 
Study Sites 
Up to 85 actively enrolling sites will participate. 
Selected sites will participate in a CT sub-study, an 
Actigraphy/QOL sub-study  [enrollment closed], or the 
Underrepresented Populations Registry. 
 
Visit Schedule 
Screening, Procedure, Post Procedure, Discharge, 30 day, 
6 month, and annually through 10 years. 
 
Primary Endpoint 
Safety and Effectiveness: 
 
Composite endpoint of all-cause mortality, all stroke, and 
rehospitalization (valve-related or procedure-related and 
including heart failure) at 1 year post procedure.  
 
Secondary Endpoints for Labeling 
 
1. 
New onset atrial fibrillation at 30 Days 
 
2. 
Length of index hospitalization 
 
3. 
Death, KCCQ < 45 or KCCQ decrease ≥ 10 points at 30 days  
 
4. 
Death or All Stroke at 30 days 
 
5. 
All Stroke at 30 days 
 
Additional Safety and Effectiveness Endpoints 
 
1. Mortality (all cause & cardiovascular) at 30 days and 1 
year 
 
2. Stroke (disabling and nondisabling) at 30 days and 1 
year 
 
3. Death or stroke at 1 year 
 
4. Death or disabling stroke at 30 days and 1 year 
 
5. Vascular complications (major) at 30 days and 1 year 
 
6. Bleeding complications (life-threatening, disabling, or 
major) at 30 days and 1 year 
7. Myocardial infarction at 30 days and 1 year 
 
8. Acute kidney injury at 30 days 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 6 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
9. Renal replacement therapy at 1 year 
 
10. New permanent pacemaker implantation resulting from 
new or worsened conductiovn disturbances at 30 days 
and 1 year 
 
11. Coronary obstruction requiring intervention at 30 days 
and 1 year 
 
12. New York Heart Association class at 30 days and 1 year 
 
13. Hemodynamic valve performance evaluation by 
echocardiography for aortic valve stenosis and aortic 
valve regurgitation (paravalvular & central) at 30 days, 
and years 1, 2, 3, 4, 5, 7, and 10 
 
14. Rehospitalization (valve- or procedure-related including 
heart failure) at 30 days, 1 year and annually (up to year 
10) 
 
15. New onset atrial fibrillation at 1 year 
 
16. ICU days and discharge location 
 
17. Structural valve deterioration at years 1-5, 7 and 10  
 
18. Days alive and out of hospital at 1 year 
 
19. Six-minute walk test at 30 days and 1 year 
 
20. Health status as evaluated by Quality of Life 
questionnaires 
 
• 
KCCQ at 30 days and 1 year 
 
• 
EQ-5D-5L at 30 days and 1 year 
 
• 
SF-36 at 30 days and 1 year 
 
 
Inclusion Criteria 
 
Candidates for this study must meet all of the following inclusion criteria: 
 
 
1. Severe, calcific aortic stenosis as follows: 
 
• 
AVA ≤ 1.0 cm2 or AVA index ≤ 0.6 cm2/m2 
• 
Jet velocity ≥ 4.0 m/s or mean gradient ≥ 40 mmHg AND 
• 
1) NYHA Functional Class ≥ 2 OR 2) exercise test that demonstrates a 
limited exercise capacity, abnormal BP response, or arrhythmia OR 3) 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 7 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
asymptomatic with LVEF <50% 
 
Note: Qualifying echo must be within the 90 days prior to 
randomization. 
 
2. Heart team agrees the patient has low risk of operative mortality and 
has an STS < 4.   
 
3. The study patient has been informed of the nature of the study, agrees 
to its provisions and has provided written informed consent as 
approved by the Institutional Review Board (IRB)/Ethics Committee 
(EC) of the respective clinical site. 
 
Exclusion Criteria 
 
Candidates will be excluded from the study if any of the following conditions 
are present: 
 
1. Native aortic annulus size unsuitable for sizes 20, 23, 26, or 29 mm 
THV based on 3D imaging analysis 
  
2. Iliofemoral vessel characteristics that would preclude safe placement 
of the introducer sheath. 
 
3. Evidence of an acute myocardial infarction ≤ 1 month (30 days) before 
randomization 
 
4. Aortic valve is unicuspid, bicuspid, or is non-calcified 
 
5. Severe aortic regurgitation (>3+) 
 
6. Severe mitral regurgitation (>3+) or ≥ moderate stenosis 
 
7. Pre-existing mechanical or bioprosthetic valve in any position. (of n ote, 
mitral ring is not an exclusion). 
 
8. Complex coronary artery disease: 
 
• 
Unprotected left main coronary artery  
• 
Syntax score > 32 (in the absence of prior revascularization) 
• 
Heart Team assessment that optimal revascularization cannot 
be performed. 
 
9. Symptomatic carotid or vertebral artery disease or successful 
treatment of carotid stenosis within 30 days of randomization 
 
10. Leukopenia (WBC < 3000 cell/mL), anemia (Hgb < 9 g/dL), 
Thrombocytopenia (Plt < 50,000 cell/mL), history of bleeding 
diathesis or coagulopathy, or hypercoagulable states. 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 8 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
11. 
Hemodynamic or respiratory instability requiring inotropic support, 
mechanical ventilation or mechanical heart assistance within 30 days 
of randomization 
 
12. 
Hypertrophic cardiomyopathy with obstruction (HOCM) 
 
13. 
Ventricular dysfunction with LVEF < 30% 
 
14. Cardiac imaging (echo, CT, and/or MRI) evidence of intracardiac 
mass, thrombus or vegetation 
 
15. Inability to tolerate or condition precluding treatment with anti-
thrombotic/anticoagulation therapy during or after the valve implant 
procedure 
16. Stroke or transient ischemic attack (TIA) within 90 days of 
randomization 
 
17. 
Renal insufficiency (eGFR < 30 ml/min per the Cockcroft-Gault 
formula) and/or renal replacement therapy  
 
18. 
Active bacterial endocarditis within 180 days of randomization 
 
19. 
Severe lung disease (FEV1 < 50% predicted) or currently on home 
oxygen 
 
20. 
Severe pulmonary hypertension (e.g., PA systolic pressure ≥ 2/3 
systemic pressure) 
21. 
History of cirrhosis or any active liver disease  
22. 
Significant frailty as determined by the Heart Team (after objective 
assessment of frailty parameters).  
 
23. 
Significant abdominal or thoracic aortic disease (such as porcelain 
aorta, aneurysm, severe calcification, aortic coarctation, etc.) that 
would preclude safe passage of the delivery system or cannulation 
and aortotomy for surgical AVR . 
 
24. 
Hostile chest or conditions or complications from prior surgery that 
preclude safe reoperation (e.g., mediastinitis, radiation damage, 
abnormal chest wall, adhesion of aorta or IMA to sternum, etc.) 
 
25. 
Patient refuses blood products 
 
26. 
BMI > 50 kg/m2 
 
27. 
Estimated life expectancy < 24 months 
 
28. 
Absolute contraindications or allergy to iodinated contrast that cannot 
be adequately treated with pre-medication 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 9 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
29. 
Immobility that would prevent completion of study procedures (e.g. 
six-minute walk tests, etc.) 
 
30. 
Patient is not a candidate for both arms of the study (not applicable to single-arm 
registries) 
 
31. 
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. 
Observational studies are not considered exclusionary. 
 
CT Imaging Sub-Study Inclusion Criteria 
 
Sites with the ability to perform high quality multi-phasic, ECG-gated CT scans 
(i.e., 4D) will be selected to participate in a CT sub-study 
 
All CT sub-study participants must meet inclusion criteria 1-3 above 
 
CT Imaging Sub-Study Exclusion Criteria 
 
In addition to the exclusion criteria noted above, patients will be excluded from 
the sub- study if the following is present: 
 
1. Condition requiring or planned use of anticoagulants following the 
valve implant procedure 
2. GFR < 50 
3. Inability to perform high-quality MDCT study for any reason (e.g., atrial 
fibrillation with rapid ventricular response) 
 
Actigraphy/QOL Sub-Study Eligibility Criteria [Enrollment Closed] 
 
Select sites will be invited to participate in an Actigraphy/QOL sub-study.  Patients must 
meet all the eligibility criteria of the PARTNER 3 study.  In addition, they must demonstrate 
a basic working knowledge of and ability to use the devices specified in the sub-study.  
Patients who are non-ambulatory (i.e, wheelchair bound) will not be eligible. 
 
Alternative Access Registry Eligibility Criteria [Enrollment Closed] 
 
Patients who do not have appropriate iliofemoral access as defined in exclusion criterion 
number 2 but meet all other inclusion and exclusion criteria should be considered for 
enrollment in the alternative access registry. 
 
Bicuspid Registry Eligibility Criteria 
 
Patients with a bicuspid valve as determined by the CT core lab (e.g., exclusion criterion 4) 
should be considered for enrollment in this registry if they meet all other eligibility criteria 
and none of the following additional exclusion criteria: 
1. Aneurysmal ascending aorta (i.e., >4.0 cm) 
2. Severe or bulky calcification of the left ventricular outflow tract (LVOT) or raphe that 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 10 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
would increase the risk of annular injury or significant paravalvular leak (PVL) post 
TAVR  
3. Coronary anatomy that increases the risk of coronary artery obstruction post TAVR 
4. Positive urine or serum pregnancy test in female subjects of childbearing potential 
 
Underrepresented Populations Registry Eligibility Criteria 
 
Up to ten (10) sites from underrepresented geographical locations will be 
selected to enroll patients in a single-arm registry for underrepresented 
populations.  Patients at these sites are eligible for this registry if they meet all 
eligibility criteria above for the randomized cohort. 
 
Principal Investigators 
 
Martin B. Leon, M.D., FACC 
New York Presbyterian Hospital/Columbia University Medical Center  
New York, NY 
 
Michael J. Mack, M.D., FACC  
Baylor University Medical Center/The Heart Hospital Baylor Plano  
Plano, TX 
 
Sponsor 
Edwards Lifesciences LLC  
 
One Edwards Way 
Irvine, CA 92614 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 11 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
INVESTIGATOR SIGNATURE PAGE 
 
 
 
A Prospective, Randomized, Controlled, Multi-Center Study to Establish the Safety and 
Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low Risk Patients who have Severe, 
Calcific, Aortic Stenosis Requiring Aortic Valve Replacement 
 
 
I have read this protocol and agree to adhere to its requirements. I will ensure that the 
study is conducted in compliance with the protocol, Good Clinical Practice and all 
applicable regulatory requirements. 
 
 
 
 
 
Investigative Site Name 
 
 
 
 
 
Site Principal Investigator Name (print) 
 
 
 
 
 
 
Site Principal Investigator Signature  
       Date 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 12 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
1.0 
INTRODUCTION  
 
1.1 
Background 
 
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). Surgical aortic valve replacement (SAVR) has been 
the standard of care therapy for patients suffering from severe AS. In the aged 
population, many patients are too sick to undergo AVR, or have extensive 
comorbidities 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. Bicuspid aortic valve morphology is a 
common congenital valvular abnormality, occurring in 0.5% to 2% of the general 
population [2]. AS is also a frequent complication in this population and may occur at a 
younger age in patients with a bicuspid valves, when compared with patients with a 
tricuspid aortic valve morphology [3, 4]. The pathology involves progressive 
calcification of the leaflet bodies which limits normal cusp opening during systole.  
 
The pathophysiology of AS includes an increase in afterload, progressive hypertrophy 
of the left ventricle, valve obstruction, and a subsequent decrease in systemic and 
coronary blood flow. Cellular aging and degeneration have been implicated in this 
form of the disease; diabetes mellitus and hypercholesterolemia are risk factors. 
 
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 without intervention.  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 [5]. Gardin [6] reported that 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.  
More than 50% of the reported deaths were sudden. 
 
Grading the severity of AS is based on a variety of hemodynamic and natural history 
data. According to the ACC/AHA guidelines, AS is best described as a continuum.  
Relief of aortic valve obstruction typically results in a reduction of symptoms and 
improvements in hemodynamic parameters, global left ventricle systolic function, as 
well as a reversal of left ventricular hypertrophy [7]. 
 
Echocardiographic criteria for determining the severity of AS, as defined by the 2006 
published practice guidelines of the joint ACC/AHA Task Force are described below in 
Table 1.1-1. 
 
Table 1.1-1 Criteria for Determining Severity of Aortic Stenosis 
 
Indicator 
Mild 
Moderate 
Severe 
Jet velocity (m/s) 
< 3.0 
3.0 - 4.0 
> 4.0 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 13 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Mean Gradient (mmHg) 
< 25 
25 - 40 
> 40 
Valve area (cm2) 
> 1.5 
1.0 - 1.5 
< 1.0 
Valve area index (cm2/m2) 
< 0.6 
 
1.1.1 Treatment options prior to introduction of transcatheter aortic valve replacement 
(TAVR) 
 
Treatment options for patients suffering from symptomatic aortic stenosis, prior to the 
introduction of transcatheter aortic valve replacement (TAVR), 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 [8-10]. Patients considered poor candidates for AVR typically present 
with significant multiple morbidities or anatomical limitations [11]. 
 
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) [8-10,12-14]. 
 
1.1.2 Transcatheter aortic valve replacement (TAVR) 
 
Transcatheter aortic valve replacement (TAVR) was first performed in man in 2002 
[15], followed by clinical trials and approval for commercialization in Europe in 2007 
[16, 17]. It is currently estimated that approximately 300,000 patients have 
undergone TAVR 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. References 
are provided in [18-25]. 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 [cite Cohort A and B papers]. The PARTNER II trial has shown safety 
and effectiveness of the next generation SAPIEN XT THV in high risk and inoperable 
patients (Cohort B). More recently results of the SAPIEN 3 THV have also 
demonstrated safety and effectiveness in high risk or greater risk patients with 
symptomatic heart disease due to severe native calcific aortic stenosis.  Early results 
in intermediate risk patients treated with SAPIEN 3 THV have been presented and 
longer term intermediate risk results with the SAPIEN XT THV and SAPIEN 3 THV 
are pending. 
 
1.1.3 General Overview of the Study Valve Technology 
 
Edwards Lifesciences has pioneered three variations of heart valve implantation 
devices over the past 50 years, starting with the first mechanical heart valve in 1960, 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 14 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
followed by the introduction of  bioprosthetic tissue valves in 1976 and the 
advancement of bovine pericardial bioprostheses in the 1980´s. The evolution of 
valve replacement therapy was again expanded in 2004, with the acquisition of 
transcatheter heart valve technologies from percutaneous valve technologies (PVT).  
Edwards’s research and development expertise in bioprosthetic heart valves was 
applied to the development of the first generation SAPIEN™ transcatheter heart 
valve (THV) in 2006 and the introduction of the second generation Edwards SAPIEN 
XT™ THV in 2008. The current generation Edwards SAPIEN 3 THV was approved 
by the FDA in June 2015 for patients with aortic valve stenosis who are inoperable or 
high risk. 
 
Figure 1.1.3-1 Edwards TAVR Technology 
 
The original Edwards SAPIEN THV was comprised of a radiopaque, stainless steel 
expandable support structure (stent), with an integrated unidirectional trileaflet tissue 
valve, and a polyethylene terephthalate (PET) fabric cuff. The SAPIEN XT THV has 
incorporated a cobalt chromium alloy stent and a proprietary valve leaflet shape. 
The valve tissue is fabricated from three equal sections of bovine pericardium that 
have been preserved in low concentration solutions of buffered glutaraldehyde to 
fully crosslink the tissue, while preserving its flexibility and strength. All SAPIEN 
family THV valves are treated with the Edwards ThermaFix™ process. 
 
The SAPIEN 3 system was designed to improve the rates of procedure related 
adverse events such as paravalvular leak, major vascular complications and major 
bleeding. The SAPIEN 3 system also improves ease of use over previous 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 15 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
generations by improving coaxial valve alignment with a greater degree of distal flex 
in the transfemoral Commander delivery system, with a flex indicator on the handle 
that shows the degree of articulation in the delivery system, and smaller expandable 
sheaths with minimum access vessel diameter requirements as low as 5.5 mm. 
 
The inflow aspect of the SAPIEN 3 THV contains an external layer of polyethylene 
terephthalate (PET) with integral scalloped geometry that is intended to acutely fill 
the voids between the valve frame and native annulus caused by eccentric calcium 
deposits and enhances the chronic re-endothelialization process to create a tissue 
bridge across these voids. 
 
 
 
Figure 1.1.3-2: SAPIEN 3 THV 
 
As with the previous generation valve (SAPIEN XT THV), the SAPIEN 3 THV leaflets 
are designed to be in the semi-closed configuration at the first heartbeat. The 
SAPIEN 3 THV leaflets, however, were given a small “cap” at the leaflet tips to 
accommodate proper coaptation under all deployment configurations (i.e., nominal, 
under, over, and oval).  The commissure attachments of the SAPIEN 3 THV also 
differ slightly from the SAPIEN XT THV; the leaflets are attached via a soft integral 
tissue tab that is inserted into slots on the frame (rather than attached to a metal bar, 
as is the SAPIEN XT THV). 
 
Delivery of the SAPIEN 3 THV may be preceded by dilation of the stenotic native 
aortic valve by means of balloon aortic valvuloplasty (BAV). Predilation tests the 
expansion capacity of the native valve and prepares the annulus for implantation of 
the THV.  For the Commander delivery system, the THV is carefully mounted and 
crimped proximal to the balloon.  The delivery system is then inserted into the 
femoral artery (retrograde approach), through the Edwards Expandable Introducer 
Sheath Set (eSheath), and into a straight section of the descending aorta. The 
balloon catheter is then brought underneath the valve, in the correct location for 
valve delivery.  The steerable delivery system is then advanced over the aortic arch 
and delivered to the site of the native stenotic aortic valve. 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 16 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
1.2 
SAPIEN 3 Clinical History 
 
There were two cohorts, in the PARTNER II (PII) Trial assessing the latest SAPIEN 3 (S3) 
THV in patients with symptomatic severe aortic stenosis: the high risk operable/inoperable 
cohort (PIIS3 HR), with nested registry (NR7 – size 20mm) and the intermediate risk cohort 
(PIIS3i). All patients receiving the S3 THV presented with severe symptomatic calcific aortic 
stenosis requiring aortic valve replacement (AVR) and due to co-morbidities were at 
intermediate or higher risk for open chest surgery. 
 
1.2.1 PIIS3HR Cohort of the PARTNER II Trial Results 
 
The PIIS3HR Cohort of the PARTNER II trial was a single arm, non-randomized, 
historical- controlled study to compare the third generation Edwards SAPIEN 3 THV 
system with the first generation Edwards SAPIEN THV system in patients who either 
have high risk for surgery or cannot undergo surgery (inoperable). The 20 mm valve 
size was introduced into the trial after enrollment was completed with the three 
larger sizes (23, 26, and 29 mm), thus a separate nested registry, NR7, with 
identical inclusion/exclusion criteria as the PIIS3HR Cohort except for the aortic 
annulus diameter, was created to collect data for the 20 mm valve. 
 
Data was collected on 583 eligible patients enrolled at 29 investigational sites in the 
United States, who were successfully implanted with a SAPIEN 3 THV, which 
constitutes the Valve Implant (VI) population. Among the VI population, 491 patients 
were implanted via the transfemoral (TF) access route, and 92 patients via the 
transapical (TA) or transaortic (TAo) access route. The overall (N=583) average 
patient age was 82.6 ± 8.1 years, and the average STS score was 8.6 ± 3.7. 
 
The primary endpoint; composite rate of all-cause mortality, all stroke, and AI ≥ 
moderate at 30 days was 6.7% in the SAPIEN 3 cohort and 15.6% in the SAPIEN 
cohort, as shown in Table 1.2.1-1. The resulting proportion difference in the average 
treatment effect on the treated (ATT) was -6.9% (90% CI: [-13.3%, -0.5%]).  Since 
the upper limit of the CI was < 7.5%, the non–inferiority was met. 
 
Table 1.2.1-1:  Primary Endpoint Analysis – Non Inferiority Test SAPIEN 3 vs. SAPIEN 
 
(PIIS3HR VI 
Population) Event 
at 30 days 
SAPIEN 3 (N=583) 
SAPIEN (N=326) 
Weighted Proportion 
Difference in Average 
Treatment Effect on 
the Treated (ATT) 
Composite of Death, 
Stroke and AI ≥ 
Moderate 
6.7% [5.1%, 8.6%]1 
15.6% [12.6%, 19.5%]1 
-6.90% [-13.3%, -0.5%] 
1. 90% stratified Wilson confidence interval 
2. Wald-type two-sided 90% confidence interval using weighted mean and SD 
 
The Kaplan-Meier (K-M) estimates for all-cause mortality, cardiac mortality, and all 
stroke at 30 days for the SAPIEN 3 cohort and the SAPIEN cohort are provided in 
Table 1.2.1-2. 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 17 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Table 1.2.1-2:  Death and Stroke at 30 Days (SAPIEN 3 vs. SAPIEN VI Population) 
 
SAPIEN 3 
(N= 583) 
SAPIEN 
(N= 326) 
Events at 30 
Days 
No. 
Events 
No. Pts 
with 
Events 
K-M Estimated 
Event Rate1 
(95% CI) 
No. 
Events 
No. Pts 
with 
Events 
K-M Estimated 
Event Rate 
(95% CI) 
Death 
13 
13 
2.2% 
([1.3%, 3.8%]) 
15 
15 
4.6% 
([2.8%, 7.5%]) 
Cardiac Death 
8 
8 
1.4% 
([0.7%, 2.7%]) 
10 
10 
3.1% 
([1.7%, 5.7%]) 
All Stroke 
9 
9 
1.6% 
([0.8%, 3.0%]) 
14 
14 
4.3% 
([2.6%, 7.2%]) 
1Kaplan-Meier (K-M) estimates at 30 days used time to first event for each patient. Events occurring after 30 days 
were not included in this analysis. 
 
The proportion of patients with AI ≥ moderate at 30 days was 3.0% in the SAPIEN 3 
cohort and 14.3% in the SAPIEN cohort, which were found to be statistically 
significantly different (p=0.0051;Table 1.2.1-3). 
 
Table 1.2.1-3:  Aortic Insufficiency at 30 Days (SAPIEN 3 vs. SAPIEN VI Population) 
 
Event at 30 
Days 
SAPIEN 3 
(N = 583) 
SAPIEN 
(N = 326 ) 
Weighted Proportion 
Difference in Average 
Treatment Effect on the 
Treated (ATT) 
P-value 
AI ≥Moderate, 
n/Total no. (%) 
[95% CI] 
16/532 
(3.0%) 
[1.7%, 4.8%]1 
40/280 
(14.3%) 
[10.4%, 18.9%]1 
-13.1% 
[-22.2%, -3.9%]2 
0.0051 
1. 95% Clopper-Pearson Exact confidence interval. 
2. The Wald-type two-sided 90% confidence interval using weighted mean and SD. 
 
The rate of major vascular complications at 30 days post implantation is shown in 
Table 1.2.1-4. The rate was 5.0% for the SAPIEN 3 cohort and 10.1% for the 
SAPIEN cohort, which were found to be not statistically significantly different 
(p=0.0578). 
 
Table 1.2.1-4: Major Vascular Complications at 30 Days (SAPIEN 3 vs. SAPIEN VI 
Population) 
 
Event at 30 Day 
SAPIEN 3 
(N=583) 
SAPIEN 
(N=326) 
Weighted Proportion 
Difference in Average 
Treatment Effect on the 
Treated (ATT) 
P-value 
Major Vascular 
Complications, n/Total 
no. (%) [95% CI] 
29/583 
(5.0%) 
[3.4% , 7.1%] 
33/326 
(10.1%) 
[7.1% , 13.9%]1 
-8.0% 
[-16.2%, 0.3%]2 
0.0578 
1. 95% Clopper-Pearson Exact confidence interval. 
2. The Wald-type two-sided 90% confidence interval using weighted mean and SD. 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 18 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Professor Howard Hermann presented the 1-year results from the PIIS3HR cohort at 
the TCT annual meeting (15 October 2015, San Francisco, California, USA). There 
were 384 high surgical risk patients (HR) (66.0%) and 199 inoperable patients 
(INOP) (34%) in this cohort.  Between the 30-day and 1-year follow-up there were 
71 additional deaths and 5 patients withdrew their participation in the study. 
 
Table 1.2.1-5: PIIS3 – Clinical Outcomes at 30 Days and 1 Year in  
Combined S3HR/INOP Cohort (AT Population) 
 
Clinical Outcomes (%) 
30 Days 
1 Year 
All-Cause Mortality 
2.2 
14.4 
Cardiac Mortality 
1.4 
8.1 
All Strokes 
1.4 
4.3 
Disabling Stroke* 
0.9 
2.4 
Rehospitalization 
8.0 
17.1 
New Permanent Pacemaker 
13.3 
16.9 
Surgical AVR 
0.2 
0.6 
Structural Valve Deterioration 
0 
0 
Valve Thrombosis 
0 
0 
*No differences between TF and TA/TAo or between HR and INOP subgroup 
defined as modified Rankin Score ≥ 2 – CEC adjudicated. 
 
A paired analysis of paravalvular regurgitation (PVL) confirmed a sustained change 
in the none/trace measurement of 64.3% at 30 days and 68.1% at 1 year (Figure 2).  
No severe PVL was reported and only 2.5% and 2.7% moderate PVL at 30 days or 1 
year. A Kaplan- Meier survival analysis by 30 day PVL demonstrated no difference 
in survival between patients with none/trace and mild PVL (88.0% and 85.9%) but a 
significant difference in survival between moderate/severe PVL (61.9%) and 
none/trace PVL (log rank p=0.0015) and mild PVL (log rank p=0.0058). 
 
1.2.2 PIIS3i Cohort of the PARTNER II Trial Results 
 
The PIIS3i Cohort consists of intermediate operable risk patients, who received the 
Edwards SAPIEN 3 THV. To assure that patients were of “intermediate” risk, an 
STS score of 4 – 8% was selected as the inclusion criteria. 
 
