SAPIEN 3 Ultra EU Post-Market Observational Study
Conditions: Aortic Stenosis, Aortic Valve Stenosis
Sponsor: Edwards Lifesciences

SAPIEN 3 Ultra EU Post-Market Observational Study 
NCT 04860752 
June 2021

PROPRIETARY DATA:  This document and the information contained herein may not be reproduced, used or 
disclosed without written permission from Edwards Lifesciences LLC. 
Edwards Lifesciences, Edwards, the stylized E logo, Commander, Edwards Commander, Edwards eSheath, Edwards 
SAPIEN 3 Ultra, eSheath and SAPIEN 3 Ultra are trademarks of Edwards Lifesciences Corporation. 
Page 1 of 27 
 
 
 
 
 
SAPIEN 3 Ultra EU Post-Market Observational Study 
 
Clinical Investigation Plan 
 
 
Study Number:  2020-02 
Version 3.0 
18 June 2021 
 
 
 
 
 
 
Study Sponsor: 
Edwards Lifesciences LLC 
One Edwards Way 
Irvine, CA 92614 
USA 
 
 

SAPIEN 3 Ultra System 
SAPIEN 3 Ultra EU Post-Market Observational Study 
 
Edwards Lifesciences LLC 
Study Number 2020-02 
CONFIDENTIAL 
Page 2 of 27 
Version 3.0, 18 June 2021 
TABLE OF CONTENTS 
LIST OF TABLES ...................................................................................................................... 3 
STUDY SYNOPSIS ................................................................................................................... 4 
INVESTIGATOR SIGNATURE PAGE ....................................................................................... 6 
1 
INTRODUCTION ................................................................................................................ 7 
2 
STUDY OBJECTIVE .......................................................................................................... 8 
3 
STUDY DESIGN ................................................................................................................. 8 
4 
STUDY DEVICES ............................................................................................................... 8 
5 
OUTCOME MEASURES .................................................................................................... 9 
6 
STUDY POPULATION ....................................................................................................... 9 
6.1 
INCLUSION CRITERIA ...................................................................................................... 9 
6.2 
EXCLUSION CRITERIA ..................................................................................................... 9 
7 
STUDY PROCEDURES .....................................................................................................10 
7.1 
INFORMED CONSENT .................................................................................................... 10 
7.2 
DATA COLLECTION ....................................................................................................... 10 
 
Baseline/Pre-Procedure ......................................................................................................... 10 
 
Procedure .............................................................................................................................. 10 
 
Post-Procedure Follow-up ..................................................................................................... 11 
7.3 
IMAGING ASSESSMENTS ............................................................................................... 11 
7.4 
COVID-19 ASSESSMENTS ............................................................................................ 11 
7.5 
SUBJECT DISPOSITION .................................................................................................. 11 
8 
ADVERSE EVENTS ..........................................................................................................13 
8.1 
DEFINITIONS ................................................................................................................ 13 
8.2 
INVESTIGATOR ASSESSMENT OF AES ............................................................................ 14 
8.3 
AE REPORTING REQUIREMENTS ................................................................................... 15 
 
Events that do not require reporting to Edwards ................................................................... 16 
9 
RISK AND BENEFIT ANALYSIS ......................................................................................17 
10 
STATISTICAL CONSIDERATIONS ...............................................................................17 
10.1 
ANALYSIS POPULATIONS ............................................................................................... 17 
10.2 
STATISTICAL ANALYSES ................................................................................................ 17 
11 
STUDY ADMINISTRATION ...........................................................................................17 
11.1 
GENERAL STUDY ORGANIZATION .................................................................................. 17 
11.2 
STEERING COMMITTEE ................................................................................................. 17 
11.3 
ECHOCARDIOGRAPHIC CORE LAB .................................................................................. 17 
11.4 
IMAGE MANAGEMENT.................................................................................................... 18 
11.5 
HISTOPATHOLOGY ........................................................................................................ 18 
11.6 
STUDY SITE PERSONNEL TRAINING ............................................................................... 18 
11.7 
DATA MANAGEMENT ..................................................................................................... 18 
11.8 
MONITORING PROCEDURES .......................................................................................... 18 
11.9 
SITE DISCONTINUATION ................................................................................................ 19 
11.10 AUDITING ..................................................................................................................... 19 
11.11 PUBLICATION POLICY .................................................................................................... 19 

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Study Number 2020-02 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS ....................................................20 
12.1 
APPLICABLE PRINCIPLES AND REGULATIONS .................................................................. 20 
12.2 
ETHICS COMMITTEE ..................................................................................................... 20 
12.3 
INFORMED CONSENT .................................................................................................... 20 
12.4 
CONFIDENTIALITY ......................................................................................................... 21 
12.5 
INVESTIGATOR RECORDS .............................................................................................. 21 
12.6 
PLAN AMENDMENTS ..................................................................................................... 21 
12.7 
PLAN DEVIATIONS ........................................................................................................ 21 
APPENDIX A 
ABBREVIATIONS ........................................................................................22 
APPENDIX B 
DEFINITIONS ...............................................................................................23 
APPENDIX C 
REFERENCES .............................................................................................27 
 
 
LIST OF TABLES 
TABLE 1. FAST-TAVI AND 3M TAVR STUDY DISCHARGE CRITERIA .................................................................. 7 
TABLE 2. FAST-TAVI AND 3M TAVR STUDY 30-DAY OUTCOMES (%) .............................................................. 8 
TABLE 3. DATA COLLECTION SCHEDULE ......................................................................................................... 12 
 
 
 

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SAPIEN 3 Ultra EU Post-Market Observational Study 
 
Edwards Lifesciences LLC 
Study Number 2020-02 
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STUDY SYNOPSIS 
Title 
SAPIEN 3 Ultra EU Post-Market Observational Study 
Objective 
To evaluate real-world outcomes for the SAPIEN 3 Ultra Transcatheter Heart 
Valve (THV) System in transcatheter aortic valve implantation (TAVI) centres 
that are implementing minimalist periprocedural practices and facilitating 
early discharge home 
Device 
Edwards SAPIEN 3 Ultra THV System 
Study Design 
Prospective, observational, single-arm, multicentre, post-market study 
Subject 
Population 
Subjects who will undergo TAVI with the Edwards SAPIEN 3 Ultra System 
as part of standard-of-care treatment. 
Sample Size 
Up to 500 subjects will be enrolled 
Study Sites 
Up to 50 centres predominantly in the European Union 
Data Collection 
Schedule 
Clinical data and imaging available from routine clinical assessments 
performed pre-procedure and through 1-year post-procedure will be 
collected. 
Outcome 
Measures 
The following outcomes will be reported: 
• 
Death 
• 
Stroke 
• 
New requirement for permanent pacemaker 
• 
Aortic valve reintervention 
• 
Valve haemodynamics 
o Aortic regurgitation 
o Mean aortic valve gradient 
o Effective orifice area 
• 
Length of index hospitalization 
• 
Discharge location 
Inclusion 
Criteria 
1. Will undergo TAVI with the Edwards SAPIEN 3 Ultra System as part of 
standard-of-care treatment 
2. Less than 80 years of age at time of the procedure 
3. Low surgical risk as determined by the Heart Team 
4. Meets clinical and procedural requirements for early discharge as 
determined by the Heart Team 

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Edwards Lifesciences LLC 
Study Number 2020-02 
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5. The subject has been informed of the nature of the study, agrees to its 
provisions and has provided written informed consent 
Exclusion 
Criteria 
1. Medical, social, or psychological conditions that preclude appropriate 
consent and follow-up, including subjects under guardianship 
2. Considered to be part of a vulnerable population 
3. Active SARS-CoV-2 infection (Coronavirus-19 [COVID-19]) or 
previously diagnosed with COVID-19 with sequelae that could confound 
endpoint assessments 
4. Cannot tolerate an anticoagulation/antiplatelet regimen 
5. Active bacterial endocarditis 
6. Participating in a drug or device study that has not reached its primary 
endpoint.  Note: Participation in required national registries is not an 
exclusion. 
Statistical 
Analysis 
No statistical hypothesis testing will be performed.  Only descriptive and 
summary statistical analysis will be provided for baseline/pre-procedure, 
procedure and outcome variables. 
Sponsor 
Edwards Lifesciences LLC 
One Edwards Way 
Irvine, CA 92614 USA 
Legal 
Representative 
Edwards Lifesciences Services GmbH 
Edisonstrasse 6 
85716 Unterschleissheim 
Germany 
 
 

SAPIEN 3 Ultra System 
SAPIEN 3 Ultra EU Post-Market Observational Study 
 
Edwards Lifesciences LLC 
Study Number 2020-02 
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INVESTIGATOR SIGNATURE PAGE 
Title:  SAPIEN 3 Ultra EU Post-Market Observational Study 
 
 
I have read this plan and agree to adhere to its requirements.  I will ensure that the study is 
conducted in compliance with the plan, Good Clinical Practice, Declaration of Helsinki and all 
applicable regulatory requirements. 
 