The PIIS3i Cohort is a single arm non-randomized, historical-controlled study to 
compare the transcatheter heart valve therapy with the third generation SAPIEN 3 
THV system, to surgical AVR in patients who have an intermediate risk for surgery 
(control arm patients from PARTNER II Cohort A). The S3 THV was available in 20, 
23, 26, and 29 mm sizes. The primary endpoint for the PIIS3i Cohort is a non- 
hierarchical composite endpoint of death, all stroke, and AI ≥ moderate at 1 year. 
The primary analysis is a non-inferiority analysis. 
 
A total of 1078 patients were enrolled in S3i, across 51 different sites. The majority 
of patients were male (62%) and the average patient age was reported as 81.9 
years. The average STS score was 5.3% (median 5.2%). The transfemoral access 
approach was used for valve delivery in 89.0%, transapical approach in 7% and 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 19 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
transaortic approach in 4.0%. 
 
Treatment was conducted with the implantation of a size 26mm valve in 43.7% of 
patients, followed by size 23mm in 32.2%, size 29mm in 20.0% and size 20mm in 
4.1% of patients. 
 
Functional improvement was observed in the AT population of the S3i Cohort, as the 
number of patients with NYHA classification III/IV decreased from baseline to 30 
days from 90% to 13% and 73% to 6%, respectively.  
 
At ACC in 2015, Dr. Susheel Kodali presented 30-day data for S3i, as seen in Table 
1.2.2-1 below.  S3i clinical events and historical SAPIEN family moderate/severe 
paravalvular leak at 30 days are described below in Table and Figure 1.2.2- 1 
respectively. 
 
Table 1.2.2-1: PIIS3 - 30-Day Clinical Events in S3i (AT Population) 
 
Event (%) 
S3i 
Overall 
(n=1076) 
S3i 
TF 
(n= 951) 
S3i 
TA/TAo 
(n=125) 
All-Cause Death 
1.1 
1.1 
1.6 
Cardiovascular Death 
0.9 
0.9 
0.8 
All Strokes 
2.60 
2.42 
4.00 
Disabling* 
1.02 
0.95 
1.60 
Non-Disabling 
1.58 
1.47 
2.40 
TIA 
0.37 
0.42 
0 
Major Vascular Complication 
5.6 
5.9 
3.2 
Life-Threatening Bleeding 
5.4 
4.4 
12.9 
Annular Rupture 
0.2 
0.2 
0 
Myocardial Infarction 
0.3 
0.3 
0 
Coronary Obstruction 
0.4 
0.4 
0 
Acute Kidney Injury 
0.5 
0.3 
1.6 
New Permanent Pacemaker 
10.1 
10.4 
7.2 
Aortic Valve Reintervention 
0.7 
0.8 
0 
Endocarditis 
0.1 
0.1 
0 
 
 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 20 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Figure 1.2.2-1: Moderate/Severe PVL at 30 Days of SAPIEN Valves 
 
 
 
Although patients with bicuspid valve morphology have historically been excluded from TAVR 
studies and are not included in the data summaries above, recent reports on the use of S3 in 
these patients is feasible and effective with favorable valve performance [38]. 
 
1.3 
Design Rationale for the Expanded Indication Trial 
 
Earlier TAVR studies, such as those evaluating the SAPIEN (2006) and SAPIEN XT 
(2009) THVs, had very selective inclusion criteria that required that the patient 
populations be high risk for surgery (STS>8) and non-operable, due to concerns of 
procedural complications including stroke, vascular complications, paravalvular leak 
(PVL), and conduction disturbances. 
 
As TAVR technology has evolved (Figure 1.1.3-1), such as with the introduction of 
the S3 enhanced frame geometry, lower frame height, outer skirt to reduce PVL, and 
improved delivery system utilizing reduced access-vessel diameter requirements, 
and new studies demonstrate procedural complication rates similar to AVR, there 
has been a natural progression towards indications including operable patients with 
decreasing risk profiles. 
 
The tenacious pursuit of technological advances in THV, in combination with over a 
decade of clinical outcomes, operator experience and input has yielded favorable 
and steadily improving safety and efficacy. Ongoing studies of the latest generation 
valve (S3) demonstrate very low rates of significant paravalvular regurgitation, major 
vascular complications, and bleeding complications; and in intermediate-risk patients 
- markedly low mortality and stroke at 30 days. 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 21 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
1.3.1 Rationale for CT Sub-Study 
 
There have been recent reports of abnormal imaging findings as assessed by multi-
phasic, ECG-gated CT (i.e., 4D CT) in some patients in the absence of clinical 
symptoms or echocardiographic abnormalities following TAVR [29, 30]. The 
abnormal imaging has been described as “leaflet thickening” and “reduced leaflet 
mobility”. This imaging phenomenon has not been definitely linked with clinical valve 
thrombosis which occurs in 1% or less of TAVR and SAVR bioprostheses. 
The purpose of the CT sub-study is to further investigate this phenomenon with the 
following specific objectives: 
 
1. Establish the prevalence of the imaging abnormality. 
 
2. Establish the relationship between the imaging abnormality and patient, 
procedural and pharmacology factors. 
 
3. Establish the relationship between imaging abnormalities and clinical events. 
 
1.3.2 Rationale for Actigraphy/QOL [Enrollment Closed] 
 
Traditional, face-to-face methods for measuring quality of life (QOL) and functional status at 
defined time points can lack the precision needed to detect changes on a more frequent or even 
day to day basis.  Advances in mobile health (mHealth) technology may enable more regular, 
convenient and accurate tracking of QOL and physical activity information through applications 
and wearable devices.  These technologies have the potential to help gather more and better 
data on patients’ response to therapy and progression of disease. 
The purpose of this sub-study is to investigate the feasibility of assessing change in QOL and 
activity levels using electronic patient-reported outcome (ePRO) applications and wearable 
activity trackers. The end goal is to publish study results and explore new and innovative ways of 
assessing QOL and functional status of aortic stenosis patients with low surgical risks. 
1.3.3   Rationale for Underrepresented Registry 
 
With the growing use of TAVR for heart valve repair, some US centers are considered “high-
volume” due to the number of TAVR procedures performed each year.  Results from past TAVR  
trials have shown that these centers enroll predominately Caucasian patients. Many patients 
that would benefit from TAVR are not enrolled into trials due to their inability to travel to the 
larger TAVR centers, due to cultural/socio-economic pressure to remain within their own 
community, or because there is no referral base for reaching these patients and increasing 
awareness of TAVR.   In order to expand the study of TAVR to a broader group of patients, 
Edwards is reaching-out to these underrepresented patients by selecting ten additional sites 
with a predominantly diverse ethnic, cultural, non-Caucasian patient base that perform a more 
limited number of TAVR procedures per year.   
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 22 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
2.0 
STUDY OBJECTIVE 
 
The purpose of this trial is to establish the safety and efficacy of the Edwards 
SAPIEN 3 THV device in patients with severe, calcific, aortic stenosis who are at low 
operative risk for SAVR. 
 
3.0 
STUDY DESIGN 
 
This is a prospective, randomized, controlled, multi-center study. Qualified study 
patients will be randomized 1:1 to receive either the Edwards SAPIEN 3 
transcatheter heart valve through iliofemoral access, or SAVR with a commercially 
available bioprosthetic valve. Selected sites will enroll qualified patients into a CT 
sub-study.  Selected sites may also enroll patients in an Actigraphy/QOL sub-study 
[Enrollment Closed]. 
 
Additional patients will be enrolled in the following single-arm registries:  
• 
Alternative Access Registry (100) [Enrollment Closed] 
• 
Bicuspid Registry (up to 75) 
• 
Underrepresented Populations Registry (up to 100) 
 
4.0 
ENROLLMENT 
 
Up to 1182 qualified patients will be randomized at up to 65 actively enrolling sites in 
the US. It is anticipated that approximately 5-10 sites may be selected outside of the 
US. Further, up to ten (10) separate US sites from targeted geographic areas will be 
selected to enroll patients in a single-arm registry for underrepresented populations. 
No site will be allowed to enroll more than 15% of patients. Edwards will notify 
investigative sites of enrollment closure. 
 
Sub-studies 
Of the 1182 patients, a subset of patients will also be enrolled in the following randomized sub-
studies: 
• 
CT sub-study (up to 440)  
• 
Actigraphy/QOL sub-study (up to 400) [Enrollment Closed] 
 
Registries 
Additional patients will be enrolled in the following single-arm registries: 
• 
Alternative Access Registry (100) [Enrollment Closed] 
• 
Bicuspid Registry (up to 75) 
• 
Underrepresented Populations Registry (up to 100) 
 
5.0  
STUDY DEVICE 
 
The  commercially available Edwards SAPIEN 3 THV and Commander Delivery 
System will be provided for use in this study for transfemoral delivery of the SAPIEN 
3 THV.  
 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 23 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Alternative Access Registry [Enrollment Closed] 
The Edwards Commander Delivery System will be provided for subclavian delivery 
and the Edwards Certitude Delivery System will be provided for transapical and 
transaortic delivery of the SAPIEN 3 THV as part of Alternative Access Registry. 
 
Edwards SAPIEN 3 System 
 
• Edwards SAPIEN 3 Transcatheter Heart Valve [Model 9600TFX (in 20 mm, 23 
mm, 26 mm and 29 mm sizes)] 
• Edwards Commander Delivery System (Models 9600LDS20, 9600LDS23, 
9600LDS26 and 9600LDS29) 
• Edwards Certitude Delivery System (Models  9620TA20, 9620TA23, 9620TA26 
and 9620TA29, 9600SDS20, 9600SDS23, 9600SDS26 and 9600SDS29) 
• Edwards Certitude Introducer Sheath Set [Models 9620IS18 (18F) and 
9620IS21 (21F), 9600IS18 and 9600IS21] 
• Edwards Crimper (Model 9600CR) 
 
5.1  
Device Descriptions 
 
5.1.1 Edwards SAPIEN 3 THV 
 
The SAPIEN 3 THV (Figure 5.1.1-1) is a catheter-delivered heart valve that combines 
a balloon expandable stent and bioprosthetic valve technology.  
 
The device is comprised of a balloon-expandable, radiopaque, cobalt-chromium alloy 
frame, a trileaflet bovine pericardial tissue valve, a polyethylene terephthalate (PET) 
internal fabric skirt, and a PET external sealing ring. The valve tissue is treated with 
Edwards ThermaFix process, packaged and terminally liquid sterilized in a buffered 
glutaraldehyde solution. 
 
Figure 5.1.1-1 Edwards SAPIEN 3 Model 9600TFX 
 
 
 
The device leaflets are designed to be in the semi-closed configuration at the first 
heartbeat. The leaflets have a small “cap” at the leaflet tips to accommodate proper 
coaptation under  all deployment configurations (i.e., nominal, under, over and oval).  
The leaflets are attached via a soft integral tissue tab that is inserted into slots on the 
frame. 
 
The SAPIEN 3 is available in 4 sizes (Table 5.1.1-1). 
 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 24 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
Table 5.1.1-1 Device Sizing 
 
Native Valve 
Annulus Size 
(TEE) 
Native Valve Annulus Size 
(CT) 
THV Size 
Valve 
Height 
Area 
Area Derived 
Diameter 
16-19 mm 
273 – 345 mm2 
18.6-21 mm 
20 mm 
15.5 mm 
18-22 mm 
338 – 430 mm2 
20.7-23.4 mm 
23 mm 
18 mm 
21-25 mm 
430 – 546 mm2 
23.4-26.4 mm 
26 mm 
20 mm 
24-28 mm 
540 – 683 mm2 
26.2-29.5 mm 
29 mm 
22.5 mm 
THV size recommendations are based on native valve annulus size, as measured by transesophageal echocardiography (TEE) 
or computed tomography (CT). Patient anatomical factors and multiple imaging modalities should be considered during THV 
size selection. 
 
5.1.2 Edwards Commander Delivery System 
 
The Commander Delivery System includes: 
 
• 
Loader 
• 
Qualcrimp Accessory 
• 
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 Flex Wheel 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. 
 
Certitude Delivery System 
 
The Edwards Certitude Delivery System includes a handle with a Flex Wheel for 
articulation of the Ballon Catheter and a Loader. The loader allows for the delivery of 
the crimped THV through the hemostasis valves of the sheath. Three radiopaque 
indicators on the catheter shaft define the position on the ballon where the THV 
should be crimped and also provide visualization of the balloon. The THV is crimped 
between the two radiopaque shoulders on the distal and proximal ends of the 
balloon. A radiopaque Center Marker in the balloon is provided to help with valve 
positioning. An inflation and guidewire hub is housed in the handle assembly. A 2-
piece crimp stopper and the Qualcrimp crimping accessory are packaged with the 
delivery system for use during crimping of the THV. 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 25 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Loader 
 
The loader 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. 
 
Qualcrimp Accessory 
 
The Qualcrimp accessory is a foam tube composed of polyurethane sponge covered 
in an outer layer of PET. The SAPIEN 3 THV is placed within the Qualcrimp 
accessory prior to placing it in crimper. The Qualcrimp accessory is intended to 
protect the leaflets of the SAPIEN 3 THV during crimping. 
 
2-piece Crimp Stopper 
 
This component is discussed in section 5.1.4. 
 
 
5.1.3 Certitude Delivery System 
 
The Certitude Delivery System includes: 
 
• 
Loader (see 5.1.2) 
• 
Qualcrimp Accessory (see 5.1.2) 
• 
2-piece Crimp Stopper (see 5.1.4) 
 
The Edwards Certitude Delivery System includes a handle with a Flex Wheel for 
articulation of the Balloon Catheter and a Loader. The loader allows for the delivery 
of the crimped THV through the hemostasis valves of the sheath. Three radiopaque 
indicators on the catheter shaft define the position on the balloon where the THV 
should be crimped and also provide visualization of the balloon. The THV is crimped 
between the two radiopaque shoulders on the distal and proximal ends of the 
balloon. A radiopaque Center Marker in the balloon is provided to help with valve 
positioning. An inflation and guidewire hub is housed in the handle assembly. A 2-
piece crimp stopper and the Qualcrimp crimping accessory are packaged with the 
delivery system for use during crimping of the THV. 
 
5.1.4 Edwards Crimper 
 
The Crimper reduces the diameter of the SAPIEN 3 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 to the appropriate 
size. 
 
The SAPIEN 3 THV, the associated Delivery Systems and components will be used 
per the Instructions for Use (IFU) and after sufficient training of physicians/site 
personnel has been achieved as determined by the study sponsor.  Further 
descriptions of these devices are provided in the respective IFUs (Appendix C). 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 26 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
6.0 
STUDY ENDPOINTS  
6.1 
Primary Endpoint Safety and Effectiveness: 
 
Composite endpoint of all-cause mortality, all stroke, and rehospitalization (valve-
related or procedure-related and including heart failure) at 1 year post procedure.  
 
 
6.2 
Secondary Endpoints for Labeling 
 
1. 
New onset atrial fibrillation at 30 Days 
 
2. 
Length of index hospitalization 
 
3. 
Death, KCCQ < 45 or KCCQ decrease ≥ 10 points at 30 days  
 
4. 
Death/All Stroke composite at 30 days 
 
5. 
All Stroke at 30 days 
 
 
6.3 
Additional Safety and Effectiveness Endpoints 
 
1. 
Mortality (all cause & cardiovascular) at 30 days and 1 year 
 
2. 
Stroke (disabling and nondisabling) at 30 days and 1 year 
 
3. 
Death or stroke at 1 year 
 
4. 
Death or disabling stroke at 30 days and 1 year 
 
5. 
Vascular complications (major) at 30 days and 1 year 
 
6. 
Bleeding complications (life threatening, disabling, or major) at 30 days and 1 
year 
 
7. 
Myocardial infarction at 30 days and 1 year 
 
8. 
Acute kidney injury at 30 days 
 
9. 
Renal replacement therapy at 1 year 
 
10. New permanent pacemaker implantation resulting from new or worsened 
conduction disturbances at 30 days and 1 year 
 
11. 
Coronary obstruction requiring intervention at 30 days and 1 year 
 
12. 
New York Heart Association class at 30 days and 1 year 
 
13. 
Hemodynamic valve performance evaluation by echocardiography for aortic 
valve stenosis and aortic valve regurgitation (paravalvular & central) at 30 
days, and years 1, 2, 3, 4, 5, 7, and 10. 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 27 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
14. 
Rehospitalization (valve-related or procedure-related and including heart 
failure) at 30 days, 1 year, and annually (up to 10 years). 
 
15. New onset atrial fibrillation at 1 year 
 
16. ICU days, and discharge location 
 
17. 
Structural valve deterioration at years 1-5, 7 and 10   
 
18. 
Days alive and out of hospital at 1 year 
 
19. 
6-minute walk test at 30 days and 1 year 
 
20. 
Health status as evaluated by Quality of Life questionnaires 
 
a. KCCQ at 30 days and 1 year 
 
b. EQ-5D-5L at 30 days and 1 year 
 
c. SF-36 at 30 days and 1 year 
 
6.4 
Actigraphy/QOL Substudy Outcome Measures  [Enrollment Closed] 
 
Primary Outcome Measures: 
 
1. Quality of life as assessed by visual analog scale for pain (VAS Pain) through 30 days. 
 
2. Activity during daytime hours (6 am to 10 pm) as assessed by mean daily steps walked 
through 30 days. 
 
Secondary Outcome Measures: 
 
1. Quality of life as assessed by  
 
a. VAS Pain 31-44 days 
 
b. Kansas City Cardiomyopathy Questionnaire (KCCQ-12) through 44 days 
 
c. PF-10 Physical Component Summary through 44 days 
 
2. Activity during daytime hours (6 am to 10 pm) through 44 days 
a. Mean daily steps walked  
 
b. Number of minutes active  
 
c. Number of minutes sedentary 
 
d. Total activity count of the most active 10 hours in the day (which need not be 10 
consecutive hours) 
 
 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 28 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
7.0 
STUDY POPULATION 
 
The study population will be comprised of patients with severe, calcific, aortic 
stenosis who are at low operative risk for SAVR. 
 
7.1 
Inclusion Criteria 
 
All study participants must meet the following inclusion criteria. 
 
1. 
Severe, calcific aortic stenosis meeting the following criteria: 
 
• 
AVA ≤ 1.0 cm2 or AVA index ≤ 0.6 cm2/m2 
• 
Jet velocity ≥ 4.0 m/s or mean gradient ≥ 40 mmHg AND 
 
 
• 
1) NYHA Functional Class ≥ 2 OR 2) exercise tolerance test that 
demonstrates a limited exercise capacity, abnormal BP response, or 
arrhythmia OR 3) asymptomatic with LVEF <50% 
 
Note: Qualifying echo must be within the 90 days prior to randomization. 
 
2. 
Heart team agrees the patient has a low risk of operative mortality and an STS 
< 4.  
 
3. 
The study patient has been informed of the nature of the study, agrees to its 
provisions and has provided written informed consent as approved by the 
Institutional Review Board (IRB)/Ethics Committee (EC) of the respective 
clinical site. 
 
7.2 
Exclusion Criteria 
 
Candidates will be excluded from the study if any of the following conditions are 
present: 
 
1. 
Native aortic annulus size unsuitable for sizes 20, 23, 26, or 29mm THV based 
on 3D imaging analysis 
 
2. 
Iliofemoral vessel characteristics that would preclude safe passage of the 
introducer sheath 
 
3. 
Evidence of an acute myocardial infarction ≤ 1 month (30 days) before 
randomization  
 
4. 
Aortic valve is unicuspid, bicuspid, or non-calcified 
 
5. 
Severe aortic regurgitation (>3+) 
 
6. 
Severe mitral regurgitation (>3+) ≥ moderate stenosis 
 
7. 
Pre-existing mechanical or bioprosthetic valve in any position. (of note, mitral 
ring is not an exclusion). 
 
8. 
Complex coronary artery disease: 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 29 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
a. 
Unprotected left main coronary artery 
 
b. 
Syntax score > 32 (in the absence of prior revascularization) 
 
c. 
Heart Team assessment that optimal revascularization cannot be 
performed 
 
9. 
Symptomatic carotid or vertebral artery disease or successful treatment of carotid 
stenosis within 30 days of randomization 
 
10. Leukopenia (WBC < 3000 cell/mL), anemia (Hgb < 9 g/dL), Thrombocytopenia 
(Plt < 50,000 cell/mL), history of bleeding diathesis or coagulopathy, or 
hypercoagulable states 
 
11. 
Hemodynamic or respiratory instability requiring inotropic support, mechanical 
ventilation or mechanical heart assistance within 30 days of randomization 
 
12. Hypertrophic cardiomyopathy with obstruction (HOCM) 
 
13. 
Ventricular dysfunction with LVEF < 30% 
 
14. 
Cardiac imaging (echo, CT, and/or MRI) evidence of intracardiac mass, 
thrombus or vegetation 
 
15. Inability to tolerate or condition precluding treatment with anti-
thrombotic/anticoagulation therapy during or after the valve implant procedure 
16. Stroke or transient ischemic attack (TIA) within 90 days of randomization 
 
17. 
Renal insufficiency (eGFR < 30 ml/min per the Cockcroft-Gault formula) and/or 
renal replacement therapy at the time of screening. 
 
18. 
Active bacterial endocarditis within 180 days of randomization 
19. 
Severe lung disease (FEV1 < 50% predicted) or currently on home oxygen 
20. Severe pulmonary hypertension (e.g., PA systolic pressure ≥ 2/3 systemic 
pressure)  
 
21. 
History of cirrhosis or any active liver disease  
22. Significant frailty as determined by the Heart Team (after objective assessment 
of frailty parameters). 
 
23. Significant abdominal or thoracic aortic disease (such as porcelain aorta, 
aneurysm, severe clacification, aortic coarctation, etc.) that would preclude safe 
passage of the delivery system or cannulation and aortotomy for surgical AVR 
 
24. 
Hostile chest or conditions or complications from prior surgery that would 
preclude safe reoperation (i.e., mediastinitis, radiation damage, abnormal chest 
wall, adhesion of aorta or IMA to sternum, etc.) 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 30 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
25. 
Patient refuses blood products 
 
26. BMI > 50 kg/m2 
 
27. 
Estimated life expectancy < 24 months 
 
28. Absolute contraindications or allergy to iodinated contrast that cannot be 
adequately treated with pre-medication 
 
29. Immobility that would prevent completion of study procedures (e.g. six-minute 
walk tests, etc.) 
 
30. Patient is not a candidate for both arms of the study (not applicable to single-
arm registries) 
 
31. 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. Observational studies are not considered exclusionary. 
 
7.3 
CT Imaging Sub-Study 
 
Sites with the ability to perform high quality 4D scans will be selected to participate in 
a CT sub-study. 
 
7.3.1 Inclusion Criteria 
 
All CT sub-study participants must meet inclusion criteria listed in Section 7.1. 
 
7.3.2 Exclusion Criteria 
 
In addition to the exclusion criteria in section 7.2, candidates will be excluded from 
the sub- study if the following is present: 
 
1. Condition requiring or planned use of anticoagulants following the valve implant 
procedure. 
2. GFR <50 
3. Inability to perform high-quality MDCT study for any reason (e.g., atrial 
fibrillation with rapid ventricular response) 
7.4 
Actigraphy/QOL Sub-Study Eligibility Criteria [Enrollment Closed] 
 
Select sites will be invited to participate in an Actigraphy/QOL sub-study.  Patients must 
meet all the eligibility criteria of the PARTNER 3 study in sections 7.1 and 7.2.  In addition, 
they must demonstrate a basic working knowledge of and ability to use the devices 
specified in the sub-study.  Patients who are non-ambulatory (i.e, wheelchair bound) will 
not be eligble. 
 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 31 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
7.5 
Alternative Access Registry Eligibility Criteria [Enrollment Closed] 
 
Patients who do not have appropriate iliofemoral access as defined in exclusion 
criterion 2 in Section 7.2 but meet all other inclusion and exclusion criteria should be 
considered for enrollment in the alternative access registry. 
 
7.6 
Bicuspid Registry Eligibility Criteria 
 
Patients who have a bicuspid valve as determined by the CT core lab (e.g., 
exclusion criterion 4) should be considered for enrollment in this registry if they meet 
all other eligibility criteria in Sections 7.1 and 7.2 and none of the following additional 
exclusion criteria: 
 
1. Aneurysmal ascending aorta (i.e., >4.0 cm) 
2. Severe or bulky calcification of the left ventricular outflow tract (LVOT) or 
raphe that would increase the risk of annular injury or significant paravalvular 
leak (PVL) post TAVR  
3. Coronary anatomy that increases the risk of coronary artery obstruction post TAVR 
4. Positive urine or serum pregnancy test in female subjects of childbearing potential  
 
7.7 
Underrepresented Populations Registry Eligibility Criteria 
 
Up to ten (10) sites from  underrepresented geographical locations will be selected to 
enroll patients in a single-arm registry for underrepresented populations.  Patients at 
these sites are eligible for this registry if they meet all eligibility criteria in Sections 7.1 
and 7.2. 
 
8.0  
STUDY PROCEDURES  
 
8.1 
Screening Period 
 
The screening period is designed to obtain patient consent, determine patient 
eligibility for the study, and to submit the presentation for case review. The 
Screening Visit procedures will occur within the 30 days prior to the valve implant 
procedure, unless otherwise noted below. All patients that sign an informed consent 
will be entered into the electronic database (EDC) and be assigned a Subject ID. All 
assessments performed will be entered into EDC. 
 
Patients that have signed the informed consent and do not meet the 
inclusion/exclusion criteria in Section 7.1 and 7.2 will be considered a Screen Failure 
(SF). All assessments performed and the inclusion or exclusion criteria that was not 
met will be entered into EDC. 
 
The patient status will be considered ‘Discontinued’ if the following occur during the 
screening period: 
 
• 
The patient withdraws consent or expires prior to or after the Case Review. 
• 
The patient completes all of the screening procedures, including Case 
Review call, and the Case Review is not approved. 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 32 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
All assessments performed and the reason for discontinuation will be entered into 
EDC and the Exit form will be completed. 
 
The following information will be collected during the screening period: 
 
Consent: 
 
• 
Patient informed consent completion, (section 8.1.1) 
 
Operability: 
 
• 
STS Risk Score 
 
Other Assessments: 
 
• 
Logistic EuroSCORE 
• 
EuroSCORE II 
 
Systems: 
 
• 
Medical history and physical assessment (including height, weight, blood 
pressure, and heart rate). 
• 
Medications including all antithrombotics/anticoagulants and HMG coA 
reductase inhibitors. 
 
Cardiopulmonary: 
 
• 
Canadian Cardiovascular Society (CCS) status of angina 
• 
12-lead ECG 
• 
New York Heart Association Class (NYHA Classification) 
• 
Comprehensive transthoracic (TTE) echocardiogram, including assessment 
of aortic valve gradients (mean and peak), areas, indices, degree of 
regurgitation, left  ventricle systolic function (global and segmental). 
Qualifying echo must be performed within 90 days prior to randomization. 
• 
Cardiac imaging (TEE, CT, or cardiac MRI) with 3D reconstruction to 
determine aortic valve annulus area. Qualifying cardiac imaging must be 
performed within 1 year prior to randomization, unless clinically indicated. 
• 
CT Angiography, including thoracic and abdomen scan with visualization of 
iliac and femoral arteries. Qualifying iliofemoral CT must be performed within 
1 year prior to randomization. 
• 
Left heart catheterization to assess the severity of aortic stenosis and 
severity of coronary artery disease, if applicable. Qualifying catheterization 
must be performed within 1 year prior to randomization, unless clinically 
indicated. 
• 
SYNTAX Score for significant native coronary artery disease (CAD) 
• 
Pulmonary Function Test for patients with a history of lung disease 
 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 33 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Neurological Assessments: 
 
• 
Mini Mental State Examination (MMSE), (Appendix G) 
• 
National Institutes of Health Stroke Scale (NIHSS), (Appendix H) 
• 
Modified Rankin Scale (mRS), (Appendix I) 
 
Every effort should be made to have a neurologist (or neurology fellow) perform the 
NIHSS and mRS assessments. If it is not possible to have the neurologist/fellow 
perform the assessments within the protocol-specified visit window, a certified study 
team member may perform the assessments. 
 
Functional Assessments: 
 
• 
Six Minute Walk Test (6MWT), (Appendix E) 
• 
Frailty Index (5 Meter Walk Test (5MWT), grip strength, Activities of Daily 
Living (ADL), and Albumin laboratory) (Appendix F) 
• 
Quality of Life Assessments 
- 
KCCQ (Appendix N) 
- 
EQ-5D-5L (Appendix M) 
- 
SF-36 (Appendix O) 
 
Clinical Laboratory Tests: 
 
• 
WBC, Hgb, and platelet count 
• 
PT or INR 
• 
CK/CKMB and/or troponins ≤ 72 hours before the valve implant procedure 
• 
Creatinine 
• 
eGFR 
• 
Albumin (as part of Frailty Index) 
• 
Total Bilirubin 
• 
AST/ALT (required for patients with chronic liver disease) 
• 
B-type natriuretic peptide (BNP) 
 
8.1.1 Informed Consent 
 
The study investigator(s) and support staff will approach patients with severe, aortic 
stenosis to assess their interest in participating in the study by providing them an 
overview of the study including the background, risks, benefits and study procedures.  
If patients are interested in participating in the study, the study patient will sign the 
Institutional Review Board (IRB) approved informed consent form prior to any study 
specific procedures are performed. All patients consented should be entered into the 
study’s electronic database (EDC). 
 
8.1.2 Case Review 
 
The Case Review Board is a select review committee comprised of Investigators who 
are participating in the trial. The role of the Case Review Board is to review 
submitted cases to determine if the patient is an appropriate candidate for the trial, 
with a focus on confirming patient operative risk, valve sizing, appropriate vascular 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 34 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
access, valve morphology and any relevant clinical factors impacting enrollment 
eligibility. In addition, the Heart Team’s strategy for treatment of concomitant 
coronary artery disease will be reviewed, as applicable. Before a case is submitted 
for review, the site Principal Investigator and Heart Team will screen the patient for 
operative risk and fundamental enrollment criteria. It is required that at least one site 
surgeon Investigator personally examine the patient to determine operative risk. 
Once fully screened and deemed an appropriate candidate, the site will submit the 
case for review and approval consideration by the Case Review Board. The Sponsor 
will maintain a record of the case presentation and case approval notes. 
 
8.2 
Randomization and Enrollment  
 
Once all screening procedures have been completed, all inclusion/exclusion criteria 
have been confirmed and the Case Review has been completed and approved, the 
patient is eligible to be randomized or enrolled into one of the single-arm registries. 
 
Randomization will occur centrally. To randomize a patient, the investigative site will 
enter the subject into the designated electronic system and obtain the treatment 
assignment (TAVR or SAVR). Once the assignment has been made, the subject will 
be considered randomized and enrolled into the study. 
 
All randomized patients will be considered part of the Intent to Treat (ITT) population. 
Randomized patients are considered enrolled in the study; for the randomized 
patients, the terms “randomized” and “enrolled” have the same meaning. 
 
If the patient has been enrolled and the patient withdraws consent prior to the valve 
implant procedure start, the patient will be considered discontinued. All assessments 
performed and the reason for withdrawal will be entered into EDC and the Exit form 
will be completed. 
 
8.3 
Procedure (Day 0) 
 
The valve implant procedure should occur within 14 days of randomization and no 
later than 30 days after informed consent is obtained. The date of the valve implant 
procedure is considered Day 0.The valve implant procedure will be considered to 
have started when: 
 
• 
The first interventional access related puncture (venous or arterial) is established 
for TAVR. 
• 
The first skin incision is performed for SAVR. 
 
Performance of TEE does not by itself constitute start of procedure. 
 
For those patients receiving TAVR, the commercially available SAPIEN 3 THV with 
the Commander Delivery System , or the Certitude Delivery system if treated with a 
transapical or transaortic approach as part of the Alternative Access registry 
[enrollment closed], and components will be used per the most current Instructions 
for Use (IFU) at all times for device sizing, preparation, and recommended implant 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 35 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
procedure. Refer to Appendix C for the IFUs to be used in this study. 
 
For those patients receiving SAVR, a commercially available bioprosthetic surgical 
valve and associated components will be used according to institution standard of 
care. 
 
Day 0 will be used to schedule all subsequent visits and calculate visit windows.  
Patients who receive the assigned TAVR or SAVR implant will continue in the study 
and complete the study through year 10 according to the visits and events described 
in section 8.0 and Schedule of Procedures. 
 
Day 0 valve implant procedure assessments will include the following: 
 
Systems: 
 
• 
Medications including all antithrombotics/anticoagulants and HMG coA 
reductase inhibitors. 
• 
Adverse event assessment 
 
Cardiopulmonary: 
 
• 
Comprehensive transthoracic (TTE) or transesophageal (TEE) 
echocardiogram 
• 
Supra-aortic angiogram or TEE 
 
If the valve implant is aborted (prior to or after the start of the valve implant 
procedure), the Day 0 visit may be re-scheduled if the patient continues to meet all 
inclusion/exclusion criteria. 
 
8.3.1 Device Preparation 
 
A detailed description of device preparation and required equipment is supplied in the 
Instructions for Use (Appendix C). 
 
8.3.2 Procedure Recommendations 
 
Table 8.3.2-1 outlines the recommended anticoagulation/antithrombotic 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 [26]. 
 
NOTE: The CHAD score only applied to patients in Atrial Fibrillation (AF) and had not been validated in 
non-AF patient populations; therefore the CHAD score reference was used as one among many 
guidelines to establish the risk stratification for intensity of anticoagulation regimen. 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 36 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Table 8.3.2-1 Recommended anticoagulation/antithrombotic regimen 
 
 
AVR 
TAVR 
Pre valve implant procedure 
Aspirin 81-100 mg QD 
Aspirin 81-100 mg QD 
• Patients with BMS within one 
month or drug eluting stent 
(DES) within 12 months should 
be continued on 
Clopidogrel/prasugrel prior to 
their implant procedure 
• Patients in atrial fibrillation on 
warfarin should be bridged 
with LMW or UF heparin 
prior to the implant 
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 the 
implant procedure.  If intra-
procedural TEE during AVR 
reveals thrombus, implant 
procedure will be aborted and 
delayed until patient has been 
on warfarin or dabigatran for 30 
days. In patients in the surgical 
group with LA clot seen on 
intraoperative TEE, implant 
procedure can proceed per 
surgical standard of care 
• Patients with BMS within one month or 
DES within 12 months should be continued 
on Clopidogrel/prasugrel prior to their 
implant procedure 
• Patients in atrial fibrillation on warfarin should 
be bridged with LMW or UF heparin prior to 
the implant 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 implant procedure.  If intra- 
procedural TEE during TAVR reveals 
thrombus, implant procedure will be aborted 
and delayed until patient has been on 
warfarin or dabigatran for 30 days.  Note: 
thrombus must be eliminated in order to 
proceed with TAVR. 
• In patients undergoing concomitant 
TAVR/PCI, clopidogrel loading with 
either 300mg or 600mg prior to the 
implant procedure is recommended in 
addition to ASA 
 
Intraprocedural 
Heparin will be given to 
achieve/ maintain ACT>250 
Heparin will be given to achieve/ maintain 
ACT>250 sec. 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 37 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
AVR 
TAVR 
Post valve implant procedure 
Category 
I for 
Stroke 
Risk 
No atrial 
fibrillation, 
No recent 
stents 
• ASA 81mg qd 
• Clopidogrel 75qd started 24 
hours post-surgery for at least 
one month if clinically safe and 
at the discretion of the surgical 
team.  In centers that use 
warfarin post-surgical AVR, 
Clopidogrel will not be started 
• ASA 81mg qd 
• Clopidogrel 300mg load within 6 hours of the 
implant procedure (either pre or post) 
• Clopidogrel 75mg qd for at least one month 
post implant procedure 
Category 
II for 
Stroke 
Risk 
No atrial 
fibrillation, 
recent 
stents 
• ASA 81mg qd 
• Clopidogrel should not be 
discontinued prior to 
surgery if patient had BMS 
within one month or DES in 
12 months 
• Clopidogrel 75qd started 24 
hours post-surgery if clinically 
safe and continued for at least 
one month post-surgical AVR 
in those with BMS and a total 
• ASA 81mg qd 
• Clopidogrel 75mg qd should be continued 
prior to the implant procedure and after the 
implant 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 81mg qd 
• Patients should be started on 
warfarin or dabigatran 24 
hours post AVR if clinically 
safe and this should be 
continued for at least one 
month or indefinitely if 
possible.  If clinically safe, 
patient’s being 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 dagibatran, 
Clopidogrel 75mg qd (in 
addition to ASA 81 mg) can be 
• ASA 81mg qd 
• Patients should be started on warfarin or 
dabigatran 24 hours post TAVR 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 dagibatran, Clopidogrel 75mg qd can 
be considered as an alternative 
 
 
 
 
 
 
 
 
 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 38 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
AVR 
TAVR 
Category IV 
for Stroke 
Risk 
Atrial 
fibrillation, 
recent 
stents 
• ASA 81mg qd 
• Clopidogrel 75mg qd for at least 
one month post BMS or 12 
months post DES 
• Patients should be started on 
warfarin or dabigatran 24 hours 
post AVR if clinically safe and 
continued indefinitely.  If clinically 
safe, patients being started on 
warfarin should be bridged with 
UF or LMW heparin until INR 
therapeutic. 
• ASA 81mg qd 
• Clopidogrel 75mg qd for at least one 
month post BMS or 12 months post 
DES 
• Patients should be started on warfarin or 
dabigatran 24 hours post TAVR 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 antithrombotic/anticoagulation regimen from study visit to study visit will be noted 
on the Case Report Form (CRF) including reason for change. 
 
8.3.3 Antibiotic Prophylaxis 
 
Study patients should be prophylactically treated for endocarditis per the 
recommendations of the American Heart Association. 
 
8.3.4 Contrast Media 
 
Careful management of contrast media is required. Accurate measurement of the 
contrast used will be captured in the case report form. 
 
8.3.5 Radiation Precautions 
 
Radiation precautions will be adhered to per institutional standards. Total 
procedural radiation exposure will be documented on the case report forms in 
accordance with institutional measures (i.e. total procedural fluoroscopy time, 
dosage, etc.). 
 
Radiation exposure of 6-15 mSv is estimated for the Screening CT and each Sub-study 
CT  [27]. If a radiation induced skin injury is suspected, the Investigator should see the 
patient at an office visit, and should arrange for appropriate follow-up care. 
 
8.4 
Post Procedure 
 
The post implant procedure time period is defined as the 48 hours after the patient 
exits the cath lab/ operating room. Study patients will be continuously monitored 
clinically, hemodynamically, and electrocardiographically during catheterization for all 
local, systemic side effects and complications.  After completion of the implant 
procedure, all study patients will be monitored per institution standard of care. 
Subsequent monitoring will also be continued according to institutional standard of 
care. 
 
 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 39 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
The following information will be collected during the Post Procedure time period: 
 
Systems: 
 
• 
Medications including all antithrombotics/anticoagulants and HMG coA 
reductase inhibitors .  
• 
Adverse event assessment 
 
Cardiopulmonary: 
 
• 
12-lead ECG 
 
Clinical Laboratory Tests: 
 
• 
WBC, Hgb, and platelet count 
• 
PT or INR 
• 
CK/CKMB and/or Troponins will be performed to monitor the patient’s cardiac 
enzymes at 3 different time intervals. Of note, patients discharged prior to the 
completion of 24 hour series of lab tests will not be issued deviations. 
- 
The first lab draw post implant procedure (within 8 hours of exit from the 
cath lab 
/ operating room) 
- 
The second lab draw, (6 – 8 hours after the first lab draw) 
- 
The third lab draw, (6 – 8 hours after the second lab draw) 
• 
Creatinine 
 
Neurological assessments: 
 
• 
NIHSS 
 
All patients should be assessed post-procedure to determine if there is evidence of 
neurological impairment. If symptoms of stroke are suspected, the NIHSS should be 
performed.  For all patients diagnosed with stroke after procedure, a follow-up mRS 
assessment 90 days after the diagnosis should be performed (on site or phone calls). 
Evaluation of stroke by mRS between 30 and 90 days is acceptable if 90-day follow-up 
not available. Every effort should be made to have a neurologist (or neurology fellow) 
perform the assessment. If it is not possible to have the neurologist/fellow complete this 
within the protocol-specified visit window, a certified study team member may perform 
the assessments. 
 
8.5  
Discharge 
 
Discharge is the actual date and time the patient is discharged.  For patients 
discharged within 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. If the patient was discharged over a weekend or holiday, the 
discharge assessments may be completed on the last weekday prior to discharge. 
 
The following information will be collected for study patients within 24 hours of the 
date and time of discharge. 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 40 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
Systems: 
 
• 
Physical assessment including weight, blood pressure, and heart rate 
• 
Medications including all antithrombotics/anticoagulants 
and HMG coA 
reductase inhibitors.  
• 
Adverse event assessment 
 
Cardiopulmonary: 
 
• 
NYHA classification 
• 
Comprehensive transthoracic echocardiogram (TTE) 
 
Clinical Laboratory Tests: 
 
• 
WBC, Hgb,  and platelet count 
• 
PT or INR 
• 
Creatinine 
• 
BNP 
 
Neurological Assessments: 
 
• 
NIHSS 
 
All patients should be assessed at Discharge to determine if there is evidence of 
neurological impairment. If symptoms of stroke are suspected, the NIHSS should be 
performed.  For all patients diagnosed with stroke after procedure, a follow-up mRS 
assessment 90 days after the diagnosis should be performed (on site or phone 
calls). Evaluation of stroke by mRS between 30 and 90 days is acceptable if 90-day 
follow-up not available. Every effort should be made to have a neurologist (or 
neurology fellow) perform the assessment. If it is not possible to have the 
neurologist/fellow complete this within the protocol-specified visit window, a certified 
study team member may perform the assessments. 
 
8.6  
Post Procedure Follow Up Visits 
  
8.6.1  
30 Day Post Procedure Visit 
 
The 30 day post procedure visit window will be calculated from the Day 0 valve implant 
date. The visit window is +7 days. 
The following data will be collected for all study patients 30 days post implant 
procedure. 
 
Systems: 
 
• 
Physical assessment including weight, blood pressure, and heart rate 
• 
Medications including all antithrombotics/anticoagulants 
and HMG coA 
reductase inhibitors.  
• 
Adverse event assessment 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 41 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Cardiopulmonary: 
 
• 
12-lead ECG 
• 
NYHA classification 
• 
Comprehensive transthoracic echocardiogram (TTE) 
• 
CT Scan (only for those patients in the CT sub-study) (section 12.5.2.1) 
 
Neurological Assessments: 
 
• 
MMSE 
• 
NIHSS 
• 
Modified Rankin Scale 
 
For all patients diagnosed with stroke between discharge and 30 days post-procedure, a 
follow-up mRS assessment 90 days after the diagnosis should be performed (on site or 
phone calls). Evaluation of stroke by mRS between 30 and 90 days is acceptable if 90-
day follow-up not available. Every effort should be made to have a neurologist (or 
neurology fellow) complete the NIHSS and mRS assessment. If it is not possible to have 
the neurologist/fellow complete this within the protocol-specified visit window, a certified 
study team member may perform the assessments. 
 
Functional Assessments: 
 
• 
6MWT 
• 
Quality of Life Questionnaires 
- 
KCCQ 
- 
EQ-5D-5L 
- 
SF-36 
 
Clinical Laboratory Tests: 
 
• 
WBC, Hgb, and platelet count 
• 
Creatinine 
• 
BNP 
 
8.6.2 6 Month Post Procedure Visit 
 
The 6 month post implant procedure visit window will be calculated from the Day 0 visit 
date. The visit window is +14 days. 
 
The following data will be collected for all study patients 6 months post valve implant 
procedure. 
 
Systems: 
 
• 
Physical assessment including weight, blood pressure, and heart rate 
• 
Medications including all antithrombotics/anticoagulants and HMG-CoA 
reductase inhibitors. 
• 
Adverse Event assessment 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 42 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Cardiopulmonary: 
 
• 
NYHA classification 
 
Neurological Assessments: 
 
The following assessments should be completed for all patients diagnosed with 
stroke after the procedure: 
 
• 
NIHSS 
• 
Modified Rankin Scale 
 
For all patients diagnosed with stroke between 30 days and 6 months post-procedure, a 
follow-up mRS assessment 90 days after the diagnosis should be performed (on site or 
phone calls). Evaluation of stroke by mRS between 30 and 90 days is acceptable if 90-
day follow-up not available. Every effort should be made to have a neurologist (or 
neurology fellow) perform the assessment. If it is not possible to have the 
neurologist/fellow complete this within the protocol-specified visit window, a certified 
study team member may perform the assessments. 
 
Functional Assessments: 
 
• 
Quality of Life Questionnaires 
- 
KCCQ 
- 
EQ-5D-5L 
- 
SF-36 
 
8.6.3 12 Month Post Procedure Visit 
 
The 12 month post implant procedure visit window will be calculated from the Day 0 
valve implant date. The visit window is +30 days. 
The following data will be collected for all study patients 12 month post implant 
procedure. 
 
Systems: 
 
• 
Physical assessment, (including weight and blood pressure) 
• 
Medications including all antithrombotics/anticoagulants 
and HMG-CoA 
reductase inhibitors. 
• 
Adverse Event assessment 
 
Cardiopulmonary: 
 
• 
12 lead ECG 
• 
NYHA classification 
• 
Comprehensive transthoracic echocardiogram (TTE) 
• 
CT Scan (only for those patients in the CT sub-study) 
 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 43 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Neurological Assessments: 
 
• 
MMSE 
 
The following assessments should be completed for all patients diagnosed with 
stroke after the procedure: 
 
• 
NIHSS 
• 
Modified Rankin Scale 
 
For all patients diagnosed with stroke between 6 months and 12 months post-
procedure, a follow-up mRS assessment 90 days after the diagnosis should be 
performed (on site or phone calls). Evaluation of stroke by mRS between 30 and 90 
days is acceptable if 90-day follow-up not available. Every effort should be made to 
have a neurologist (or neurology fellow) perform the assessment. If it is not possible to 
have the neurologist/fellow complete this within the protocol-specified visit window, a 
certified study team member may perform the assessments. 
 
Functional Assessments: 
 
• 
6MWT 
• 
Quality of Life Questionnaires 
- 
KCCQ 
- 
EQ-5D-5L 
- 
SF-36 
 
8.6.4 Years 2 through 10 Annual Post Procedure Visit 
 
The yearly post implant procedure visit window will be calculated from the Day 0 
valve implant date. The visit window is +45 days. 
 
The following data will be collected for all study patient’s years 2 through 10 annually 
post implant procedure visit. 
 
Systems: 
 
• 
Physical assessment including weight, blood pressure and heart rate 
• 
Medications including  all antithrombotics/anticoagulants and HMG coA 
reductase inhibitors. 
• 
Adverse event assessment 
 
Cardiopulmonary: 
 
• 
NYHA classification 
• 
Comprehensive transthoracic echocardiogram (TTE) [years 2, 3, 4, 5, 7, and 
10 only] 
 
 
 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 44 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Functional Assessments: 
 
• 
Quality of Life Questionnaire 
- 
KCCQ 
- 
SF-36 
 
Neurological Assessment (2 Year Post Procedure Visit only): 
 
For all patients diagnosed with stroke between 1 year and up to 2 years post-
procedure, a follow-up mRS assessment 90 days after the diagnosis should be 
performed (on site or phone calls). Evaluation of stroke by mRS between 30 and 90 
days is acceptable if 90-day follow-up not available. Every effort should be made to 
have a neurologist (or neurology fellow) perform the assessment. If it is not possible to 
have the neurologist/fellow complete this within the protocol-specified visit window, a 
certified study team member may perform the assessments. 
 
8.7 
Missed Visits 
 
Site personnel should make all reasonable efforts to locate and communicate with 
the subject at each visit time point.  For each missed visit, a minimum of 3 attempts 
to contact the subject should be recorded in source documentation, including date, 
time and name of site personnel trying to make contact. 
 
8.8 
Lost to Follow-Up 
 
If the patient has missed multiple visits (with multiple attempts to contact as noted in 
section 8.9) and no record of death is found, the patient may be considered a lost to 
follow up. All assessments performed and the reason for discontinuation will be 
entered into EDC and Exit form completed. 
 
8.9 
Discontinuation after entering procedure room 
 
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.  All attempts should 
be made to have the patient come into the clinic for an Exit visit. 
 
If the following situations occur, the patient status will be considered ’Discontinued’: 
 
• 
The patient has entered the cath lab or operating room (procedure room) and 
an inclusion or exclusion criteria failure has been found. 
• 
The patient has entered the procedure room and expires prior to the start of 
the valve implant procedure. 
• 
The patient expires after the procedure has started. 
• 
The patient withdraws consent after the valve implant procedure and prior to 
the final study visit. 
• 
The patient expires after the valve implant procedure and prior to the final 
study visit. 
 

The PARTNER 3 Trial, Version 5.0  DEC 2018  
CONFIDENTIAL 
Page 45 
 
  
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
If the patient is randomized to TAVR but has a THV other than the SAPIEN 3 
implanted, the patient status will be considered discontinued and the patient will be 
monitored through Day 30 or until any AEs occurring are resolved. 
 
All assessments performed and the reason for discontinuation will be entered into 
EDC and Exit form completed. 
 
8.10 
Randomized TAVR patient receives SAVR 
 
Patients who are randomized to TAVR but undergo SAVR will continue in the study 
and complete all remaining study visits. The reason for conversion from TAVR to 
SAVR will be entered into EDC. 
 
8.11 
Death Registries 
 
In the event of a patient lost to follow-up or early withdrawal, Edwards may opt to 
search the Social Security Death Index and/or other death registries. If the patient is 
confirmed to be expired, Edwards may opt to obtain the death certificate. 

The PARTNER 3 Trial, Version 5.0 DEC 2018  
        CONFIDENTIAL 
 
 
 
Page 46 
 
 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Schedule of Procedures 
 
Screening 
Procedure 
(Valve Implant) 
Post 
Procedure 
Discharge 
30D 
6M 
12M 
2-10Y 
Visit Window 
Day -30d 
Day 0 
+7 days 
+14 days 
+30 days 
+45 days 
Physical Assessment 
Informed Consent 
X 
Medical History 
X 
Physical Assessment 
X 
X 
X 
X 
X 
X 
CCS Angina 
X 
NYHA Classification 
X 
X 
X 
X 
X 
X 
MMSE 
X 
X 
X 
STS Risk Score 
X 
Logistic EuroSCORE 
X 
EuroSCORE II 
X 
SYNTAX Score 
X 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
NIHSSa 
X 
Xa 
Xa 
X 
Xa 
Xa 
Modified Rankin Scalea 
X 
 
 
X 
Xa 
Xa 
 
6 Minute Walk Test 
X 
X 
X 
Frailty Indexk 
X 
Laboratory Measurements 
WBC, Hgb, Platelet Count 
X 
X 
X 
X 
PT or INR 
X 
X 
X 
CK/CKMB and/or Troponins 
Xb 
Xc 
eGFR 
X 
Creatinine 
X 
X 
X 
X 
Albumin, Total Bilirubin 
X 
AST/ALTm 
X 
BNP 
X 
X 
X 
 

The PARTNER 3 Trial, Version 5.0 DEC 2018  
        CONFIDENTIAL 
 
 
 
Page 47 
 
 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
Screening 
Procedure 
(Valve Implant) 
Post 
Procedure 
Discharge 
30D 
6M 
12M 
2-10Y 
Visit Window 
Day -30d 
Day 0 
+7 days 
+14 days 
+30 days 
+45 days 
Non-Invasive Tests 
Pulmonary Function Test (PFT) 
Xl 
ECG 
X 
X 
X 
X 
Echocardiogram (TTE) 
 Xe 
Xj 
X 
X 
 
X 
Xe 
Final Eligibility Review 
Case Reviewi 
X 
Invasive Tests 
Sub-study CTf 
X 
X 
3D Cardiac imaging (CT, TEE, or 
cardiac MRI) h 
 X 
Iliofemoral CT Angiographyg 
X 
Valve implant procedure (TAVR 
or SAVR) 
X 
Cardiac Catheterization 
X 
Supra-aortic angiogram or TEE 
Xj 
Quality-of-Life Assessments 
KCCQ 
X 
X 
X 
X 
X 
EQ-5D-5L 
X 
X 
X 
X 
SF-36 
X 
X 
X 
X 
X 
a 
All patients should be assessed post-procedure to determine if there is evidence of neurological impairment. If symptoms of a stroke are suspected, the NIHSS should be performed. Every 
effort should be made to have a neurologist or neurology fellow perform the neurological assessments. 6M and 1Y assessments to be performed only for patients diagnosed with a stroke after 
the procedure. 
b 
CK/CKMB and/or Troponins are required ≤ 72 hours before the valve implant procedure. 
c 
Post Procedure CK/CKMB and/or Troponins are required at 3 different time intervals: 1.) At the first lab draw post valve implant procedure (within 8 hours of exiting the cath lab or operating 
room) 2.) At the second lab draw 6 – 8 hours after the first lab draw 3.) At the third lab draw 6 – 8 hours after the second lab draw. 
d 
Screening procedures will be completed within 30 days prior to the valve implant procedure unless otherwise noted.  
e 
Qualifying echocardiogram must have been performed within the 90 days prior to randomization. Echocardiograms to be 
obtained years 2, 3, 4, 5, 7, and 10. 
f 
Only for those patients participating in the CT sub-study (section 12.5.2.1). Additionally, if the patient presents with symptoms, an unscheduled CT scan should be performed, 
g 
Includes thoracic and abdomen scan with visualization of iliac and femoral arteries. 
h 
All patients will have cardiac imaging at the screening visit regardless of participation in the CT sub-study. 
i 
Case Review will be completed when all screening procedures have been completed, all inclusion/exclusion criteria have been fundamentally confirmed and the site is ready to present a case. 
j 
TTE or TEE on date of valve implant procedure. 
k 
Frailty Index includes activities of daily living (ADLs), 5 meter walk test (5MWT), grip strength, and albumin laboratory.     
l 
Only for patients with a history of lung disease. 
m        Only required for patients with chronic liver disease.
 

The PARTNER 3 Trial, Version 5.0 DEC 2018  
CONFIDENTIAL 
Page 48 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
8.12 
Procedures for Actigraphy/QOL Sub-study [Enrollment Closed] 
 
 
Patients will receive a tablet and wearable activity tracker during the screening process 
and prior to randomization.  A trained research assistant at each site will instruct patients 
on how to wear and use the devices.  Baseline QOL and activity will be established during 
a pre-procedure phase (between screening and the procedure date).  A preprogrammed 
algorithm will send alarm prompts to complete the VAS Pain assessment on the tablet 
every other day beginning at screening and ending on day 44 post procedure.  The 
KCCQ-12 and PF-10 Physical will be completed via the tablet at 1, 2, 3, 5 and 6 week time 
points following the procedure.  Activity data will be tracked continuously in 15-minute 
increments from screening through 44 days post procedure. Quality of life data will be 
captured via Medidata’s Patient Cloud ePRO system, which allows patients to enter 
questionnaire data into commercially available smartphones and tablets that automatically 
synchronize with the Medidata platform.  Activity data will be captured via Medidata’s 
mobile health offering, which involves direct integration with wearable devices (i.e., Garmin 
Vivofit2).  Activity data is authenticated and securely ingested by the Medidata Clinical 
Cloud, where it is then audited, processed and integrated with the rest of the clinical 
record. 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
The PARTNER 3 Trial, Version 5.0 DEC 2018 
        CONFIDENTIAL 
 
 
 
Page 49 
 
 
 
Schedule of Procedures Actigraphy/QOL Sub-Study [Enrollment Closed] 
 
 
Screening 
 
Procedure Day 
Post-Procedure  
Time window: + 12 hours 
+ 
2 
+ 
4 
+ 
6 
+ 
8 
+ 
10 
+ 
12 
+ 
13 
+ 
14 
+ 
16 
+ 
18 
+ 
20 
+ 
22 
+ 
24 
+ 
26 
+ 
28 
+ 
30 
+ 
32 
+ 
34 
+ 
36 
+ 
37 
+ 
38 
+ 
40 
+ 
42 
+ 
44 
VAS Pain 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Time window: + 1 day 
KCCQ-12 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
PF-10 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Notes: 
- 
ePRO based VAS pain assessment will be completed every other day.  A 12 hour time window will be allowed for patients to 
complete each assessment 
- 
ePRO based KCCQ-12 and PF-10 assessments will be completed at 1-week, 2-weeks, 3-weeks, 5-weeks and 6-weeks post 
procedure.  A one day time window will be allowed for patients to complete each assessment.  Note: to lessen patient burden, 
ePRO based KCCQ-12 and PF-10 assessments will not be completed at baseline and 30-day follow-up as paper based 
assessments are already administered at those time points 
- 
Paper based KCCQ, EQ-5D-5L and SF-36 will be administered at screening, 30-days, 6 months, 12 months.  Note: KCCQ-12 
and PF-10 scores can be derived from the longer KCCQ and SF-36 instruments 
- 
Daily activity data is defined based on the subject’s time zone and day 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 50 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
9.0 
ADVERSE EVENTS 
 
9.1 
Adverse Event 
 
An Adverse Event (AE) is any untoward medical occurrence, unintended disease or 
injury or untoward clinical signs (including abnormal laboratory findings) in patients, 
users or other persons, whether or not related to the investigational medical device. 
 
Adverse events may be volunteered by patients, elicited by the Investigator or 
designee, the CEC, safety team, monitoring team, or collected via observation by the 
Investigator.  All AEs will be assessed by the Investigator who will determine 
whether or not the event is related to the device and/or implant procedure, and 
whether or not the event meets serious criteria. If i t  is determined that an AE has 
occurred, the investigator should obtain all the information required to complete the 
AE Form of the CRF.   
 
In addition, patients will be instructed to contact the investigator, and/or study 
coordinator if any significant adverse events occurs between study visits. 
All clinically significant AEs will be reported by the Investigator and reviewed by the 
Sponsor in compliance with applicable regulations as indicated below section 9.5. 
 
9.2 
Serious Adverse Event 
 
An Adverse Event is considered serious if the event: 
 
• 
Leads to death; 
• 
Leads to a serious deterioration in the health of the study patient that: 
o Results in life-threatening illness or injury; 
o Results in a permanent impairment of a body structure or a body 
function; 
o Requires inpatient hospitalization or prolongation of existing 
hospitalization; 
o Results in medical or surgical intervention to prevent permanent 
impairment to body structure or a body function; 
• 
Led to fetal distress, fetal death or congenital abnormality or birth defect; 
• 
Significant medical event. 
 
 
Important medical events that do not meet the above criteria may still be considered 
an SAE if they seriously jeopardize the patient and require immediate medical or 
surgical intervention to prevent one of the aforementioned outcomes. 
 
 
Death should not be recorded as an adverse event, but should only be reflected as 
an outcome to another specific AE. 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 51 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
9.3 
Anticipated Adverse Events 
 
Anticipated adverse events are AEs that have been identified as possible adverse 
events related to the investigational device or implant procedure. 
 
9.4 
Unanticipated Adverse Device Effect 
 
An Unanticipated Adverse Device Effect (UADE) is any serious adverse effect on 
health or safety or any life-threatening problem or death caused by, or associated 
with a device, if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious problem 
associated with a device that  relates to the rights, safety or welfare of patients. 
 
The Investigator shall submit to the Sponsor and the reviewing EC/IRB a report of 
any UADE occurring during an investigation as soon as possible, but no later 
than 10 working days of awareness. 
 
All UADE adverse events must be followed until resolution or until a stable clinical 
endpoint is reached.  All required treatments and outcomes of the UADE adverse 
event must be recorded. 
 
Edwards will notify FDA as well as all participating clinical investigators and IRBs of 
all UADEs that occur during this study within 10 working days after becoming aware 
of the event. Investigators are responsible for reviewing information received about 
UADEs. 
 
9.5 
AE Reporting Requirements 
 
All relevant AEs will be captured from the time of randomization/enrollment until the 
study patient’s participation has ended (i.e. completion of study or withdrawal of 
consent). 
 
Adverse events must be followed until resolution, stabilization or study completion. 
The AE and/or SAE should be reported, and CRF Forms completed as soon as 
possible but no later than 10 working days of awareness. 
 
In the event that the EDC system is not in service, a paper copy of the AE Case 
Report Form (CRF) must be faxed or emailed to Sponsor THV Medical Safety at 
(949) 809-2933 or emailed to THV_Safety@edwards.com within 10 business days 
of becoming aware of the event. At the time of initial notification, the following 
minimal information must be provided: 
 
• 
Study site 
• 
Patient ID 
• 
Adverse event description 
• 
Causal relationship to device and implant procedure 
• 
Aware date 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 52 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
The site will provide a copy of supporting documentation (example: admission H&P, 
implant procedure reports, anesthesia records, discharge summary, echocardiogram 
and ECG reports, laboratory results, etc.) for all endpoint-related and device or 
procedure-related events and UADEs to Edwards Lifesciences (or designee).  
Source documentation may be requested by the Edwards Medical Safety Officer for 
other AEs in order to verify that events are being assessed appropriately. 
 
Enrolling sites must provide to the Sponsor at a minimum an admission history and 
physical, index procedure report and discharge from index hospitalization along with 
relevant echocardiographic reports. This will be done irrespective of subject having 
any AE/SAE.  
 
All AEs must be reported over the 12 month period following the initial valve implant 
procedure.  Reportable AEs after year 1 through year 10 or study exit include only the 
following events: 
 
• 
All AEs that are assessed or suspected to be device or implant procedure 
related 
• 
All AEs that meet the criteria for serious adverse event irrespective of device 
or implant procedure relationship 
• 
All AEs considered to be an Unanticipated Adverse Device Effect 
 
The site Principal Investigator is responsible for informing the Institutional Review 
Board (IRB) of SAEs, UADE and/or AEs as required. A copy of this report should be 
provided to the Sponsor (or designee). 
 
Events that do not Require Reporting to the Sponsor: 
 
For purposes of this study, the following events will not be required to be reported as 
adverse events to the Sponsor, because they are normally expected to occur in 
conjunction with transcatheter valve implantation and surgical valve replacement or 
are associated with customary, standard care of patients undergoing THV 
implantation or surgical AVR: 
 
• 
Post-operative pain. 
• 
Post-anesthesia emesis, nausea, or headache (within 24 hours of procedure). 
• 
Electrolyte imbalance without clinical sequelae following procedure, even if 
requiring correction. 
• 
Pre-planned future surgical procedures not associated with the study procedure 
or device. 
• 
Low grade temperature increase (≤ 101°F or 38.5°C). 
• 
Dizziness: Imprecise term commonly used to describe various symptoms such as 
faintness, giddiness, imbalance, lightheadedness, unsteadiness or vertigo 
without signs of TIA or stroke. 
• 
Elevated white blood count, outside the standard laboratory normal value, without 
signs and symptoms of infection. 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 53 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
• 
Minor, localized tenderness, swelling, induration, oozing, etc. at incision / delivery 
system insertion site. 
• 
Systolic or diastolic blood pressure changes that do not require treatment or 
intervention. 
• 
Thrombocytopenia: does not become an AE until treatment is administered; 
Suspected heparin-induced thrombocytopenia (HIT) should be reported 
• 
Hyperglycemia - The use of insulin in the post-operative period does not 
constitute hyperglycemia if during the index hospitalization. An elevated blood 
sugar of less than 250 mg/dl during the first 48 hours post-operative does not 
constitute hyperglycemia. 
• 
Expected, non-clinically significant events such as non-significant lab variances. 
 
9.6 
Pre-existing Condition 
 
Pre-existing medical conditions or symptoms reported prior to subject enrollment will 
not be recorded as an AE. In the event there is a worsening in the pre-existing 
medical condition or symptoms due to the device, implant procedure, or study 
related procedures, then an AE must be recorded. 
 
Death should not be recorded as an adverse event, but should only be reflected as an 
outcome to another specific AE. 
 
9.7 
Causality of AEs 
 
For each AE, the Investigator will determine whether the event is related to the 
device and/or the implant procedure, and whether the event meets the 
definition of a SAE as outlined in section 9.2. 
 
The causal relationship of the event to the device and the implant procedure will be 
categorized as follows: 
• 
None:  The event is not associated with the device or implant procedure. 
There is no relation between the event and the device or implant procedure. 
• 
Possibly Related: The temporal sequence between the device or implant 
procedure and the event is such that the relationship is not unlikely or there is no 
contradicting evidence that can reasonably explain the study patient’s condition. 
There is a possibility of any relation between the event and the device or implant 
procedure. 
• 
Definitely Related: The temporal sequence is relevant or the event abates upon 
device application completion/removal or the event cannot be reasonably 
explained by the patient’s condition or comorbidities. The event is related or most 
likely associated with the device or implant procedure. 
 
9.8 
Sponsor Assessment of AEs 
 
All AEs will be reviewed by the Medical Safety Officer.  Each AE will be assessed as 
to its relationship to the study device and/or implant procedure, whether it was 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 54 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
anticipated or not anticipated, (based on the list of potential risks provided in section 
10.2), and whether it qualifies as an SAE. 
 
9.9 
Device Malfunctions 
 
A device malfunction is defined as the failure of a device to meet its performance 
specifications or otherwise perform as intended. Performance specifications include 
all claims made in the labeling for the device. The intended performance of a device 
refers to the intended use for which the device is labeled or marketed.   
 
All device malfunctions with or without adverse events should be reported to Edwards 
Lifesciences as soon as possible (preferably within 24 hours) but no later than 
10 working days of awareness. 
 
10.0 
RISKS AND BENEFIT ANALYSIS 
 
There are potential risks associated with transcatheter valve replacement. There are 
risks related to the overall procedures (complications associated with standard 
cardiac catheterization, balloon valvuloplasty, local and/or general anesthesia) as 
well as additional possible risks uniquely associated with the use of the study valve 
and its delivery systems. 
 
10.1 
Potential Benefits 
 
There are no guaranteed benefits from participation in this study. Information gained 
from this study may be of benefit to other people with the same medical condition in 
the future. The long-term results of using the SAPIEN 3 THV are not known at the 
present time. Alternative treatments include surgical AVR and BAV. 
 
Implantation of the transcatheter heart valve may result in improved valvular function, 
acute alleviation of symptoms related to aortic stenosis, and improved quality of life 
in patients with low operative risk of mortality. 
 
10.2 
Potential Risks 
 
There are potential risks associated with transcatheter valve replacement. There are 
risks related to the overall procedures (complications associated with standard 
cardiac catheterization, balloon valvuloplasty, local and/or general anesthesia) as 
well as additional possible risks uniquely associated with the use of the study valve 
and its delivery systems. 
 
Potential risks associated with anesthesia and interventional procedures include but 
are not limited to: 
 
• 
Abnormal lab values (including electrolyte imbalance) 
• 
Allergic reaction to anesthesia, contrast media or device materials 
• 
Anemia 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 55 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
• 
Angina 
• 
Arrhythmia 
• 
Bleeding 
• 
Cardiovascular injury including perforation or dissection of vessels, ventricle, 
myocardium or valvular structures that may require intervention 
• 
Conduction system injury (defect) which may require a permanent pacemaker 
• 
Death 
• 
Embolization including air, calcific/thrombotic valve material, or thrombus 
• 
Exercise intolerance or weakness 
• 
Femoral AV fistula or pseudoaneurysm 
• 
Fever 
• 
Heart failure 
• 
Heart murmur 
• 
Hematoma 
• 
Hemorrhage requiring transfusion or intervention 
• 
Hypertension or hypotension 
• 
Infection including septicemia and endocarditis 
• 
Inflammation 
• 
Myocardial infarction 
• 
Pain or changes at the access site 
• 
Paralysis 
• 
Pericardial effusion or cardiac tamponade 
• 
Peripheral ischemia or nerve injury 
• 
Permanent disability 
• 
Pleural effusion 
• 
Pulmonary edema 
• 
Renal insufficiency or renal failure 
• 
Reoperation 
• 
Respiratory insufficiency or respiratory failure 
• 
Restenosis 
• 
Retroperitoneal bleed 
• 
Stroke/transient ischemic attack, clusters or neurological deficit 
• 
Syncope 
 
In addition to the risks listed above, additional potential risks specifically associated 
with the use of the SAPIEN 3 THV, the delivery systems and/or accessories include, 
but may not be limited to, the following: 
 
• 
Cardiac arrest 
• 
Cardiac failure or low cardiac output 
• 
Cardiogenic shock 
• 
Coronary flow obstruction/transvalvular flow disturbance 
• 
Device degeneration 
• 
Device embolization 
• 
Device explants 
• 
Device migration or malposition requiring intervention 
• 
Device thrombosis requiring intervention 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 56 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
• 
Emergency cardiac surgery 
• 
Hemolysis 
• 
Injury to mitral valve 
• 
Mechanical failure of delivery system, and/or accessories 
• 
Non-emergent reoperation 
• 
Nonstructural dysfunction 
• 
Paravalvular or transvalvular leak 
• 
Structural valve deterioration (wear, fracture, calcification, leaflet tear/tearing 
from the stent posts, leaflet retraction, suture line disruption of components of 
a prosthetic valve, thickening, stenosis) 
• 
Valve deployment in unintended location 
• 
Valve regurgitation 
• 
Valve stenosis 
• 
Valve thrombosis 
 
10.2.1 Risk Minimization 
 
Product handling and implant procedure guidance are provided in the IFU and 
training manual, which will be used for device training to minimize risks associated 
with device use. 
Additionally, efforts will be made to minimize risks through 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. 
 
The SAPIEN 3 THV represents a third generation THV for Edwards Lifesciences and 
was developed with the experience from the first and second generation SAPIEN 
THVs. The SAPIEN 3 System has undergone extensive clinical testing in the aortic 
position and is commercially available for TAVR in the US and countries that honor 
the CE mark. 
 
11.0 
STATISTICAL ANALYSIS 
 
11.1 
Sample Size Calculations 
 
The sample size for the trial is based on obtaining at least 90% power to pass the 1-
year safety and effectiveness endpoint. 
Event rate estimates for the primary safety and effectiveness endpoint were based 
on data from prior studies. Since the current study patients are a lower risk 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 57 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
population, and to account for procedural refinement over time in both arms as well 
as changes in definitions for components of the endpoint, the rates have been 
lowered. 
 
The sample size is based on the composite primary endpoint which assumes an 
event rate of 16.6% in the SAVR arm and 14.6% in the TAVR arm.  A randomized 
sample size of 864 patients with 1-year data would produce 90% power for passing 
the endpoint. The test statistic used for this computation is the one-sided Z test 
(Unpooled), at alpha = 0.025, using the specified non-inferiority margin of 6.0%. The 
sample size was computed in PASS. 
 
The sample size determination was based on a pure frequency analysis, whereas 
the endpoint analysis will use the Kaplan-Meier estimates. Since the two methods 
are equivalent in the absence of censoring, and a sufficient number of uncensored 
patients is anticipated, the sample size should be adequate. 
 
Because the feasibility assumptions are uncertain in this previously unstudied 
population, an actual sample size of   1000 has been chosen, which is higher than 
the minimum statistically justified size to allow for trial contingencies, such as 
withdrawals and lost to follow-up.   
 
11.2 
Analysis Populations 
 
• 
The Intent to Treat (ITT) population consists of all randomized patients. 
 
• 
The As Treated (AT) population is the subset of the ITT population consisting of 
all patients for whom the index procedure is begun, whether or not the index 
procedure is completed. If multiple procedures were attempted, the last 
procedure with the study valve deployed will be considered the index procedure 
and used for determining the As Treated trial arm assignment and the date of the 
index procedure will be used for determining all follow-up visits and related 
assessment. A randomized TAVR patient for whom the TAVR procedure is 
never started will not be part of the AT population, even if that patient should 
receive a SAVR implant. 
• 
The Valve Implant (VI) population is the subset of the AT population consisting of 
all patients who receive and retain the intended valve during the index 
procedure. Patients who receive a valve in valve implant will be part of the VI 
population. Patients who are converted from TAVR to SAVR during the 
procedure will not be part of the VI population. 
 
The AT population will be the primary population for trial endpoint analysis. The VI 
population will be used for analysis of echo data and related endpoints. Selected 
sensitivity analyses will be performed using the ITT population. 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 58 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
11.3 
Timing 
 
• 
The index procedure date is defined as Day 0. For randomized patients who do 
not have the procedure attempted, the randomization date will be used as Day 
0. 
 
• 
Time intervals for events will be computed by subtracting the event date minus 
day 0. For example, if the procedure occurs on January 1, and the patient dies 
on January 31, the death will be considered a 30 day death for analysis. 
 
• 
The timing for all visits will be based on the index procedure date. If the patient 
never receives the procedure the 30-day visit will never be due; later visits for 
such patients will be based on the randomization date. 
 
• 
In analysis of time-dependent variables, one year is defined as 365.25 days, and 
one month as 30.4375 (= 365.25/12) days. 
 
For information depending on follow-up windows any visit within the specified 
window will be used, without regard to the actual timing of the visit. 
 
• 
Analysis close date: 
 
o The analysis close date for the initial analysis will be the earlier of the 
following two dates: One year past the last index procedure 
 
o One year plus 60 days past the last randomization. This condition is in 
order to account for a potential patient with a severely delayed 
procedure. 
 
• 
The analysis close date for later reports will be determined prior to the report. 
Unless otherwise specified such dates will be at annual intervals past the initial 
analysis close date. 
 
• 
All database information will be used to determine patient survival as of the 
analysis close date. 
 
• 
Adverse events occurring after the relevant analysis close date will not be 
included in adverse event analysis. 
 
• 
Information dependent on a visit window, such as echo or NYHA, will be included 
in analysis as long as the window starts on or before the analysis close date. 
 
11.4 
Primary endpoint analysis (Non-inferiority) 
 
The primary safety and effectiveness endpoint is the composite of all-cause 
mortality, all stroke, and rehospitalization (valve-related or procedure-related and 
including heart failure) at 1 year post procedure. The endpoint will be evaluated as a 
non-inferiority analysis based on a non-inferiority margin of 6.0%.The components of 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 59 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
the composite endpoint will be evaluated by the CEC. 
 
To precisely formulate the test, let rT denote the true event proportion in the test arm 
at 1 year, and rC denote the true event proportion in the Control arm at 1 year. The 
hypotheses are: 
 
H0:  rT - rC  ≥  Δ 
HA:  rT - rC  <  Δ 
 
The value Δ is the non-inferiority margin, and is taken to be 0.06.  The test will be 
performed as a one-sided test at alpha = 0.025.   
 
A 95% confidence interval for the difference rT - rC will be computed using the 
Kaplan-Meier algorithm with the standard errors being computed using Greenwood’s 
formula.  The null hypothesis shall be rejected at alpha = 0.025 if the upper 
confidence limit is less than 0.06. 
Covariates will not be included in analysis of the primary endpoint. 
 
11.5  
Primary Endpoint (Superiority) and Secondary endpoints for labeling  
 
The analysis for the superiority in the primary endpoint and secondary endpoints for 
labeling will be performed only if the primary endpoint passes the non-inferiority test.  
 
The superiority in the primary endpoint and secondary endpoints will be evaluated for 
labeling purposes  in the order shown below. Each endpoint will be tested between 
the treatment arms by a two-sided test at alpha = 0.05. If any of the endpoints does 
not achieve statistical significance at alpha = 0.05, the lower endpoints in the list will 
not be considered for this purpose. The analyses will be performed in the As 
Treated population. 
 
1. New onset atrial fibrillation, as a superiority analysis comparing trial arms 
(Secondary endpoint for labeling) 
 
Let rT and rC be the true new onset atrial fibrillation rate at 30 days for test and 
control arms respectively. The hypotheses for the superiority test are:  
 
H0:  rT = rC 
HA:  rT ≠ rC 
 
The endpoint will be evaluated as a binary endpoint. The trial arms will be 
compared using the Fisher’s exact test. The null hypothesis shall be rejected 
and the superiority will be established if the p-value of test is less than 0.05 and 
the point estimates r ̂T < r ̂C. 
 
The counts and percentages of the new onset atrial fibrillation at 30 days will be 
presented for TAVR and SAVR arms, the p-value of trial arm comparison will 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 60 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
also be presented. The subjects with pre-procedural atrial fibrillation or those 
undergoing concomitant ablation will be excluded from the analysis unless CEC 
adjudicated the event as “new onset” or “both”. 
 
2. Length of index hospitalization, as a superiority analysis comparing 
trial arms (Secondary endpoint for labeling) 
 
Let dT and dC be the distribution of the true lengths of index hospitalization for 
test and control arms, respectively. For this analysis, patients who die before 
discharge will be considered to have been discharged on the death date.The 
hypotheses for the superiority test are:  
 
H0:  dT = dC 
HA:  dT ≠ dC 
 
Length of index hospitalization will be treated as a continuous variable, with trial 
arms compared using the Wilcoxon rank-sum test. The null hypothesis shall be 
rejected and the superiority will be established if the p-value of test is less than 
0.05 and the point estimates of the median lengths 𝑑𝑑̂𝑇𝑇 < 𝑑𝑑̂𝐶𝐶. 
 
The mean, standard deviation, median, minimum and maximum of Length of 
index hospitalization will be presented for TAVR and SAVR arms, the p-value of 
trial arm comparison will also be presented. 
 
3. Primary endpoint as a superiority analysis comparing trial arms 
 
The superiority test for the primary endpoint will be performed as a one-sided test at 0.025, 
where α is the amount of Type I error passed, The hypotheses for the superiority test are:  
 
H0:  rT  ≥  rC         or equivalently  
H0:  rT - rC ≥  0 
HA:  rT  <  rC 
 
 
  
HA:  rT - rC  < 0 
 
 
The following Z statistic will be used for the superiority test.  
 
 
𝑍𝑍= 𝑟𝑟̂𝑇𝑇 − 𝑟𝑟̂𝐶𝐶
ට𝑠𝑠𝑇𝑇
2 + 𝑠𝑠𝐶𝐶
2
 
 
The null hypothesis shall be rejected and the superiority will be established if the p-value of 
the one-sided Z test is less than 0.025. 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 61 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
4. KCCQ and death composite at the 30 day visit, as a superiority analysis 
comparing trial arms (Secondary endpoint for labeling) 
 
Let rT and rC be the true rate of the composite events at 30 days for test and 
control arms respectively. The hypotheses for the superiority test are:  
 
H0:  rT = rC 
HA:  rT ≠ rC 
 
The endpoint will be evaluated as a binary endpoint. The trial arms will be 
compared using Fisher’s exact test. The null hypothesis shall be rejected and the 
superiority will be established if the p-value of test is less than 0.05 and the point 
estimates 𝑟𝑟̂𝑇𝑇 < 𝑟𝑟̂𝐶𝐶.   
 
A patient will be counted as meeting this endpoint if one or more of the following 
three conditions hold. 
 
a) The patient dies on day 30 or earlier, whether or not a KCCQ score 
has been collected within the follow-up window. 
 
b) The KCCQ score at the 30 day visit is < 45. 
 
c) The KCCQ score at 30 days is ≥ 10 points decreased from the baseline 
score. 
 
 
Missing data will be handled as described in section 11.8.5. 
 
 
 
5. Death/All Stroke composite at 30 days, as a superiority analysis comparing trial 
arms (Secondary endpoint for labeling) 
 
Let rT and rC be the true rate of the death/all stroke composite events at 30 days 
for test and control arms, respectively. The hypotheses for the superiority test 
are:  
 
H0:  rT = rC 
HA:  rT ≠ rC 
 
The endpoint will be evaluated as a binary endpoint. The trial arms will be 
compared using the Fisher’s exact test. The null hypothesis shall be rejected 
and the superiority will be established if the p-value of test is less than α and the 
point estimates 𝑟𝑟̂𝑇𝑇 < 𝑟𝑟̂𝐶𝐶.  
The counts and percentages of the composite event at 30 days will be 
presented for TAVR and SAVR arms, the p-value of trial arm comparison will 
also be presented. 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 62 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
6. All Stroke at 30 days, as a superiority analysis comparing trial arms (Secondary 
endpoint for labeling) 
 
Let rT and rC be the true stroke rate at 30 day for test and control arms, 
respectively. The hypotheses for the superiority test are:  
 
H0:  rT = rC 
HA:  rT ≠ rC 
 
Stroke will be evaluated as a binary endpoint. The trial arms will be compared 
using the Fisher’s exact test. The null hypothesis shall be rejected and the 
superiority will be established if the p-value of test is less than α and the point 
estimates 𝑟𝑟̂𝑇𝑇 < 𝑟𝑟̂𝐶𝐶. 
 
The number of events, number of patients with event and Kaplan-Meier 
estimates of stroke rate at 30 day will be presented for TAVR and SAVR arms, 
the p-value of trial arm comparison will also be presented. 
11.6  
Additional Safety and Effectiveness Endpoints 
 
The endpoints in this section will be evaluated according to the general statistical 
methods described in section 11.8. These endpoints will not be subject to the formal 
multiple comparisons correction; they are presented as part of the totality of 
information. All the statistical tests between the treatment arms will be two-sided tests 
at alpha=0.05. 
 
• 
Mortality (all cause & cardiovascular) at 30 days and 1 year 
 
• 
Stroke (disabling and nondisabling) at 30 days and 1 year 
 
• 
Death or stroke at 1 year 
 
• 
Death or disabling stroke at 30 days and 1 year 
 
• 
Vascular complications (major) at 30 days and 1 year 
 
• 
Bleeding complications (life threatening, disabling or major) at 30 days and 1 year 
 
• 
Myocardial infarction at 30 days and 1 year 
 
• 
Acute kidney injury at 30 days 
 
• 
Requirement for renal replacement therapy at 1 year 
 
• 
New permanent pacemaker implantation resulting from new or worsened 
conduction disturbances at 30 days and 1 year. 
 
• 
Coronary obstruction requiring intervention at 30 days and 1 year 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 63 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
• 
New York Heart Association class at 30 days and 1 year 
 
• 
Hemodynamic valve performance evaluation by echocardiography for aortic 
valve stenosis and aortic valve regurgitation at 30 days and years 1, 2, 3, 4, 5, 
7, and 10. Echo readings to be evaluated include aortic valve area, mean 
gradient, peak gradient, perivalvular aortic regurgitation, total aortic 
regurgitation, and mitral regurgitation. 
 
• 
Rehospitalization (valve-related or procedure-related and including heart 
failure) at 30 days, 1 year and annually (up to 10 years) 
 
• 
Days alive and out of hospital at 1 year 
 
• 
Six-minute walk test at 30 days and 1 year 
 
• 
Health status as evaluated by Quality of Life questionnaires at 30 days and 1 
year 
 
• 
New onset atrial fibrillation at 1 year 
 
• 
ICU days and discharge location 
 
• 
Structural valve deterioration at years 1-5,7 and 10 
 
11.7  Additional analyses 
 
• 
Baseline data will be reported by summary statistics, separately by trial arm with 
p- values. 
 
• 
The various procedural variables will be reported by summary statistics, 
separately by trial arm with p-values. 
 
• 
Visit compliance data will be presented. 
 
• 
Analysis of echo and procedural variables will be presented by valve size, at the 
various echo collection time points. 
 
• 
Analyses past one year will be the same as the analyses for 1 year, but limited to 
those variables collected after the 1 year visit. 
 
11.8  
General Statistical Methodology 
 
11.8.1 Time Dependent Variables 
 
Time-dependent variables will be analyzed using the Kaplan-Meier algorithm, with 
standard errors computed by Greenwood’s formula. The number of patients-at-risk 
will be computed at exact time points, without reference to any nominal follow-up 
windows. The log-rank statistic will be used for any comparison among groups. 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 64 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Thirty day analysis will present both pure frequency and Kaplan-Meier rates; for later 
analyses only Kaplan-Meier rates will be presented.  Kaplan-Meier rates will be 
presented at 30 days and 1 year as well as other time points as appropriate. 
 
 
 
 
11.8.2 Continuous and ordinal variables 
 
• 
For continuous variables, summary statistics will include means, standard 
deviations, medians and quartiles. Confidence limits will be computed using the 
t-distribution. Groups will be compared using t-tests or analysis of variance. 
Where severe departures from normality are observed, comparisons will also be 
performed using the Wilcoxon rank-sum test. 
 
• 
For ordinal variables, summary statistics will include medians and quartiles; 
means will also be presented when appropriate.  Group comparisons will be 
performed using the Wilcoxon rank-sum test. 
 
• 
NYHA and regurgitation will be considered as ordinal variables.  Group counts 
and means will be presented for these variables. 
 
11.8.3 Categorical Variables 
 
• 
For categorical variables, summary statistics will include counts and percentages. 
Confidence limits for binary variables will be computed using the exact binomial 
distribution. 
 
• 
Categorical variables will be compared by Fisher’s exact test. 
 
11.8.4  Non-Inferiority Analyses 
 
• 
Non-inferiority tests at a point in time are based on the rate difference approach. 
 
• 
The test is performed at a point in time T, using the Kaplan-Meier estimates for 
freedom from the endpoint being evaluated, and the Greenwood standard errors 
for these estimates. The test will be performed by computing the two-sided 95% 
confidence limit for the event rate difference (TAVR - SAVR). The acceptance 
criterion is that the upper confidence limit is less than Delta, where Delta is the 
predetermined non-inferiority margin of 6.0%. 
 
• 
In analysis of the primary endpoint, there will be little or no censored data. The 
only censoring would be due to lost to follow-up or withdrawal from the trial. 
 
• 
It is conceivable that there will be no censored data at all in evaluating the 
primary endpoint. In such a case the Kaplan-Meier estimators are pure 
proportions, and the Greenwood variance is the standard variance for an 
estimated proportion. The confidence limits would agree with those produced by 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 65 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
standard frequency analysis. 
 
• 
For the primary endpoint in this trial the non-inferiority margin of 6.0% has been 
chosen.  
 
 
 
11.8.5  Missing Data 
 
• 
Missing variables will not be imputed for planned analyses, except where 
otherwise specified. 
 
• 
The primary safety and effectiveness endpoint will be based on Kaplan-Meier 
estimates, which automatically account for censored data. 
 
• 
For sensitivity purposes, tipping point analyses for the primary endpoints are 
defined in the SAP. 
 
• 
Tipping point analysis will also be presented for the secondary endpoint involving 
KCCQ. 
 
11.8.6  Multiple comparisons 
 
A formal multiple comparisons analysis is presented in section 11.5 for the named 
secondary endpoints for labeling purposes. In all other cases p-values will be 
presented as computed, without any adjustments for the comparisons. 
 
11.8.7  Adverse event analysis 
 
• 
Adverse event analysis will involve both site and CEC reporting. 
 
o Where events have been adjudicated by the CEC, those adjudications will be 
used in preference to site reports. 
 
o Where site events are analyzed, the MedDRA coding will be used. The 
underlying site evaluations will not be used for analysis, but may appear in 
listings as appropriate. 
 
• 
Adverse events to be analyzed include the composites involved in the primary 
and secondary endpoints, as well as all events contained in these 
composites. All events adjudicated by the CEC will also be analyzed. 
 
• 
Adverse event tables will present data at 30 days, 6 months, and 1 year. The 
tables will include counts of events, patients with event, and Kaplan-Meier event 
rates at the specific time point. The trial arms will be compared by the log-rank 
test 
 
• 
Late adverse events (> 30 days) will be analyzed by a constant hazard 
model, and upper one-sided confidence limits will be given for the rates. 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 66 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
• 
Adverse event data past 1 year will be presented as counts of events and 
patients with event. No formal analyses will be performed for such data. 
 
 
 
 
11.8.8  Periodic analyses 
 
Periodic analyses will be performed during the trial to the extent required by the 
appropriate regulatory authorities and the DSMB.  The sample size and endpoint 
timing for this trial is fixed in advance, and not based on these periodic analyses.  
Accordingly, there is no adjustment to alpha. 
 
Other than the required reports mentioned in the previous paragraph, there will be no 
reporting of trial outcome data prior to the 1-year analysis close date. 
It is anticipated that reporting will continue throughout the trial, with formal reports 
based on analysis close dates at annual intervals. 
 
11.8.9  Quality of life questionnaires 
 
Quality of life questionnaires will be scored according to algorithms provided by the 
vendor. The various summary scores produced by the algorithms will be analyzed 
as continuous variables. 
 
11.8.10  
General Specifications 
 
• 
Trial arm comparisons will be presented wherever meaningful. P-values will be 
computed using a null hypothesis of no difference. 
 
• 
Unless otherwise specified, Wald p-values will be presented. 
 
• 
Unless otherwise specified, confidence limits and hypotheses tests will be two 
sided, using alpha = 0.05. 
 
• 
Unless otherwise specified, the precise form of each algorithm will be the default 
of SAS, using the latest release installed at Edwards at the time of analysis. This 
will be version 
9.3 or later. 
 
• 
Various CRFs will contain comment fields.  Data in these fields will not be 
analyzed, but listings will be provided for internal use on request. 
 
11.9 
CT Sub-Study 
 
The purposes of the study are to: 
 
1. Investigate the prevalence of the imaging abnormality. 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 67 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
The prevalence data come in two forms. A Yes/No value, which will be analyzed 
as a binary variable. A grading, which will be analyzed as an ordinal variable. 
 
2. Investigate the relationship between the imaging abnormality and patient, 
procedural and pharmacology factors. 
The Yes/No value will be the dependent variable in logistic regression models, 
with the independent variables chosen based on potential clinical relevance. 
 
Multivariable models will be developed if the univariate analyses so suggest. 
 
3. Investigate the relationship between imaging abnormalities and clinical events. 
 
The clinical events to be considered will include stroke, TIA, and death. These 
will be modeled as time-dependent variables using proportional hazards 
regression, with the Yes/No value of the imaging abnormality as an independent 
variable. 
 
Key echo parameters (valve area, mean gradient, and AR) will be modeled, with 
the Yes/No value of the imaging abnormality as an independent variable. 
This sub-study analysis is unpowered. 
 
The choice of variables for items 2 and 3 will be based on the tables presented in the 
papers of Makkar [26] and Pache [27]. 
 
It should be noted that the prior studies found few statistically significant baseline 
predictors of the imaging abnormality, and they found only minor clinical impact 
resulting from the abnormality. There is no reason to expect any different results in 
this sub-study. 
 
12.0 
STUDY ADMINISTRATION 
 
12.1 
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 be responsible for obtaining IDE approval for the study, 
selecting investigators, ensuring that sites have IRB/EC approval prior to 
investigational device shipment, and conducting clinical site monitoring to ensure 
that patients are being properly consented and the study is being conducted 
according to the protocol. 
 
As appropriate, Edwards Lifesciences will submit changes in the Investigational Plan 
to the FDA and Investigators to obtain IRB/EC re-approval. 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 68 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Edwards Lifesciences will maintain copies of correspondence, data, shipment of 
devices, adverse device effects and other records related to the clinical trial as 
appropriate. 
Edwards Lifesciences will submit all reports required by the FDA as identified in 21 
Code of Federal Regulations (CFR) 812.150(B). This includes UADEs, withdrawal of 
IRB/EC approval, current investigators list, annual progress reports, recall 
information, final reports and protocol violations. 
 
12.2  
Data Safety Monitoring Board (DSMB) 
 
A Data Safety Monitoring Board (DSMB) will monitor all AEs and SAEs to provide 
safety oversight.  DSMB members will not be involved in the study and have no 
conflict of interest. At least one member will be a cardiothoracic surgeon with 
specific expertise in aortic stenosis.  DSMB activities, including stopping rules for 
early termination, will be defined in the DSMB Charter. 
 
12.3 
Clinical Event Adjudication Committee (CEC) 
 
The Clinical Events Committee (CEC) will adjudicate endpoint events and provide 
assessment of SAEs and device/procedure relatedness from enrollment through the 
primary endpoint. The CEC will include cardiologists and cardiothoracic surgeons 
with experience in the field of aortic stenosis who are not involved in the study and 
have no conflict of interest. CEC activities will be defined in the CEC Charter. 
 
12.4 
Study Procedures 
 
12.4.1 Echocardiogram 
 
Study patients will receive an echocardiogram at the visits specified in section 8.0. A 
central imaging core lab will be established to independently review and analyze 
echocardiographic images.  A standardized protocol for acquiring images will be 
developed by the core lab and be provided to the clinical sites prior to study 
initiation.  Sites will be trained on acquiring images prior to study initiation. Appendix 
J includes the echocardiogram manual of operations. 
 
12.4.2 Computed Tomography (CT) 
 
All study patients will have a screening CT as referenced in section 8.0. Sites will be 
trained on acquiring images prior to study initiation. In addition, all Screening CTs 
will be independently analyzed with regards to annular measurements by a 
CT/angiographic core lab. Appendix K-1 includes CT acquisition information. 
 
 
12.4.2.1 
CT Sub-Study 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 69 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Study patients enrolled in the CT sub-study will have a 4D CT at visits specified in 
section 
8.1. A central imaging core lab will independently review sub-study CTs. Appendix K-
2 includes the sub-study CT acquisition information. 
 
Investigational sites will be blinded to the resulting images unless specific clinical or 
echo abnormalities are present.  
 
If any of the following events occur, a repeat 4D CT will be mandated unless the 
event occurs within 24 hrs of the 30 day CT; in which case the CT will be unblinded. 
: 
 
• 
Any neurological event 
• 
Any potential embolic event 
• 
Myocardial infarction 
• 
A change in echo parameters including an increase in mean gradient of 10-
20 mm Hg or a change in DVI of 0.05 - 0.1 
 
Patients whose initial imaging data are determined to be unevaluable will not 
undergo subsequent imaging. 
 
12.4.3 Quality of Life Questionnaires 
 
Investigational sites will be provided with paper QoL questionnaires (KCCQ, EQ-5D-
5L, and the SF-36). Patient questionnaires will be IRB approved prior to patient 
administration. 
Investigational staff will administer patient questionnaires to study patients. Patients 
will be instructed to complete each questionnaire at visits specified in section 8.0. 
The patient will be instructed by the investigational staff to sign and date the paper 
questionnaire once the questionnaire is completed. Patients will be instructed by the 
investigational staff not to change questionnaire answers once the questionnaire has 
been completed. Investigational sites should retain the completed questionnaire in 
the patients’ source documents. Site staff will enter data collected from the 
completed patient questionnaire into the EDC. 
 
The patient level summary scores will be computed by the Edwards Biostatistics 
group, and these scores will be used in evaluating protocol endpoints. A QoL core 
lab may prepare reports of additional analyses. 
 
Quality of life will be measured through standard surveys: 
 
1) The Kansas City Cardiomyopathy Questionnaire (KCCQ) is an assessment of 
disability and quality of life impairment due to congestive heart failure. 
 
2) EQ-5D-5L is a standardized questionnaire for describing and valuing patients’ 
health- related quality of life for clinical and economic appraisal. 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 70 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
3) The SF- 36 is a generic health status instrument and rating scale that allows 
mapping of health status to population-level utility weights. This is an important 
metric for cost- effectiveness analysis. 
 
 
 
12.4.4 Image Management 
 
A central image management lab will be established to receive, maintain, and 
provide cardiac images (echocardiogram and CT) to the appropriate core lab for 
analyzing. 
Instructions for image upload will be provided to investigative staff prior to study 
initiation. Investigative staff should upload all images to the image management core 
lab within 5 business days of data collection. 
 
 
12.4.5 Histopathology 
 
Histopathology studies of explanted valves will be performed. Explants will be 
appropriately prepared and preserved and sent to the independent histopathology 
laboratory for macroscopic and microscopic analysis. Investigational valves that are 
removed at any time with an allegation of device malfunction should be returned to 
the Sponsor for evaluation. All other explants (those not with an allegation of device 
malfunction) should be sent to the Histopathology Core Lab. Appendix L contains a 
complete explant protocol which includes detailed procedures for the histopathology 
studies. 
 
Gross pathological examination of the entire valve and the support structure (i.e., and 
shape, if occurrence of intravascular trauma, tissue abrasion, uniformity of the frame, 
position the natural valve cusps) will be assessed. 
 
The valves will be assessed for cusp excursion and the presence of leaflet 
fenestrations, rigidity tears, hematoma, thrombi and calcified nodules, cell 
proliferation tissue overgrowth, 
fibrous sheath, and local inflammatory reaction. (One half of each leaflet must be 
used for the quantitative determination of inorganic calcium and phosphate). 
 
12.5 
Training 
 
To ensure proper device usage, uniform data collection, and protocol compliance, 
training is required for relevant study site personnel in accordance to roles outlined 
in the Delegation of Authority (DoA). 
 
At the beginning of the study, Edwards Lifesciences will provide training to site 
personnel. Training will include review of the instructions for use of the device, study 
protocol, case review process, identification of eligible patients, instructions on in-
hospital data collection, standardized data collection for core laboratory analysis, 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 71 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
methods for soliciting data from alternative sources, and regulatory requirements. 
 
Documentation of site personnel qualification and training should be maintained in 
the site’s clinical trial files and copies collected and forwarded for the Sponsor site 
file. 
 
Ongoing training may be provided in one of the following formats by the Sponsor or 
its designee: live training sessions, teleconference, WebEx, online, or read and 
review. The Sponsor reserves the right to enforce retraining for sites who have 
demonstrated study or implant procedure compliance issues. 
 
12.6 
Device Management 
 
12.6.1 Study Device 
 
All SAPIEN 3 products will be supplied by Edwards Lifesciences. Each SAPIEN 3 
THV will have a unique identifier which should be recorded in the patient’s medical 
file as well as on the implant card that is given to the patient. 
 
 
Refer to Appendix C for the IFUs to be used in this study. The IFUs will also be 
available electronically. 
 
12.6.2 Device Storage 
 
All SAPIEN 3 System components provided for the study should be stored in a 
secure location where only study personnel can access the device for use. Only 
physicians identified in the Investigator’s Delegation of Authority Log on file at 
Edwards Lifesciences may implant this device in study patients. 
 
12.6.3 Device Accountability 
 
The study site will maintain detailed records of the receipt and disposition of all 
investigational devices on the Device Accountability Log (DAL).  Device disposition 
will be verified by the clinical monitor periodically throughout the study. The 
Investigator will return unused devices to Edwards along with the completed device 
disposition log at completion of the investigation.  Use of the SAPIEN 3 THV and 
accessories provided for use in the study is prohibited outside of this protocol. 
 
12.7 
Data Management 
 
Edwards Lifesciences will provide data management through a secure, password 
protected Electronic Data Capture (EDC) system accessible via the Internet.  A 
unique Patient ID will be assigned for each patient enrolled in the study.  All 
pertinent data will be entered by the study site and core lab personnel into the 
electronic Case Report Forms (eCRFs). 
 
Every reasonable effort should be made to complete data entry within 5 business 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 72 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
days of data collection. Data review by Edwards Lifesciences personnel will occur 
remotely as well as during on site monitoring.  Data discrepancies will be queried 
and resolved through the EDC system. 
 
The site Principal Investigator or designee must ensure the accuracy and 
completeness of the recorded data and then provide his/her electronic signature on 
the appropriate eCRFs. Changes to data previously submitted to the Sponsor will 
require a new electronic signature to acknowledge/approve the changes. 
 
 
12.8 
Monitoring Procedures 
 
All clinical sites will be monitored periodically by Edwards Lifesciences or designee to 
ensure compliance with the protocol and the Investigator’s Agreement and that all 
study patients have been properly consented. The monitor will ensure that the 
completed eCRFs match the source documents and work with the site to resolve 
differences through electronically generated queries or formal action items. 
 
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. 
 
12.9 
Auditing 
 
The study may be subject to a quality assurance audit by Edwards Lifesciences or a 
designee, as well as inspection by appropriate regulatory authorities. It is important 
that the Investigator and relevant study personnel are available during any audits 
and that sufficient time is devoted to the process. In the event of an audit by 
regulatory authorities, the Investigator should contact Edwards Lifesciences as soon 
as possible. 
 
12.10 
Record Retention 
 
All clinical sites will maintain study records for a minimum of two years after 
marketing for this patient population approval is obtained or after the site is notified 
by Edwards  
 
Lifesciences that the study has been terminated. Record retention dates will be 
provided to all parties concerned by Edwards Lifesciences. 
 
13.0 
ETHICAL AND REGULATORY CONSIDERATIONS  
 
13.1 
Compliance with Good Clinical Practices 
 
The Investigator will ensure that this study is conducted in accordance with Good 
Clinical Practice (GCP) and applicable regulatory (local) requirements. 
 
13.2 
Institutional Review Board/Ethics Committee 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 73 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
This protocol, the proposed Informed Consent Form (ICF), other written patient 
information and any proposed advertising material must be submitted to the IRB for 
written approval.  A copy of the written IRB approval of the protocol and ICF must be 
received by Edwards Lifesciences before recruitment of patients into the study and 
shipment of investigational product. 
 
The Investigator must submit and, where necessary, obtain approval from the IRB for 
all subsequent protocol amendments and changes to the ICF. 
 
The Investigator is responsible for obtaining annual IRB approval and renewal 
throughout the duration of the study. Copies of the Investigator’s reports and the IRB 
continuance of approval must be sent to Edwards Lifesciences. 
 
13.3 
Patient Informed Consent 
 
Edwards Lifesciences will provide a sample ICF to the Investigator to prepare for use 
at his/her site. The site-specific ICF must be in agreement with current GCP 
guidelines. 
Edwards Lifesciences must approve the site-specific ICF prior to submission to the 
IRB. The reviewing IRB must approve the ICF before use at that site. 
 
Before participating in the clinical trial, each patient must give written Informed 
Consent after the context of the study has been fully explained in a language that is 
easily understood by the patient. The subject must also be given the opportunity to 
ask questions and have those questions answered to his/her satisfaction. 
 
A copy of each patient’s signed and dated consent form must be maintained by each 
Investigator in a designated clinical trial administrative file.  A signed copy of the 
consent form must be given to each subject. The consent process must be 
documented in the subject’s medical chart. 
 
Any modifications to the site-specific ICF must be approved by Edwards Lifesciences 
and the IRB. 
 
13.4 
Confidentiality 
 
All data used in the analysis and reporting of this evaluation will be without 
identifiable reference to the patient. Authorized personnel assigned by Edwards 
Lifesciences will have access to the confidential files and will 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 subject. 
 
 
13.5 
Investigator Records 
 
Records to be maintained by the Investigator include, but are not limited to, the 
following: 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 74 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
• 
Clinical trial protocol and all amendments 
• 
Signed Clinical Trial Agreement and any amendments 
• 
IRB approval letters, including continuing reviews and all amendments/changes 
• 
IRB approved informed consent documents 
 
The following records must be maintained for each subject enrolled in the trial: 
 
• 
Signed patient informed consent 
• 
All relevant source documentation for study visits and study-related procedures 
• 
Supporting documentation of any adverse events 
 
13.6 
Investigator Reports 
 
Adverse event reporting requirements are discussed in section 9.0. 
 
Withdrawal of IRB Approval. Within 5 working days, the Principal Investigator will 
report to Edwards Lifesciences a withdrawal of approval by the reviewing IRB of the 
investigator’s part of an investigation. 
 
Informed Consent. If an investigator uses a device without obtaining informed 
consent, the investigator shall report such use to Edwards Lifesciences and the 
reviewing IRB within 5 working days after the use occurs. 
 
Progress Reports. The Principal Investigator will submit progress reports on the 
investigation to Edwards Lifesciences and the IRB at least yearly. 
 
 
Final Report. Upon completion or termination of this Trial, the Principal Investigator 
must submit a final written report to Edwards Lifesciences and the IRB as required 
by the regulations. The report must be submitted within 3 months of completion or 
termination of the trial. 
 
13.7 
Amending the Protocol 
 
This protocol must be followed exactly.  It can be altered only by written amendments 
made by Edwards Lifesciences.  Following appropriate approval by Edwards 
Lifesciences, the amended protocol will be submitted to the required regulatory 
agencies before being distributed to all enrolling sites.  Each site must obtain 
IRB/EC approval, complete required training (if any, and as required by DoA role), 
and receive written approval from Edwards Lifesciences before implementing the 
revised protocol. 
 
13.8 
Protocol Deviations 
An investigator must not make any changes or deviate from this protocol, except to 
protect the life and physical well-being of a subject in an emergency.  Emergency 
changes to protect the life of the patient do not require prior approval, but must be 
reported to Edwards Lifesciences and the reviewing IRB within 5 days of the 
incident. 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 75 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
Each deviation from the protocol must be documented with the date and reason for 
the deviation and reported to Edwards Lifesciences as soon as possible, and to the 
IRB per local guidelines and government regulations. 
 
 
13.9 
Publication Policy 
 
Publication or presentation of the overall clinical study results and/or site-specific 
results requires prior written approval of Edwards Lifesciences.  If Edwards 
Lifesciences approves the publication or presentation of the overall clinical study 
results and/or site-specific results, then Institutions and Investigators will comply with 
the Publications and Public Disclosure section of the Clinical Trial Agreement.  
Edwards Lifesciences will provide statistical support for the publication process. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 76 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
Appendix A      Abbreviations 
 
Abbreviation 
Full Term 
ACT 
Activated Clotting Time 
AE 
Adverse Event 
AR 
Aortic Regurgitation 
ASD 
Atrial Septal Defect 
AT 
As Treated 
AV 
Atrioventricular 
AV 
Aortic Valve 
BARC 
Bleeding Academic Research Consortium 
BAV 
Balloon Aortic Valvuloplasty 
CBC 
Complete Blood Count 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CHD 
Congenital Heart Defects 
CHF 
Congestive Heart Failure 
CK-MB 
Creatine Kinase MB 
CPB 
Cardiopulmonary Bypass 
CT 
Computed Tomography 
CTA 
Computed Tomography Angiography 
CV 
Curriculum Vitae 
DAL 
Device Accountability Log 
DOA 
Delegation of Authority 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
Echo 
Echocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMEA 
Europe, Middle East, Africa 
ePRO 
Electronic Patient-Reported Outcome 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption 
IFU 
Instructions For Use 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 77 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
Abbreviation 
Full Term 
KM 
Kaplan Meier 
LAR 
Legally Authorized Representative 
LBBB 
Left Bundle Branch Block 
LVOT 
Left Ventricular Outflow Tract 
MI 
Myocardial Infarction 
MR/MRI 
Magnetic Resonance / Magnetic Resonance Imaging 
NYHA 
New York Heart Association 
PA 
Pulmonary Artery 
PCWP 
Pulmonary Capillary Wedge Pressure 
PET 
Polyethylene Terephthalate 
PLT 
Platelets 
QOL 
Quality of Life 
RA 
Right Atrium 
RBC 
Red Blood Cell 
RV 
Right Ventricle 
SAE 
Serious Adverse Event 
SAVR 
Surgical Aortic Valve Replacement 
STS 
Society of Thoracic Surgeons 
TAVR 
Transcatheter Aortic Valve Replacement 
THV 
Transcatheter Heart Valve 
TIA 
Transient Ischemic Attack 
TTE 
Transthoracic Echocardiogram 
UADE 
Unanticipated Adverse Device Effect 
VARC 
Valve Academic Research Consortium 
VAS 
Visual Analogue Scale 
VI 
Valve Implant 
WBC 
White Blood Cell 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 78 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Appendix B 
Definitions 
Term 
Definition 
Reference/ 
Justification 
Adverse Event 
(AE) 
 Any untoward medical occurrence, unintended disease or 
injury, or untoward clinical signs (including abnormal 
laboratory findings) in subjects, users or other persons, 
whether or not related to the investigational medical 
device 
 
ISO 14155-1:2011 
GCP 
Access Site 
Any location (arterial or venous) traversed by a guide-
wire, a catheter or a sheath for TAVR or skin incision for 
SAVR 
VARC 1  
Access site 
related 
complication 
Any adverse clinical consequence possibly associated 
with any of the access sites used during the procedure 
VARC 1  
Acute kidney 
injury 
 
 
An abrupt loss of kidney function, resulting in the retention 
of urea and other nitrogenous waste products 
 
The increase in creatinine meeting at least Stage 1 must 
occur within 48 hours. Staging will be based on the 
worse stage that occurs within 7 days of the index 
procedure. 
 
Stage 1 
•    Increase in serum creatinine to 150-199% (1.5-1.99 × 
increase compared with baseline) OR increase of ≥0.3 
mg/dL (≥26.4 mmol/L) OR 
•    Urine output <0.5 ml/kg per hour for >6 but <12 hours 
 
Stage 2 
•    Increase in serum creatinine to 200-299% (2.0-2.99 × 
increase compared with baseline) OR 
•    Urine output <0.5 ml/kg per hour for >12 but <24 
hours 
 
Stage 3 
•    Increase in serum creatinine to ≥300% (>3 × increase 
compared with baseline) OR serum  
creatinine of ≥4.0 mg/dL (≥354 mmol/L) with an acute 
increase of at least 0.5 mg/dL (44 mmol/L) OR 
•    Urine output <0.3 ml/kg per hour for ≥24 hours OR 
•    Anuria for ≥12 hours 
 
Patients receiving renal replacement therapy (dialysis, 
hemodialysis, peritoneal dialysis, hemofiltration, 
transplant) are considered to meet Stage 3 criteria 
irrespective of other criteria irrespective 
Sponsor/VARC 2 
Anemia  
 
A condition in which the blood is deficient in red blood 
cells, in hemoglobin, or in total volume, without clear 
evidence of overt bleeding, that is actionable (e.g. 
requires medications, transfusion etc)  
Sponsor 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 79 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Term 
Definition 
Reference/ 
Justification 
Angina / Cardiac 
chest pain 
 
Chest pain due to an inadequate supply of oxygen to the 
heart muscle 
Sponsor 
Angina, grading 
scale 
Grade 
Description 
 
 
 
Grade I 
Ordinary physical activity, such as 
walking and climbing stairs, does not 
cause angina.  Angina occurs with 
strenuous, rapid, or prolonged 
exertion at work or during recreation 
 
 
 
 
 
 
 
 
Grade II 
Slight limitation of ordinary 
activity.  Angina occurs with walking 
or climbing stairs rapidly, walking 
uphill, walking or stair climbing after 
meals, walking in the cold, into the 
wind, while under emotional stress, 
or during the first hours after 
awakening.  Walking more than two 
blocks on the level and climbing 
more than one flight of ordinary 
stairs at a normal pace and in normal 
conditions, does not cause angina 
 
 
 
 
Grade III 
Marked limitation of ordinary 
physical activity.  Angina occurs with 
walking one to two blocks on the 
level and climbing one flight of stairs 
in normal conditions and at a normal 
pace 
 
 
 
Grade IV 
Inability to carry on any physical 
activity without discomfort.  Angina 
syndrome may be present at rest 
 
Canadian 
Cardiovascular 
Society 
Aortic coarctation 
A narrowing of the aorta usually in the area of the 
ligamentum arteriosum 
Groenemeijer BE, 
Bakker A, Slis HW, 
Waalewijn RA, 
Heijmen RH. An 
unexpected finding 
late after repair of 
coarctation of the 
aorta. Netherlands 
Heart Journal. 
2008;16(7-8):260-
263. 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 80 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Term 
Definition 
Reference/ 
Justification 
Aortic dissection 
Aortic dissection is a separation of an intimal of wall that 
may or may not require intervention 
 
 
Sponsor  
Aortic stenosis, 
native  
 
 
Aortic stenosis is classified as “severe” when the following 
are present: 
• Jet velocity > 4.0 m/s 
• Mean gradient > 40mmHg 
• Valve area < 1.0 cm2 
• Valve area index < 0.6cm2/m2 
2014 AHA/ACC 
Arrhythmia / 
Conduction 
System Injury 
(Defect) 
 
Arrhythmia: an irregular heart rate or abnormal rhythm 
resulting in symptoms or requiring medical intervention. 
 
Conduction system defect: an impairment of the electrical 
pathways and specialized muscular fibers that conduct 
impulses through the heart (ex. bundle branch block, 
heart block, etc.).  
Sponsor 
Bicuspid aortic 
valve 
Congenital malformation resulting in 2 functioning leaflets 
as defined by Sievers and Schmidtke 
A classification 
system for the 
bicuspid aortic valve 
from 304 surgical 
specimens. Sievers 
HH, Schmidtke C. J 
Thorac Cardiovasc 
Surg. 2007 
May;133(5):1226-33. 
Bioprosthetic 
valve dysfunction 
Bioprosthetic valve dysfunction can be structural (ex. 
leaflet tears, leaflet mobility restriction, etc.) or non-
structural (ex. paravalvular leak or endocarditis) or 
hemodynamic(aortic regurgitation or aortic stenosis) or a 
combination of these dysfunctions.  Patients with BVD 
maybe asymptomatic or symptomatic requiring medical 
therapy (ex. addition of anticoagulation), hospitalization, 
or require intervention and/or valve explant.  
Sponsor 
 
Bleeding  
Bleeding, including, but not limited to fatal bleed, bleeding 
associated with transfusion, drop in Hgb or visible sign of 
blood loss 
For the purposes of this trial, an overt source of 
bleeding for subjects undergoing TF-TAVR is > 100 mL 
blood loss during the procedure.  For subjects 
undergoing SAVR and for subjects undergoing TAVR 
using an alternative approach (i.e. TAo, TA), an overt 
source of bleeding is considered to be > 600 mL bloody 
chest tube 
output (as captured on Intake and Output Chart, I/O) 
within 24 hours of leaving the OR/cath lab or bleeding 
requiring a transfusion of RBCs 
Sponsor 
 
CABG 
Coronary artery bypass surgery 
Sponsor 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 81 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Term 
Definition 
Reference/ 
Justification 
Cardiac arrest 
Cardiopulmonary arrest or  circulatory arrest, is a sudden 
stop in effective blood circulation due to the failure of the 
heart to contract effectively or at all 
 
Sponosor / STS 
 
Cardiogenic 
shock 
Sustained (>30 min) episode of systolic BP <90 mmHg 
and/or cardiac index <2.2 L/min/m2 determined to be 
secondary to cardiac dysfunction, and/or the requirement 
for parenteral inotropic or vasopressor agents or 
mechanical support (e.g., intra-aortic balloon pump, 
extracorporeal circulatory support, ventricular assist 
device) to maintain BP and cardiac index above those 
specified levels 
2014 ACC/AHA Key 
Data Elements and 
Definitions for 
Cardiovascular 
Endpoint Events in 
Clinical Trials 
Cardiac 
tamponade  
 
Evidence of a new pericardial effusion associated with 
hemodynamic instability evident by:  
 
1. Echo showing pericardial fluid and signs of tamponade 
such as right heart compromise, or 
2. Systemic hypotension due to pericardial fluid 
compromising cardiac function  
VARC 2 / STS  
Hypertrophic 
Cardiomyopathy 
Cardiomyopathy is a term applied to a wide spectrum of 
cardiac diseases in which the predominant feature is poor 
myocardial function in the absence of any anatomic 
abnormalities.  
 
Idiopathic hypertrophic subaortic stenosis (IHSS) is also 
know as hypertrophic obstructive cardiomyopathy 
(HOCM), 
and is characterized by a primary hypertrophy of the 
myocardium. The obstructive forms involve different 
degrees of dynamic subvalvar aortic obstruction 
from a thickened ventricular wall and anterior motion 
of the mitral valve.  
 
Cardiomyopathies are into three entities:  
 
1. Dilated, characterized by ventricular dilatation and 
systolic dysfunction 
2. Hypertrophic, characterized by physiologically 
inappropriate hypertrophy of the left ventricle 
3. Restrictive, characterized by diastolic dysfunction, 
with a presentation often identical to constrictive 
pericarditis.  
 
STS Congenital 
Heart Surgery 
Database Data 
Specifications 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 82 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Term 
Definition 
Reference/ 
Justification 
Cerebrovascular 
disease 
Cerebrovascular disease includes all disorders in which 
an area of the brain is temporarily or permanently affected 
by ischemia or bleeding and one or more of the cerebral 
blood vessels are involved in the pathological process 
 
It includes:  
 
• 
Stroke 
• 
TIA 
• 
Noninvasive or invasive arterial imaging test 
demonstrating >=50% stenosis of any of the 
major extracranial or intracranial vessels to the 
brain  
• 
Previous cervical or cerebral artery 
revascularization surgery or percutaneous 
intervention 
 
This does not include chronic (nonvascular) neurological 
diseases or other acute neurological insults such as 
metabolic and anoxic ischemic encephalopathy 
 
STS  
CHADS2 Score 
(Annual Stroke 
Risk) 
The CHADS2 score can help physicians estimate stroke 
risk in patients with non-valvular atrial fibrillation and 
determine which antithrombotic therapy is most 
appropriate. 
 
The CHADS2 score is one of several risk stratification 
schema that can help determine the 1 year risk of an 
ischemic stroke in a non-anticoagulated patient with non-
valvular AF. 
 
Annual Stroke risk 
CHADS2 Score 
Stroke Risk % 
95% CI 
0 
1.9 
1.2–3.0 
1 
2.8 
2.0–3.8 
2 
4.0 
3.1–5.1 
3 
5.9 
4.6–7.3 
4 
8.5 
6.3–11.1 
5 
12.5 
8.2–17.5 
6 
18.2 
10.5–27 
 
Gage BF, Waterman 
AD, Shannon W, 
Boechler M, Rich 
MW, Radford MJ. 
Validation of Clinical 
Classification 
Schemes for 
Predicting Stroke: 
Results From the 
National Registry of 
Atrial Fibrillation. 
JAMA. 
2001;285(22):2864-
2870. 
doi:10.1001/jama.285
.22.2864 
Chest deformity 
(see also “Hostile 
chest)” 
 
Chest deformities that would preclude an open chest 
procedure and include pectus excavaatum, mastectomy, 
iatrogenic radiation exposure 
 
Sponsor 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 83 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Term 
Definition 
Reference/ 
Justification 
Child-Pugh 
Classification  
 
The Child-Pugh score consists of five clinical features and 
is used to assess the prognosis of chronic liver disease and 
cirrhosis: 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, 
µmol/l (mg/dl) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, 
g/dl 
>3.5 
2.8-3.5 
<2.8 
Prothrombin 
time, 
prolongation 
(secs) 
<4.0 
4.0-6.0 
> 6.0 
Ascites 
None 
Mild 
Moderate to 
Severe 
Hepatic 
encephalopathy 
None 
Grade I-II (or 
suppressed 
with 
medication) 
Grade III-IV (or 
refractory) 
 
Chronic liver disease is classified into Child-Pugh class A 
to C, employing the added score from above: 
Points 
Class 
One year 
survival 
Two year survival 
5-6 
A 
100% 
85% 
7-9 
B 
81% 
57% 
10-15 
C 
45% 
35% 
 
 
CHOLONGITAS, E., 
PAPATHEODORIDIS
, G. V., VANGELI, 
M., TERRENI, N., 
PATCH, D. and 
BURROUGHS, A. K. 
(2005), Systematic 
review: the model for 
end-stage liver 
disease – should it 
replace Child-Pugh's 
classification for 
assessing prognosis 
in cirrhosis. 
Alimentary 
Pharmacology & 
Therapeutics, 22: 
1079–1089. doi: 
10.1111/j.1365-
2036.2005.02691. 
Coagulopathy 
A pathologic condition that affects the ability of the blood 
to coagulate.  
Examples include hemophilia, drug-induced clotting 
disorder, thrombocytopenia and Von Willebrand's disease 
Sponsor 
Continuous Atrial 
fibrillation 
Atrial fibrillation > 24 hours, requiring  new drug treatment 
/ anticoagulation OR requiring chemical or electrical 
cardioversion 
Sponsor 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 84 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Term 
Definition 
Reference/ 
Justification 
Congestive Heart 
Failure (CHF) 
Diagnosis requires physician documentation or report of 
any of the following:   
• 
Unusual dyspnea on light exertion  
• 
Recurrent dyspnea occurring in the supine 
position 
• 
Fluid retention; or the description of rales, jugular 
venous distension 
• 
Pulmonary edema on physical exam, or 
pulmonary edema on chest x-ray presumed to be 
cardiac dysfunction 
A low ejection fraction alone, without clinical evidence of 
heart failure does not qualify as heart failure.  
An elevated BNP without other supporting documentation 
should not be reported as CHF 
STS 
Cardiopulmonary 
bypass (CPB) 
 Bypass of the heart and lungs as in open heart surgery 
Sponsor 
Conversion to 
open surgery  
Any conversion to complete TAVR procedure secondary 
to any procedure-related complications  
Sponsor 
Coronary artery 
disease (CAD) 
Coronary artery disease is characterized by a narrowing 
or "stenosis" of the blood vessels to the heart resulting in 
inadequate blood flow to the heart muscle itself. 
STS 
Coronary 
obstruction  
 
Angiographic or echocardiographic evidence of a new, 
partial or complete, obstruction of a coronary ostium, 
either by the valve prosthesis itself, the native leaflets, 
calcifications, or dissection, occurring during or after the 
TAVR or SAVR procedure.  
Mechanical coronary artery obstruction following TAVR or 
index SAVR includes: 
• impingement of the coronary ostia by the valve support 
structure in the setting of suboptimal valve positioning 
and/or ‘small aortic root’ anatomy; OR 
• displacement of native aortic valve leaflets towards the 
coronary ostia during TAVR ; OR 
• suture-related kinking or obstruction or cannulation- 
related obstruction of the coronary ostia associated with 
SAVR. 
VARC 2/STS 
Device 
For the determination of device relationship, the study 
device consists of:  
• 
The Edwards SAPIEN 3 valve  
• 
The Edwards Valve Delivery System 
• 
The Edwards Expandable Sheath 
• 
Any surgical valve used implanted during index 
procedure 
 
Sponsor 
Device (Valve) 
fracture 
The separation of any portion of the frame into two or 
more parts; as may be determined by radiography, 
computed tomography,magnetic resonance imaging or by 
direct examination. 
Sponsor 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 85 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Term 
Definition 
Reference/ 
Justification 
Device 
malfunction 
The failure of a device to meet any of its performance 
specifications or otherwise perform as 
intended.  Performance specifications include all claims 
made in the labeling of the device. 
 
FDA., 21 CFR 
803.3(m) 
Device (Valve) 
thrombosis 
Any thrombus attached to or near an implanted valve that 
occludes part of the blood flow path, interferes with valve 
function, or is sufficiently large to warrant treatment. Note 
that valve-associated thrombus identified at autopsy in a 
patient whose cause of death was not valve-related 
should not be reported as valve thrombosis  
VARC 2 
Endocarditis 
Endocarditis must meet at least 1 of the following criteria:  
1. Patient has organisms cultured from valve or 
vegetation 
2. Patient has 2 or more of the following signs or 
symptoms:  
• 
Fever (>38°C) 
• 
New or changing murmur 
• 
Embolic phenomena 
• 
Skin manifestations (i.e., petechiae, splinter 
hemorrhages, painful subcutaneous nodules) 
• 
CHF 
• 
Cardiac conduction abnormality  
 
With no other recognized cause and at least 1 of the 
following:  
a. organisms cultured from 2 or more blood cultures  
b. organisms seen on Gram’s stain of valve when culture 
is negative or not done  
c. valvular vegetation seen during an invasive procedure 
or autopsy  
d. positive laboratory test on blood or urine (e.g., antigen 
tests for H influenzae, S pneumoniae, N meningitidis, or 
Group B Streptococcus)  
e. evidence of new vegetation seen on echocardiogram 
and if diagnosis is made antemortem, physician institutes 
appropriate antimicrobial therapy. Infection of the 
endocardial surface of the heart which may include one or 
more heart valves, the mural endocardium, or a septal 
defect 
STS 
EuroSCORE II 
http://www.euroscore.org/calc.html  
European System for 
Cardiac Operative 
Risk Evaluation 
EuroSCORE, 
logistic 
http://www.euroscore.org/calcold.html  
 
European System for 
Cardiac Operative 
Risk Evaluation 
Explant  
Removal of the investigational valve implant for any 
reason 
Sponsor 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 86 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Term 
Definition 
Reference/ 
Justification 
Hemolysis 
Evidence of RBC destruction best explained by 
hemolysis (LDH >350 u/L and decreased haptoglobin 
based on site lab normals) and no other explanation for 
the findings. Microscopic evidence may be considered 
supportive. 
Sponsor 
Hospitalization 
(repeat) 
Any unplanned admission to the hospital (including 
an emergency department visit) for either a 
diagnostic or therapeutic purpose (e.g. diuretics, 
inotropes, chronotropes, oral or intra-venous 
therapy) following discharge from the index 
hospitalization 
Sponsor 
Hospitalization 
for CHF 
An event where the patient is admitted to the hospital 
with a primary diagnosis of CHF where the length of stay 
is at least 24 h (or extends over a calendar date if the 
hospital admission and discharge times are unavailable), 
and the patient exhibits new or worsening symptoms of 
CHF on presentation, has objective evidence of new or 
worsening CHF, and receives initiation or intensification 
of treatment specifically for CHF. 
 
Clinical symptoms of CHF include, but not limited to a 
pulmonary edema, hypoperfusion, or documented 
volume overload AND administration of IV diuresis or 
inotropic therapy, performance of aortic valvuloplasty, 
institution of mechanical support (IABP or ventilation for 
pulmonary oedema) or haemodialysis for volume 
overload.  
2014 ACC/AHA Key 
Data Elements and 
Definitions for 
CardiovascularEndpo
int Events in Clinical 
Trials/VARC 2 
Hypertension 
Systolic pressure > 140 or a diastolic pressure > 90 
mmHg 
Sponsor 
Hypotension 
Systolic pressure < 90 or a diastolic pressure < 60 mmHg 
Sponsor 
Index 
hospitalization 
The beginning of the Index Hospitalization is defined as 
the day  the patient is admitted for  valve implant 
procedure and continues until the patient is discharged 
from the hospital.  
Sponsor 
Infection 
Known infection requiring intravenous antibiotics for other 
than prophylaxis, and/or extended hospitalization 
Sponsor 
Lung disease, 
severe 
FEV1 < 50% predicted or currently on home oxygen 
 
Sponsor 
Liver disease, 
chronic 
MELD Score ≥ 10 or Child-Pugh Class B or C 
Sponsor 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 87 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Term 
Definition 
Reference/ 
Justification 
Mini-mental state 
examination 
(MMSE) 
A questionnaire that is used extensively in clinical and 
research settings to measure cognitive impairment. 
Pangman, VC; Sloan, 
J; Guse, L. (2000). 
"An Examination of 
Psychometric 
Properties of the 
Mini-Mental State 
Examination and the 
Standardized Mini-
Mental State 
Examination: 
Implications for 
Clinical 
Practice". Applied 
Nursing 
Research 13 (4): 
209–213. 
MELD (Model 
For End-Stage 
Liver Disease) 
Score 
 
A scoring system for assessing the severity and 
quantification of chronic liver disease.  
• 
It is preferable to using the calculator 
(http://www.mdcalc.com/meld-score-model-for-
end-stage-liver-disease-12-and-older/)  to calculate 
the MELD as there are several caveats relating 
to minimum and maximum values assigned in 
the MELD 
• 
Values should be no more than 48 hours old 
 
In interpreting the MELD Score in hospitalized patients, 
the 3 month mortality is:  
 
40 or more — 71.3% mortality 
30–39 — 52.6% mortality 
20–29 — 19.6% mortality 
10–19 — 6.0% mortality 
<9 — 1.9% mortality 
Wiesner et al. Model 
for end-stage liver 
disease (MELD) and 
allocation of donor 
livers. 
Gastroenterology 
(2003) vol. 124 (1) pp. 
91-6 
Modified Rankin 
Scale (mRS) 
A commonly used scale for measuring the degree of 
disability or dependence in the daily activities of people 
who have suffered a stroke, as follows:  
 
0 No symptoms at all 
1 No significant disability despite symptoms; able to 
carry out all usual duties and activities 
2 Slight disability; unable to carry out all previous 
activities, but able to look after own affairs without 
assistance 
3 Moderate disability; requiring some help, but able to 
walk without assistance 
4 Moderately severe disability; unable to walk without 
assistance and unable to attend to own bodily needs 
without assistance 
5 Severe disability; bedridden, incontinent and requiring 
constant nursing care and attention 
6 Dead 
Van Swieten, J. C., et 
al. "Interobserver 
agreement for the 
assessment of 
handicap in stroke 
patients." Stroke 19.5 
(1988): 604-607. 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 88 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Term 
Definition 
Reference/ 
Justification 
Mortality, all-
cause 
Cardiovascular mortality  
 
Any of the following criteria:  
• 
Death due to proximate cardiac cause (e.g. 
myocardial infarction, cardiac tamponade, 
worsening heart failure)  
• 
Death caused by non-coronary vascular conditions 
such as neurological events, pulmonary embolism, 
ruptured aortic aneurysm, dissecting aneurysm, or 
other vascular disease  
• 
All procedure-related deaths, including those related 
to a complication of the procedure or treatment for a 
complication of the procedure  
• 
All valve-related deaths including structural or 
nonstructural valve dysfunction or other valve-
related adverse events  
• 
Sudden or unwitnessed death  
• 
Death of unknown cause  
 
Non-cardiovascular mortality  
• 
Any death in which the primary cause of death is 
clearly related to another condition (e.g. trauma, 
cancer, suicide).  
VARC 2 
Myocardial 
Infarction 
An acute ischemic event that is associated with 
documented and clinically significant myocardial necrosis 
Any one of the following criteria meets the diagnosis for 
MI:  
 
• 
Detection of a rise and/or fall of cardiac 
biomarker values [preferably cardiac troponin 
(cTn)] with at least one value above the 99th 
percentile upper reference limit (URL) and with at 
least one of the following:  
 
- Symptoms of ischemia  
 
- New or presumed new significant ST-segment–
T wave (ST–T) changes or new left bundle 
branch block (LBBB)  
 
- Development of pathological Q waves in the 
ECG  
 
- Imaging evidence of new loss of viable 
myocardium or new regional wall motion 
abnormality  
 
• 
Identification of an intracoronary thrombus by 
angiography  
 
STS 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 89 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Term 
Definition 
Reference/ 
Justification 
National 
Institutes of 
Health Stroke 
Scale (NIHSS) 
The NIHSS can help physicians determine the severity of 
a stroke, predict clinical outcomes and can help guide 
management.  
NIHSS 
New York Heart 
Association 
Classification 
(NYHA) 
. 
NYHA 
Class 
Functional Capacity 
I 
Patients with cardiac disease but without 
resulting limitation of physical activity. 
Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or 
anginal pain. 
II 
Patients with cardiac disease resulting in 
slight limitation of physical activity. They 
are comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, 
dyspnea, or anginal pain. 
III 
Patients with cardiac disease resulting in 
marked limitation of physical activity. They 
are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, 
dyspnea, or anginal pain. 
IV 
Patients with cardiac disease resulting in 
inability to carry on any physical activity 
without discomfort. Symptoms of heart 
failure or the anginal syndrome may be 
present even at rest. If any physical 
activity is undertaken, discomfort is 
increased. 
 
The Criteria 
Committee of the 
New York Heart 
Association. 
(1994). Nomenclature 
and Criteria for 
Diagnosis of 
Diseases of the Heart 
and Great 
Vessels. (9th ed.). 
Boston: Little, Brown 
& Co. pp. 253–256. 
Paravalvular 
Leak  
Paravalvular or paraprosthetic leak (PVL) is a 
complication associated with the implantation of a 
prosthetic heart valve whether traditional (surgical) or a 
transcatheter (TAVR) approach.  
 
PVL refers to blood flowing through a channel between 
the structure of the implanted valve and cardiac tissue as 
a result of a lack of appropriate sealing 
ESC 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 90 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Term 
Definition 
Reference/ 
Justification 
Peripheral 
vascular disease 
(PVD) 
Includes peripheral arterial disease of upper and lower 
extremity, renal, mesenteric, and abdominal aortic 
systems, as follows:  
• 
Claudication , either with exertion or at rest 
• 
Amputation for arterial vascular insufficiency 
• 
Vascular reconstruction, bypass surgery, or 
percutaneous intervention to the extremities 
(excluding dialysis fistulas and vein stripping) 
• 
Documented abdominal aortic aneurysm with or 
without repair 
• 
Positive noninvasive test (e.g., ankle brachial 
index =< 0.9, ultrasound, magnetic resonance or 
computed tomography imaging of > 50% 
diameter stenosis in any peripheral artery, i.e., 
renal, subclavian, femoral, iliac) or angiographic 
imaging  
 
Peripheral arterial disease excludes disease in the 
carotid, cerebrovascular arteries or thoracic aorta.  
PVD does not include DVT. 
STS 
Porcelain aorta 
or severely 
atherosclerotic 
aorta  
Heavy circumferential calcification or severe 
atheromatous plaques of the entire ascending aorta 
extending to the arch such that aortic cross-clamping is 
not feasible. 
VARC 2 
Pulmonary 
hypertension 
A mean pulmonary artery pressure >or equal 25 mm Hg 
in presence of LAP/wedge <= 15 mm Hg 
ACC 
Pre-existing 
condition 
A pre-existing condition is one that is present at the start 
of study treatment. A preexisting condition is not an 
adverse event unless it worsens as a result of the study 
treatment. 
Sponsor 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 91 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Term 
Definition 
Reference/ 
Justification 
Prosthetic aortic 
valve stenosis 
criteriaa 
Normal 
Mild 
Moderate/severe  
Quantitative Parameters (flow-dependent)b 
 
Peak velocity 
(m/s) 
<3 m/s 
3-4 m/s 
>4m/s 
Mean gradient 
(mmHg) 
<20 mmHg 
20-40 
mmHg 
>40 mmHg 
Quantitative parameters (flow-independent) 
Doppler velocity 
indexc 
>0.35 
0.35-0.25 
<0.25 
Effective orifice 
aread 
>1.1 cm2 
>1.1-0.8 
cm2 
<0.8 cm2 
Effective orifice 
areae 
>0.9 cm2 
>0.9-0.6 
cm2 
<0.6 cm2 
 
 
 
 
 
aIn conditions of normal or near normal stroke volume 
(50–70 mL). 
bThese parameters are more affected by flow, including 
concomitant aortic regurgitation. 
cFor LVOT >2.5 cm, significant stenosis criteria is <0.20. 
dUse in setting of BSA ≥1.6 cm2 (note: dependent on the 
size of the valve and the size of the native annulus). 
eUse in setting of BSA <1.6 cm2. 
VARC-2 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 92 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Term 
Definition 
Reference/ 
Justification 
Prosthetic aortic 
valve 
regurgitation 
criteria 
Normal 
Mild  
Moderate/severe  
Semi-quantitative Parameters  
 
Diastolic flow 
reversal in the 
descending 
aorta—PW 
Absent or 
brief early 
diastolic 
Intermediate 
Prominent, 
holodiastolic 
Circumferential 
extent of 
prosthetic 
valve 
paravalvular 
regurgitation 
(%)a 
<10% 
10-29% 
≥30% 
Quantitative parametersb 
Regurgitant 
volume 
(mL/beat) 
<30 mL 
30-59 mL 
≥60 mL 
Regurgitant 
fraction (%) 
<30% 
 
30-49% 
 
≥50% 
EROA (cm2) 
0.10 cm2 
0.10-0.29 
cm2 
≥0.30 cm2 
 
 
 
 
 
aNot well-validated and may overestimate the severity 
compared with the quantitative Doppler. 
bFor LVOT >2.5 cm, significant stenosis criteria is <0.20. 
 
VARC 2 
Reintervention 
Any intervention that repairs, alters or replaces a 
previously implanted or operated  valve, which occurrs 
after the completion of the valve implant procedure and 
the transfer to the procedure room. These interventions 
include:  
 
• 
Balloon aortic valvuloplasty 
• 
Surgical aortic valve replacement 
• 
Valve in valve 
• 
Paravalvular leak closure 
 
 
STS/AATS 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 93 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Term 
Definition 
Reference/ 
Justification 
Serious Adverse 
Event (SAE) 
Adverse Event that:  
 
• 
Leads to death; 
 
• 
Leads to a serious deterioration in the health of 
the study patient that: 
 
o 
Results in life-threatening illness or injury; 
 
o 
Results in a permanent impairment of a 
body structure or a body function; 
 
o 
Requires inpatient hospitalization or 
prolongation of existing hospitalization; 
 
o 
Results in medical or surgical intervention 
to prevent permanent impairment to body 
structure or a body function; 
 
• 
Led to fetal distress, fetal death or congenital 
abnormality or birth defect; 
• 
Significant medical event 
 
Important medical events that do not meet the above 
criteria may still be considered an SAE if they seriously 
jeopardize the patient and require immediate medical or 
surgical intervention to prevent one of the aforementioned 
outcomes. 
 
ISO 14155-1:2011 
FDA (21 CFR 312.32 
(a) 
 
Sternal wound 
dehiscence 
Opening of sternal with negative cultures and no signs of 
infection requiring a procedure or operation for treatment 
Sponsor 
Valve implant 
procedure 
Placement of study device and/or additional procedures 
occurring in the cath lab and/or operating room which are 
completed prior to subject transfer to a post-procedure 
recovery unit (e.g. Recovery Room, ICU/CCU, etc.  
 
The valve implant procedure will be considered to have 
started when: 
  
• 
The first interventional access related puncture 
(venous or arterial) is established for TAVR. 
• 
The first skin incision is performed for SAVR. 
  
Performance of TEE does not by itself constitute start of 
procedure 
Sponsor 
Valve 
Thrombosis 
Valve thrombosis is any thrombus not caused by 
infection attached to or near an operated valve that 
occludes part of the blood flow path, interferes with valve  
function, or is sufficiently large to warrant treatment. 
VARC2 
Stroke / 
Transient 
Ischemic Attack 
Diagnostic Criteria  
 
VARC 2 

 
P A R T N E R 3  Tri al,  V er si o n 5. 0 D E C 2 0 1 8 
C O N FI D E N TI A L 
P a g e 9 4 
 
 
 
 
 
T h e P A R T N E R 3 -U S I D E Tri al  
 
E d w ar d s Lif e s ci e n c e s  
 
 
T er m  
D efi niti o n  
R ef er e n c e/  
J u stifi c ati o n  
( TI A) 
A c ut e e pi s o d e of a f o c al or gl o b al n e ur ol o gi c al d efi cit wit h 
at l e a st o n e of t h e f oll o wi n g:  
 
 c h a n g e i n l e v el of c o n s ci o u s n e s s  
 h e mi pl e gi a  
 h e mi p ar e si s  
 n u m b n e s s or s e n s or y l o s s aff e cti n g o n e si d e of t h e 
b o d y  
 d y s p h a si a or a p h a si a  
 h e mi a n o pi a  
 a m a ur o si s f u g a x  
 or ot h er n e ur ol o gi c al si g n s or s y m pt o m s c o n si st e nt wit h 
str o k e  
 
D ur ati o n of a f o c al or gl o b al n e ur ol o gi c al d efi cit > 2 4 h; O R 
< 2 4 h, if a v ail a bl e n e ur oi m a gi n g d o c u m e nt s a n e w 
h e m orr h a g e or i nf ar ct; O R t h e n e ur ol o gi c al d efi cit r e s ult s 
i n d e at h  
 
N o ot h er r e a dil y i d e ntifi a bl e n o n str o k e c a u s e f or t h e 
cli ni c al pr e s e nt ati o n ( e. g., br ai n t u m or, tr a u m a, i nf e cti o n, 
h y p o gl y c e mi a, p eri p h er al l e si o n, p h ar m a c ol o gi c al 
i nfl u e n c e s)t o b e d et er mi n e d b y or i n c o nj u n cti o n wit h 
d e si g n at e d n e ur ol o gi st*  
 
C o nfir m ati o n of t h e di a g n o si s b y at l e a st o n e of t h e 
f oll o wi n g #:  
 
 N e ur ol o g y or n e ur o s ur gi c al s p e ci ali st  
 N e ur oi m a gi n g pr o c e d ur e ( M R or C T s c a n)  
 Cli ni c al pr e s e nt ati o n al o n e  
 
Str o k e d efi niti o n s † :  
 
 N o n -di s a bli n g: a m R S s c or e of l e s s t h a n 2 at 9 0 d a y s 
or t h e l a st a v ail a bl e cli ni c al vi sit wit h e v al u a bl e d at a or 
o n e t h at d o e s n ot r e s ult i n a n i n cr e a s e of at l e a st o n e 
m R S c at e g or y fr o m a n i n di vi d u al’ s pr e -str o k e b a s eli n e  
 
 Di s a bli n g: a m R S s c or e of 2 or m or e at 9 0 d a y s or t h e 
l a st a v ail a bl e cli ni c al vi sit wit h e v al u a bl e d at a a n d a n 
i n cr e a s e of at l e a st o n e m R S c at e g or y fr o m a n 
i n di vi d u al’ s pr e-str o k e b a s eli n e  
 
Str o k e cl a s sifi c ati o n :  
 
 H e m orr h a gi c: a n a c ut e e pi s o d e of f o c al or gl o b al 
c er e br al or s pi n al d y sf u n cti o n c a u s e d b y 
i ntr a p ar e n c h y m al, i ntr a v e ntri c ul ar, or s u b ar a c h n oi d 
h e m orr h a g e.  
 

 
P A R T N E R 3  Tri al,  V er si o n 5. 0 D E C 2 0 1 8 
C O N FI D E N TI A L 
P a g e 9 5 
 
 
 
 
 
T h e P A R T N E R 3 -U S I D E Tri al  
 
E d w ar d s Lif e s ci e n c e s  
 
 
T er m  
D efi niti o n  
R ef er e n c e/  
J u stifi c ati o n  
 I s c h e mi c: a n a c ut e s y m pt o m ati c e pi s o d e of f o c al 
c er e br al, s pi n al, or r eti n al d y sf u n cti o n c a u s e d b y a n 
i nf ar cti on of t h e c e ntr al n er v o u s s y st e m ti s s u e  
 
 U n d et er mi n e d: str o k e wit h i n s uffi ci e nt i nf or m ati o n t o 
all o w c at e g ori z ati o n a s i s c h e mi c or h e m orr h a gi c.  
 
Tr a n si e nt I s c h e mi c Att a c k ( TI A)  
 
D ur ati o n of f o c al or gl o b al n e ur ol o gi c al d efi cit < 2 4 h, a n y 
v ari a bl e n e ur oi m a gi n g d o e s n ot d e m o n str at e a n e w 
h e m orr h a g e or i nf ar ct  
 
 
* P ati e nt s wit h n o n-f o c al gl o b al e n c e p h al o p at h y will n ot b e 
r e p ort e d a s a str o k e wit h o ut u n e q ui v o c al e vi d e n c e b a s e d 
u p o n n e ur oi m a gi n g st u di e s.  
#If a str o k e i s r e p ort e d wit h o ut e vi d e n c e of c o nfir m a ti o n of 
t h e di a g n o si s b y o n e of t h e s e m et h o d s, t h e e v e nt m a y still 
b e c o n si d er e d a str o k e o n t h e b a si s of t h e cli ni c al 
pr e s e nt ati o n al o n e.  
† M o difi e d R a n ki n s c or e a s s e s s m e nt s s h o ul d b e m a d e b y 
q u alifi e d i n di vi d u al s a c c or di n g t o a c ertifi c ati o n pr o c e s s.  
 
 
Str u ct ur al 
p erf or m a n c e  
E v al u ati o n of mi gr ati o n, e m b oli z ati o n, fr a ct ur e, or 
t hr o m b o si s 
F D A  
Str u ct ur al 
V al v ul ar 
D et eri or ati o n 
( S V D) 
Str u ct ur al v al v e d et eri or ati o n i n cl u d e s d y sf u n cti o n or 
d et eri or ati o n e x cl u si v e of i nf e cti o n or t hr o m b o si s a s 
d et er mi n e d b y r e o p er ati o n, a ut o p s y or cli ni c al 
i n v e sti g ati o n.  T h e t er m str u ct ur al d et eri or ati o n r ef er s t o 
c h a n g e s i ntri n si c t o t h e v al v e, s u c h a s w e ar, fr a ct ur e, 
c al cifi c ati o n, l e afl et t e ar, l e afl et r etr a cti o n, s ut ur e li n e 
di sr u pti o n of c o m p o n e nt s a pr ot h eti c v al v e, t hi c k e ni n g, 
st e n o si s  
A ki n s, C ar y W., et al. 
" G ui d eli n e s f or 
r e p orti n g m ort alit y 
a n d m or bi dit y aft er 
c ar di a c v al v e 
i nt er v e nti o n s." 
E ur o p e a n J o ur n al of 
C ar di o -T h or a ci c 
S ur g er y  3 3. 4 ( 2 0 0 8): 
5 2 3 -5 2 8.  
S T S A d ult 
C ar di a c S ur g er y 
Ri s k C al c ul at or  
T h e S o ci et y of T h or a ci c S ur g e o n s’ ri s k m o d el s pr e di ct 
t h e ri s k of o p er ati v e m ort alit y a n d m or bi dit y aft er a d ult 
c ar di a c s ur g er y o n t h e b a si s of p ati e nt  d e m o gr a p hi c a n d 
cli ni c al  v ari a bl e s . 
 
htt p://ris kc alc.sts. or g/sts w e bris kc alc/ #/   
S T S  
S y n c o p e  
A f ai nti n g s p ell or l o s s of c o n s ci o u s n e s s  
S T S  
S Y N T A X S c or e  
A n a n gi o gr a p hi c gr a di n g t o ol t o d et er mi n e t h e c o m pl e xit y 
of c or o n ar y art er y di s e a s e . 
htt p:// w w w.s y nt axsc or e.c o m/   
htt p://ir -n wr.r u/c alc ul at ors/sy nt axsc or e/fr a m es et. ht m   
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 96 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Term 
Definition 
Reference/ 
Justification 
6 Minute Walk 
Test 
A performance-based measure of functional exercise 
capacity. The test measures the distance an individual is 
able to walk over a total of six minutes on a hard, flat 
surface. See more at: http://www.rheumatology.org/I-Am-
A/Rheumatologist/Research/Clinician-Researchers/Six-
Minute-Walk-Test-SMWT#sthash.cFCDWfkn.dpuf 
ATS 
THV-in-THV 
An additional valve prosthesis is implanted within a 
previously implanted prosthesis because of suboptimal 
device position and/or function, during or after the valve 
implant procedure 
VARC 2 
Transient 
Ischemic Attack 
(TIA) 
See “Stroke / Transient Ischemic Attack (TIA)” 
 
Unanticipated 
Adverse Device 
Effect (UADE) 
Any serious adverse effect on health or safety or any 
life-threatening problem or death caused by, or 
associated with, a device, if that effect, problem, or 
death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or 
application (including a supplementary plan or 
application), or any other unanticipated serious 
problems associated with a device that relates to the 
rights, safety, or welfare of patients. 
FDA 
Vascular injury  
Injury that may be caused by a guidewire, vascular 
sheath, delivery catheter, or any balloon used for aortic 
valve predilatation and can include arterial dissection, 
perforation, arteriovenous fistula, pseudoaneurysm 
formation, retroperitoneal hemorrhage, or incomplete 
arteriotomy closure.  
Venous injuries can include perforation, tears and 
thromboembolism.  
Cardiac vascular injury can include perforation or tearing 
of the major cardiac structures that require repair.  
Sponsor 
Valve 
malpositioning  
 
Valve migration  
• 
After initial correct positioning, the valve prosthesis 
moves upward or downward, within the aortic 
annulus from its initial position, with or without 
consequences  
 
Valve embolization  
• 
The valve prosthesis moves during or after 
deployment such that it loses contact with the aortic 
annulus  
 Ectopic valve deployment  
• Permanent deployment of the valve prosthesis in a 
location other than the aortic root  
VARC 2 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 97 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Appendix C 
Instructions For Use (IFU)  
Refer to device package label to access electronic IFU or contact an Edwards Clinical Affairs representative. 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 98 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Appendix D 
Physician and Support Staff Training 
Title:         Edwards Lifesciences Physician Training and Procedural Case Support Plan  
 
Date: 
October 2017 
 
Purpose: 
The purpose of this plan is to document and standardize the requirements for physician 
training for transcatheter heart valve (THV) implantation.  It further describes the procedural 
case support provided by an Edwards Lifesciences representative (e.g., Clinical Specialist).  
Scope: 
This plan applies to the implanting physician Investigators (Interventional 
Cardiologists/Surgeon for the PARTNER 3 trial. This plan addresses training for current users 
who have previously completed training under prior Edwards’s trials and newly designated 
implanting physicians. 
 
 
I. 
Current User Physician Training Plan 
 
1. Didactic Presentation and Device Demonstration 
A didactic presentation including room set-up and patient preparation, sizing, device description 
and usage, procedural steps, complications and technical tips is given to the implanting 
physicians.  In addition, a hands-on device demonstration is given.  Both the didactic 
presentation and device demonstration are provided by an Edwards Lifesciences representative 
(e.g., Edwards Clinical Specialist). 
 
2. Documentation 
Training for the implanting physicians will be documented on the appropriate Training Forms 
(i.e., checked-off, dated and signed) by an Edwards Lifesciences representative as training is 
completed. Training records are maintained by Edwards Lifesciences in addition to being filed in 
the site study files. 
II. 
New User Physician Training Plan includes: 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 99 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
1. THV Fundamentals Training Program 
All new implanting physicians must attend the Edwards THV Fundamentals Training Program, 
which consists of the following: 
a) Didactic training/review of training manual: Focuses of key aspects of patient 
evaluation, device overview, procedural and technical tips, potential complications 
and troubleshooting tips. 
b) Device demonstration 
c) Simulation: Not required. Used as an enhancement to device demonstration and 
procedure training when available or applicable. 
d) Case observation or Case Review: 1 case observation or case review prior to first THV 
case. 
e) Certain requirements may be waived for physicians with applicable prior experience 
including but not limited to:  prior involvement in THV or procedural development, or 
prior clinical experience in the aortic position.  Any requirements waived to be indicated 
by a letter to file summarizing the reason for waiver and applicable prior experience. 
2. Proctoring 
The implanting physician must be proctored by an experienced physician for a minimum of two 
successful valve implantation procedures and deemed ready for independence by both the 
proctor and Clinical Specialist. These are to be performed at the Investigator’s institution with his 
staff. If the proctor is not satisfied that these two procedures provide sufficient preparation, then 
subsequent proctoring sessions may be added as needed.  Proctor requirements may be waived 
for physicians with applicable prior experience including but not limited to:  prior involvement in 
THV or procedural development, or prior clinical experience in the aortic position.  Any 
requirements waived to be indicated by a letter to file summarizing the reason for waiver and 
applicable prior experience. 
3. Proctor Requirements  
An implanting physician is considered a proctor only after having completed a minimum of eight 
procedures. Proctors should have extensive experience in recognition and management of intra-
procedural complications and advanced troubleshooting skills.  

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 100 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
4. Refresher THV Fundamentals Training 
Required for implanting physicians if greater than 3 months from THV Fundamentals completion to first 
case or 5 months in between THV cases. 
5. Didactic Presentation and Device Demonstration 
Once THV Fundamentals Training and Proctoring have been complete, the implanting physicians 
required to be trained by an Edwards Representative (e.g., Clinical Specialist) on the study 
specific didactic presentation and receive a hands-on device demonstration (if different from 
training received for commercial device). 
 
6. Documentation 
Training for the implanting physicians will be documented on the appropriate Training Forms (i.e., 
checked-off, dated and signed) by an Edwards Lifesciences representative as training is completed.  
Training records are maintained by Edwards Lifesciences and copies will be filed in the site study files. 
 
III. Procedural Case Support 
An Edwards Lifesciences representative (e.g., Clinical Specialist) will attend all procedures to 
answer device and procedural questions, and is responsible for ensuring that all Edwards THV 
devices are prepared in accordance to the Instructions for Use Throughout the PARTNER 3 trial  
in no instance will any site perform a THV procedure without an Edwards’s representative (e.g., 
Clinical Specialist) present. 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 101 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Appendix E 
Six Minute Walk Test 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 102 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 103 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 104 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 105 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 106 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 107 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 108 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Appendix F 
Frailty Index 
The assessment should be administered by either an investigator or research coordinator. The study patient will 
first be given a series of questions related to their ability to perform activities of daily living and scored 
accordingly on their responses. The second portion of the assessment involves a series of three hand grip 
strength tests which are averaged. Study patients will then be given a score for frailty based on their average 
score. Finally, study patients will be asked to walk 5 meters. Based on the overall assessment, a score will be 
given for frailty. 
 
FRAILTY INDEX DATA  
 
1.  Was Frailty Index Obtained?   Yes 
 No 
 
 
2.  Date Completed: _____/_____/______ 
    
               
 
 
 
 
            
(mm/dd/yyyy) 
3.  Height __ __ __.__(cm/in)     
4.  Weight __ __ __.__(kg/lb) 
 
5.  BMI ____ 
6.  Serum Albumin: ___.___g/dL 
 
7.  Time (lab): ____:____  (24 Hr)           
 
Katz Activities of Daily Living 
ACTIVITIES 
POINTS (1 OR 0) 
INDEPENDENCE: 
(1 POINT) 
NO supervision, direction or 
personal assistance 
DEPENDENCE: 
(0 POINTS) 
WITH supervision, direction, 
personal assistance or total care  
 
BATHING 
POINTS:___________ 
(1 POINT) Bathes self completely or 
needs help in bathing only a single 
part of the body such as the back, 
(0 POINTS) Needs help with bathing 
more than one part of the body, 
getting in or out of the tub or 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 109 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
genital area or disabled extremity. 
shower. 
Requires total bathing. 
 
DRESSING 
POINTS:___________ 
 
(1 POINT) Gets clothes from closets 
and drawers and puts on clothes 
and outer garments complete with 
fasteners. May have help tying 
shoes. 
 
(0 POINTS) Needs help with 
dressing self or needs to be 
completely dressed. 
 
TOILETING 
POINTS:___________ 
 
(1 POINT) Goes to toilet, gets on and 
off, arranges clothes, cleans genital 
area without help. 
 
(0 POINTS) Needs help transferring 
to the toilet, cleaning self or uses 
bedpan or commode. 
 
TRANSFERRING 
POINTS:___________ 
 
(1 POINT) Moves in and out of bed 
or chair unassisted. Mechanical 
transferring aides are acceptable. 
 
(0 POINTS) Needs help in moving 
from bed to chair or requires a 
complete transfer.  
 
CONTINENCE 
POINTS:___________ 
 
(1 POINT) Exercises complete self 
control over urination and 
defecation. 
 
(0 POINTS) Is partially or totally 
incontinent of bowel or bladder. 
 
FEEDING 
POINTS:___________ 
 
(1 POINT) Gets food from plate into 
mouth without help. Preparation of 
food may be done by another 
person. 
 
(0 POINTS) Needs partial or total 
help with feeding or requires 
parenteral feeding.   
 
TOTAL POINTS = ______ 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 110 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Grip Strength 
 
Note to the Examiner:  Elbow should be at a 90 degree angle,              ____________ Grasp 1 
with arm not resting on table or “pinned” against chest wall.                  ____________ Grasp 2  
All tests should be completed with the dynamometer in the                   ____________ Grasp 3 
dominant hand.   
                    _____________ Average 
 
Men                                               Cutoff for grip strength (Kg) criterion for frailty 
 
BMI < 24                                          < 29 
BMI 24.1-26                                     < 30 
BMI 26.1-28                                     < 30 
BMI > 28                                          < 32 
 
Women                                          Cutoff for grip strength (Kg) criterion for frailty 
 
BMI < 23                                          < 17 
BMI 23.1-26                                     < 17.3 
BMI 26.1-29                                     < 18 
BMI > 29                                          < 21 
 
____________________________________________________________________________ 
 
5-Meter Walk                                                                           __________ Seconds 
 
Men                                               Cutoff Time to walk 5 meters criterion for frailty 
 
Height < 173 cm                             > 7 seconds 
Height > 173 cm                             > 6 seconds       
 
Women 
 
Height < 159 cm                             > 7 seconds 
Height > 159 cm                             > 6 seconds       
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 111 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Appendix G 
Mini Mental State Examination (MMSE) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 112 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 113 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 114 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 115 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Appendix H 
NIH Stroke Scale (NIHSS) 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 116 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 117 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 118 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 119 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 120 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 121 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 122 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Appendix I 
Modified Rankin Scale (mRS) 
The Modified Rankin Scale (mRS) is a 6-point scale to determine if the patient is severely 
disabled (5), has a moderately severe disability (4), is moderately disabled (3), is slightly 
disabled (2), has no significant disability (1), or has no symptoms at all and is not limited (0).   
 
Instructions 
The Modified Rankin Scale (mRS) will be administered to all study patients by a neurologist 
or neurology fellow.  The mRS will be completed after the Mini Mental State Examination 
(MMSE) and the National Institutes of Health Stroke Scale (NIHSS).   
 
Because subjects and family members may understate the severity of disability, it is 
important for the rating clinician to understand that the mRS is a clinical scale and not a 
patient-reported outcome.  The clinician may ask questions but must assess the disability 
according to the 6-point scale whether or not in agreement with the subject, family, close 
friend, or caregiver. 
 
The rater should use the best sources of information available. Information should be 
obtained from the patient and/or family, friends, nursing staff, physical and occupational 
therapists, any person who is familiar with the daily routine of the patient, and from medical 
records.  The rater should interview both the patient and a close family member/friend or 
caregiver whenever possible. If the patient lacks insight into some difficulties, or responses 
are inconsistent, it is often helpful to interview a caregiver or relative independently.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 123 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
Modified Rankin Scale Interview  
 
5_Severe disability; someone needs to be available at all times; care may be provided by 
either a trained or an untrained caregiver.  
Question: Does the person require constant care? 
4_Moderately severe disability; need for assistance with some basic ADL, but not requiring 
constant care.  
Question: Is assistance essential for eating, using the toilet, daily hygiene, or walking? 
3_Moderate disability; need for assistance with some instrumental ADL but not basic ADL.  
Question: Is assistance essential for preparing a simple meal, doing household chores, 
looking after money, shopping, or traveling locally? 
2_Slight disability; limitations in participation in usual social roles, but independent for ADL.  
Questions: Has there been a change in the person’s ability to work or look after others if 
these were roles before stroke? Has there been a change in the person’s ability to participate 
in previous social and leisure activities? Has the person had problems with relationships or 
become isolated?  Do any of the following interfere with the subject's ability to perform all 
usual activities: difficulty reading or writing, difficulty speaking or finding the right word, 
problems with balance or coordination, visual problems, numbness (face, arms, legs, hands, 
feet), loss of movement (face, arms, legs, hands, feet), difficulty with swallowing, or other 
symptom resulting from stroke? 
1_No significant disability; symptoms present but not other limitations.  
Question: Does the subject have any symptoms that do not interfere with the performance of 
all usual activities? 
0_No symptoms at all; no limitations and no symptoms. 
Note:  The above questions are a modification of the questions from Wilson, et. al, Stroke.  2002:33:2243-2246 and are modified here for the 
use in Transcatheter  heart valve trials for the FDA Division of CV Devices. 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 124 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Appendix J 
Echocardiogram 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 125 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 126 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 127 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 128 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 129 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 130 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 131 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 132 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 133 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 134 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 135 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 136 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 137 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 138 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 139 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 140 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 141 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 142 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 143 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 144 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 145 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 146 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 147 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 148 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 149 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 150 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 151 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 152 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 153 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 154 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 155 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 156 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 157 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 158 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 159 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 160 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 161 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 162 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 163 
 
Appendix K-1 
Computed Tomography (CT) 
 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 164 
 
 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 165 
 
 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 166 
 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 167 
 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 168 
 
 
 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 169 
 
 
 
 
 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 170 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 171 
 
 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 172 
 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 173 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 174 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 175 
 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 176 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 177 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 178 
 
 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 179 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 180 
 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 181 
 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 182 
 
 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 183 
 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 184 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 185 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 186 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 187 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 188 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 189 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 190 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 191 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 192 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 193 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 194 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 195 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 196 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 197 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 198 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 199 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 200 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 201 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 202 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 203 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 204 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 205 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 206 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 207 
 
 
 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 208 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 209 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 210 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 211 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 212 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 213 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 214 
 
 

 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
PARTNER 3 Trial, Version 5.0 DEC 2018 
                                         CONFIDENTIAL 
 
                                                Page 215 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 216 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Appendix K-2 
Sub-Study CT 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 217 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 218 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 219 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 220 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 221 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 222 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 223 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 224 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 225 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 226 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 227 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 228 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 229 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 230 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 231 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 232 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 233 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 234 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Appendix L 
Histopathology 
1.0 Purpose 
 
The purpose of the following protocol is to provide the Investigator (clinical site) with procedures for 
handling and assessing the study valve after explantation.  The assessment should include gross 
examination, identification of the primary failure mode and contributory factors leading to the explant (if 
possible), photographs and other documentation, and preparation of the explanted valve for shipment 
to the Sponsor or designated Histopathology Laboratory for further analysis.  Also, included is an 
overview of the procedures to be followed by the Sponsor and/or designated Histopathology 
Laboratory for gross analysis, as well as macro and micro histopathology analysis.  Investigational 
valves that are removed at any time an allegation of device malfunction should be returned to the 
Sponsor for evaluation.  All other explants (those not with an allegation of device malfunction) should 
be sent to the Histopathology Core Lab. Refer to section 6.0 for tissue shipment information.  
 
2.0 Valve Explanation Procedure 
 
Upon autopsy (only), prior to removal of the valve from the heart, obtain in situ photographs of the 
inflow and outflow tracts, valve leaflets, and conduit tissue.  Using care, the valve should be excised in 
a fashion so as to keep the valve and surrounding structure as intact as possible.   
 
For all explants (those obtained at autopsy as described above or through valve replacement surgery 
following standard surgical practice), once removed the valve should be rinsed of all residual blood by 
gently agitating in sterile Lactated Ringers solution.   
 
Prior to shipment of the valve to the Sponsor or designated Histopathology Laboratory for further 
dissection and pathologic analysis, grossly examine the explanted tissue in toto and record 
observations on the explanted valve CRF.  Gross photographs will be taken of both inflow and outflow 
tracks. Observations of stent frame apposition and neointimal incorporation will be documented.  
 
Swab cultures of possibly infected areas should be taken, sent to the appropriate laboratory and 
documented in the pathology report.  If no infection is obvious, then no culture swab is necessary. 
 
3.0 Tissue Dissection Procedure 
 
Once the valve has been explanted, grossly examined, and photographed, the tissue should be sent to 
the Sponsor or designated Histopathology Laboratory for histological analysis.  Place the sample into a 
specimen cup or equivalent container.  The specimen cup should contain 10% buffered formalin 
solution.  On the outside of the container, label the study patient number, valve serial number, site 
number, and date of explant.  The tissues will be examined at the Sponsor or designated 
histopathology laboratory to determine the morphology of the tissue/valve, as well as to assess leaflet 
calcification, and general histopathology.  The valve tissues will be stained with H&E, Von Kossa, or 
other relevant stains and will be reviewed by a certified pathologist. 
 
4.0 Fixation 
 
Explanted study valve samples shall be submitted in 10% formalin. 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 235 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
5.0 Documentation 
Please provide the following supporting documents to enable complete explant assessment.  The 
documents should enable the Sponsor to determine explant date, duration of implant, surgical 
pathology, mediating study patient history, reason for reoperation, gross description, and 
pathology notes.  The documents may be returned with the shipped tissue. 
 
• 
Operative report dictated at the explant 
• 
Sponsor Case Report Forms 
• 
Pathology report (once available) 
• 
Blood study results (once available) 
• 
Preoperative Echocardiographic Report (Just Prior to Explant) 
 
6.0 Tissue Shipment 
Investigational valves that are removed at any time with an allegation of device malfunction 
should be returned to the Sponsor for evaluation. Contact your sponsor representative for 
assistance with the return which will include a Compliant Report (completed by the Sponsor) and 
biohazard packaging. 
 
Shipping Address: 
 
Edwards Lifesciences LLC  
1212 Alton Pkwy 
Irvine, CA  92606 
Attention:  Returned Goods 
CER/RGA#:________________ 
 
Investigational valves that are removed for any reason other than an allegation of device malfunction 
should be sent to the Histopathology Laboratory. Place the specimen container within two, separately 
sealed biohazard plastic bags. Place the sealed sample in a small non-crushable box.  Ship the tissue 
to the Sponsor’s designated Histopathology Laboratory by Federal Express PRIORITY (Sponsor billing 
number 0900-2768-9) or equivalent shipping service: 
 
Histology Core Laboratory: Renu Virmani, MD 
CV Path Institute, Inc. 
19 Firstfield Road 
Gaithersburg, MD 20878 
Phone: 301-208-3745 Ext. 105 
 
7.0 Procedure for Evaluation at Sponsor or Designated Histopathology Laboratory 
Gross Examination and Photographs: 
If possible, photographs should be taken at each stage of dissection to better document observations.  
Assessment of the valve leaflets and commissures will include presence of leaflet fenestrations, tears, 
thrombus formations and calcified nodules.  Photographs will be taken of all suspected abnormalities.  
The gross examination should include macroscopic assessment of the following: 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 236 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
Mobility and shape of leaflets; 
Calcification (leaflet and conduit); 
Host tissue overgrowth; 
Evidence of infection; 
Leaflet wear or degeneration; 
Aneurysm formation; 
Leaflet thickness; 
Valve thrombosis; 
Leaflet fenestrations; 
Tissue rejection; 
Fibrosis sheathing; 
Inflammation. 
 
 
8.0 Radiographic Analysis 
Additionally, X-rays will be taken of all valve/devices to assess placement and apposition of the stent 
frame to the host vessel and to identify leaflet calcification.  X-rays will be in both transverse and 
longitudinal planes. 
 
9.0 Dissection and Sampling 
A portion of each valve assembly, to include one commissure and one half of each adjacent valve 
leaflet, will be removed from the assembly and submitted for scanning electron microscopic 
examination.  The portion will be removed by making two longitudinal cuts through the length of the 
host vessel and metal stent frame.  The remaining valve leaflets will be excised away at the point of 
attachment to the assembly.  
 
Scanning Electron Microscopy 
Scanning electron microscopy will be employed to assess degree of intimal incorporation of the metal 
stent frame, endothelial coverage of the host vessel neointima and valve leaflets.  Leaflet surface 
topology will be assessed and any defects in the surface identified.  
 
10.0 Histopathology Evaluation 
Paraffin: 
Valve leaflets will be inked on the outflow surfaces to maintain orientation. Serial slices of the leaflets 
will be made from base to free edge and flat embedded for cross-sectional examination.  Hematoxylin 
and eosin, trichrome, Movat pentachrome, Von Kossa calcium, and Phosphotungstic acid-hematoxylin 
stains will be performed on all sections. 
 
Plastic: 
The remaining valve assembly (minus the portion removed for SEM) will be processed and embedded 
in methylmethacrylate plastic.  Transverse sections will be sawed and ground from the area of the 
superior tip of the first stent strut (proximal end), from the mid portion near the proximal end of the short 
bar assembly (not to include PET skirt) and from the distal end through the short bar assembly and 
commissures. 
 
Transmission electron microscopy (TEM) 
One half of each valve leaflet from the mid-portion will be reserved for transmission electron 
microscopy.  The section will be of full leaflet thickness, flat embedded in epoxy resin and cross-
sectioned.  TEM will be employed to assess collagen integrity and calcium deposition. 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 237 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
Explant Shipping Form 
Please enter the following information and fax the form to CV Path at (301) 208-3745 24 hours prior to 
shipment. 
Ship to: 
TBD 
 
 
Protocol #: ___SAPIEN 3 Expanded Indication                                   Subject ID: ___________________ 
 
Sponsor: _____Edwards Lifesciences_______________                  Device Type: __SAPIEN 3 ™ THV_____ 
 
Study Site: _______________                                                          Site Principal Investigator: ___________________ 
 
 
 
 
Please keep a copy of this form in the subject study file.  If possible, please include a copy of this form in the 
package 
 
 
Item 
Shipped 
(Serial Number) 
Sender: 
Print Name / Signature 
Date 
Harvested 
 (If available) 
Shipping Tracking Number 
Date Sent 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 238 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Appendix M 
EQ-5D-5L  
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 239 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 240 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 241 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Appendix N 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 242 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 243 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 244 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 245 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Appendix O 
SF-36 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 246 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 247 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 248 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 249 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 250 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 251 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Appendix P 
References 
1. 
Bonow, R.O., et al., ACC/AHA 2006 guidelines for the management of patients with valvular 
heart disease: a report of the American College of Cardiology/American Heart Association 
Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the 
management of patients with valvular heart disease) developed in collaboration with the 
Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular 
Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol, 
2006. 48(3): p. e1-148. 
2. 
Siu SC, Silversides CK. Bicuspid aortic valve disease. J Am Coll Cardiol. 2010; 55(25):2789-
2800. DOI: 10.1016/j.jacc.2009.12.068. 
3. 
Michelena HI, Desjardins VA, Avierinos JF, et al. Natural history of asymptomatic patients 
with normally functioning or minimally dysfunctional bicuspid aortic valve in the community. 
Circulation. 2008; 117(21):2776-2784. DOI: 10.1161/circulationaha.107.740878. 
4. 
Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves 
in adults having isolated aortic valve replacement for aortic stenosis, with or without 
associated aortic regurgitation. Circulation. 2005; 111(7):920-925. DOI: 
10.1161/01.cir.0000155623.48408.c5. 
 
5. 
Frank, S., A. Johnson, and J. Ross, Jr., Natural history of valvular aortic stenosis. Br Heart J, 
1973. 35(1): p. 41-6. 
 
6. 
Gardin, J.M., et al., Aortic stenosis: can severity be reliably estimated noninvasively? Chest, 
1980. 77(2): p. 130-1. 
 
7. 
Murakami, T., et al., Changes in patterns of left ventricular hypertrophy after aortic valve 
replacement for aortic stenosis and regurgitation with St. Jude Medical cardiac valves. Artif 
Organs, 2000. 24(12): p. 953-8. 
 
8. 
Rankin, J.S., et al., Determinants of operative mortality in valvular heart surgery. J Thorac 
Cardiovasc Surg, 2006. 131(3): p. 547-57. 
 
9. 
Chiappini, B., et al., Outcome after aortic valve replacement in octogenarians. Ann Thorac 
Surg, 2004. 78(1): p. 85-9. 
 
10. 
Thourani, V.H., et al., Outcomes of surgical aortic valve replacement in high-risk patients: a 
multiinstitutional study. Ann Thorac Surg, 2011. 91(1): p. 49-55; discussion 55-6. 
 
11. 
Connolly, H.M., et al., Severe aortic stenosis with low transvalvular gradient and severe left 
ventricular dysfunction: result of aortic valve replacement in 52 patients. Circulation, 2000. 
101(16): p. 1940-6. 
 
12. 
Bouma, B.J.v.D.B., R. B.; van Der Meulen, J. H.; Verheul, H. A.; Cheriex, E. C.; Hamer, 
H. P.; Dekker, E.; Lie, K. I.; Tijssen, J. G., To operate or not on elderly patients with aortic 
stenosis: the decision and its consequences. Heart, 1999. 82(2): p. 143-8. 
 
13. 
Brown, J.M., et al., Isolated aortic valve replacement in North America comprising 108,687 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 252 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
patients in 10 years: changes in risks, valve types, and outcomes in the Society of Thoracic 
Surgeons National Database. J Thorac Cardiovasc Surg, 2009. 137(1): p. 82-90. 
 
14. 
Thourani, V.H., et al., Long-term outcomes after isolated aortic valve replacement in 
octogenarians: a modern perspective. Ann Thorac Surg, 2008. 86(5): p. 1458-64; discussion 
1464-5. 
15. 
Cribier, A., et al., Percutaneous transcatheter implantation of an aortic valve prosthesis for 
calcific aortic stenosis: first human case description. Circulation, 2002. 106(24): p. 3006-8. 
 
16. 
Thomas, M. and O. Wendler, Transcatheter aortic valve implantation (TAVI): how to interpret 
the data and what data is required? EuroIntervention, 2009. 5(1): p. 25-7. 
 
17. 
Grube, E., et al., Percutaneous aortic valve replacement for severe aortic stenosis in high-risk 
patients using the second- and current third-generation self-expanding CoreValve prosthesis: 
device success and 30-day clinical outcome. J Am Coll Cardiol, 2007. 50(1): p. 69-76. 
 
18. 
Walther, T., et al., One-year interim follow-up results of the TRAVERCE trial: the initial 
feasibility study for trans-apical aortic-valve implantation. Eur J Cardiothorac Surg, 2011. 
39(4): p. 532-7. 
 
19. 
Svensson, L.G., et al., United States feasibility study of transcatheter insertion of a stented 
aortic valve by the left ventricular apex. Ann Thorac Surg, 2008. 86(1): p. 46-54; discussion 
54-5. 
 
20. 
Thomas, M., et al., One-Year Outcomes of Cohort 1 in the Edwards SAPIEN Aortic 
Bioprosthesis European Outcome (SOURCE) Registry: The European Registry of 
Transcatheter Aortic Valve Implantation Using the Edwards SAPIEN Valve. Circulation, 2011. 
124(4): p. 425-33. 
 
21. 
Thomas, M. Balloon-Expandable Edwards SAPIEN: The Expanding (including Cohort 2) 
SOURCE Registry: 30 Day Outcomes from 2,300 Edwards TAVI Patients and Predictors of 
Mortality. in TCT. 2010. Washington, DC. 
 
22. 
Thomas, M. Updates from the SOURCE Registry: Echo Data, Subset Analyses, and Impact of 
EuroSCORE on Clinical Outcomes. in TCT. 2009. San Francisco, CA. 
 
23. 
Wendler, O. Transapical Aortic Valve Implantation Early Results from the SOURCE Registry. 
in EACTS. 2009. Vienna, Austria. 
 
24. 
Lefevre, T., et al., One year follow-up of the multi-centre European PARTNER transcatheter 
heart valve study. Eur Heart J, 2011. 32(2): p. 148-57. 
 
25. 
Kodali, S. Pooled Analysis with Extended Follow-Up from the REVIVE II and REVIVAL II 
Transfemoral Feasibility Registries. in TCT. 2008. Washington, DC. 
 
26. 
Finsterer, J. and C. Stollberger, Strategies for primary and secondary stroke prevention in 
atrial fibrillation. Neth J Med, 2008. 66(8): p. 327-33. 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 253 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
27. 
Thoracic Aorta: Prospective Electrocardiographically Triggered CT Angiography with Dual-
Source CT—Feasibility, Image Quality, and Dose Reduction. Blanke P, Bulla S, Baumann T, et 
al. Radiology 2010:255;207-217. 
28. 
Freitag G. Methods for assessing noninferiority with censored data. Biometrical journal. 
Biometrische Zeitschrift. 2005; 47(1):88-98; discussion 99-107. 
 
29. 
Makkar RR, Fontana G, Jilaihawi H, et al. Possible Subclinical Leaflet Thrombosis in 
Bioprosthetic Aortic Valves. The New England journal of medicine. 2015; 373(21):2015- 2024. 
 
30. 
Pache G, Schoechlin S, Blanke P, et al. Early hypo-attenuated leaflet thickening in balloon-
expandable transcatheter aortic heart valves. European heart journal. 2015. 
 
31. 
O'Brien, S.M., et al., The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 
2--isolated valve surgery. Ann Thorac Surg, 2009. 88(1 Suppl): p. S23-42. 
 
32. 
Comparison of 12 risk stratification schemes to predict stroke in patients with nonvalvular atrial 
fibrillation. Stroke, 2008. 39(6): p. 1901-10. 
 
33. 
Independent predictors of stroke in patients with atrial fibrillation: a systematic review. 
Neurology, 2007. 69(6): p. 546-54. 
 
34. 
Gottesman, R.F., et al., Delirium after coronary artery bypass graft surgery and late mortality. 
Ann Neurol, 2010. 67(3): p. 338-44. 
 
35. 
Durack, D.T., A.S. Lukes, and D.K. Bright, New criteria for diagnosis of infective endocarditis: 
utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med, 1994. 
96(3): p. 200-9. 
 
36. 
Fried, L.P., et al., Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med 
Sci, 2001. 56(3): p. M146-56. 
 
37. 
Stolerman, Ian. Encyclopedia of Psycho-pharmacology. London UK: Springer; 2010. 
 
38. 
Perlman GY, Blanke P, Dvir D, et al. Bicuspid Aortic Valve Stenosis: Favorable Early Outcomes 
With a Next-Generation Transcatheter Heart Valve in a Multicenter Study. JACC. Cardiovascular 
interventions. 2016;9(8):817-824. DOI: 10.1016/j.jcin.2016.01.002. No Epub. 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 254 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
Appendix Q 
Actigraphy/QOL Sub-Study QOL measures [Enrollment Closed] 
Visual Analogue Scale (VAS) 1 
A Visual Analogue Scale (VAS) is a measurement instrument that tries to measure a 
characteristic or attitude that is believed to range across a continuum of values and 
cannot easily be directly measured. For example, the amount of pain that a patient feels 
ranges across a continuum from none to an extreme amount of pain. From the patient's 
perspective this spectrum appears continuous ± their pain does not take discrete jumps, 
as a categorization of none, mild, moderate and severe would suggest. It was to capture 
this idea of an underlying continuum that the VAS was devised.  
Operationally a VAS is usually a horizontal line, 100 mm in length, anchored by word 
descriptors at each end, as illustrated in Fig. 1. The patient marks on the line the point 
that they feel represents their perception of their current state. The VAS score is 
determined by measuring in millimeters from the left hand end of the line to the point that 
the patient marks.  There are many other ways in which VAS have been presented, 
including vertical lines and lines with extra descriptors.  As such an assessment is clearly 
highly subjective, these scales are of most value when looking at change within 
individuals. 
 
Figure 1    VAS example 
 
 
PF-10 Health Survey2 
The Optum™ PF-10 Health Survey is a Health Survey that uses just 10 questions to 
measure physical health and well-being from the patient’s point of view. 
Taking only two to three minutes to complete, the PF-10 is a practical, reliable and valid 
measure of physical health and is particularly useful in large population health surveys 
or for applications that combine a generic and disease-specific health survey.  
As the survey uses norm-based scoring, comparisons can be made among the other 
generic health surveys (SF-36v2® and SF-8™).  It is a widely used tool for monitoring 
population health, comparing and analyzing disease burden and predicting medical 
expenses. 
The PF-10 is available in multiple modes of administration and in both standard four-
week and acute one-week recall periods. 
 
KCCQ-123 
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item, self-
administered instrument that quantifies physical function, symptoms (frequency, 
                                                            
 
 
 
 

PARTNER 3 Trial, Version 5.0 DEC 2018 
CONFIDENTIAL 
Page 255 
 
 
 
The PARTNER 3-US IDE Trial  
 
Edwards Lifesciences 
 
 
severity and recent change), social function, self-efficacy and knowledge, and quality of 
life. 
In the KCCQ, an overall summary score can be derived from the physical function, 
symptom (frequency and severity), and social function and quality of life domains. For 
each domain, the validity, reproducibility, responsiveness and interpretability have been 
independently established. Scores are transformed to a range of 0-100, in which higher 
scores reflect better health status.  
The KCCQ-12 reduces the KCCQ’s 23 items to 12.  This short version significantly 
increase the speed and ease of questionnaire administration while preserving the 
sensitivity, specificity, and reliability of the original instruments.  
 
1 VAS source: http://buderimosteopathy.com.au/wp-content/uploads/2012/02/VAS.pdf 
1 https://www.optum.com/optum-outcomes/what-we-do/health-surveys/sf-12v2-health-
survey.html 
1 http://cvoutcomes.org/pages/3214