_____________________________________________________ 
Study Site Name 
 
_______________________________________________________ 
Site Principal Investigator Name (print) 
 
__________________________________ 
 
_______________ 
Site Principal Investigator Signature 
 
Date 
 
 

SAPIEN 3 Ultra System 
SAPIEN 3 Ultra EU Post-Market Observational Study 
 
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Study Number 2020-02 
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1 INTRODUCTION 
Transcatheter aortic valve implantation (TAVI) is an established treatment for patients with severe 
aortic stenosis and has been performed for over a decade, however, there are currently no 
recommendations for the duration of post-procedure monitoring for patients undergoing TAVI and 
practices vary widely by institution and country. 
Several studies have evaluated minimalist periprocedural approaches based on individual patient 
risk and criteria-driven discharge in order to standardize post-procedure care and reduce length 
of stay; these approaches also ultimately maximize the efficiency of hospital resources.  In the 
European FAST-TAVI trial, a set of pre-specified discharge criteria established to allow safe and 
timely discharge were applied to a group of patients undergoing TAVI with the SAPIEN 3 
transcatheter heart valve (THV) and 30-day outcomes were evaluated.  A total of 328 patients 
had a low risk of complications and were discharged between 1- and 3-days post procedure.1  
Similarly, the 3M TAVR study evaluated the safety, effectiveness and feasibility of next-day 
discharge in patients undergoing balloon-expandable transfemoral TAVI when implementing 
objective pre-procedural screening criteria and standardized peri- and post-procedural 
management guidelines.  A total of 411 patients with a mean age of 84 years and STS score of 
4.9% had a median length of stay of 1.0 days, with next-day discharge achieved in 80.1% of 
patients and 89.5% discharged within 48 hours of the procedure.2  The discharge criteria used in 
these studies are shown in Table 1; thirty-day outcomes are shown in Table 2.  Both studies 
concluded that the event rates compare favourably with other recent trials and, thus, have 
demonstrated that early discharge home is safe and feasible for selected patients. 
Table 1. FAST-TAVI and 3M TAVR Study Discharge Criteria 
FAST-TAVI 1 
3M TAVR Study 2 
• 
NYHA Class ≤II 
• 
no chest pain attributable to cardiac ischaemia 
• 
no untreated major arrhythmias 
• 
patients having complications on day 0 to 1, 
but free of signs or symptoms on day 3 
• 
no fever during the last 24 hours and no signs 
of an infectious cause 
• 
independent mobilisation and self-caring 
• 
preserved diuresis (>40 ml/hour during the 
preceding 24 hours) 
• 
no unresolved AKI type 3 (according to VARC-
2 criteria) 
• 
no RBC transfusion during the preceding 72 
hours 
• 
stable haemoglobin in two consecutive 
samples (defined as a decrease of no more 
than 2 mg/dl) 
• 
no paravalvular leak (PVL) with aortic 
regurgitation less than moderate 
• 
no stroke/transient ischaemic attack (TIA) 
• 
no haemodynamic instability 
Monitoring 
• 
Completion and review of post-procedure transthoracic 
echocardiogram to confirm acceptable bioprosthetic 
haemodynamic with the absence of delayed 
complications 
• 
Absence of persistent intraventricular conduction delay 
• 
Absence of vascular access site complications 
• 
Absence of laboratory contraindications.  If Hgb <100 g/L 
and eGFR <30 mL/min, obtain and review outpatient 
bloodwork 2 and 4 d after discharge 
• 
Facilitated reconditioning 
• 
Return to baseline mobilization 
• 
Absence of elimination issues (e.g., urinary retention) 
Communication 
• 
Multidisciplinary agreement of safety of discharge 
• 
Confirmation of discharge plan with patient/family 
• 
Confirmation of availability of social support during the 
initial 48 h after discharge 
• 
Completion of verbal discharge teaching and confirmation 
of patients/family’s understanding of the discharge 
guidelines and provision of written discharge education 
resources and prescription of medications 

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SAPIEN 3 Ultra EU Post-Market Observational Study 
 
Edwards Lifesciences LLC 
Study Number 2020-02 
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Table 2. FAST-TAVI and 3M TAVR Study 30-Day Outcomes (%) 
Outcome 
FAST-TAVI 1 
3M TAVR Study 2 
Mortality 
0.6 
1.5 
Stroke 
0 
1.5 
Permanent pacemaker 
4.3 
5.7 
Cardiac rehospitalization 
3.4 
5.7 
 
2 STUDY OBJECTIVE 
The SAPIEN 3 Ultra THV design builds upon the technical knowledge and experience gained 
from the SAPIEN 3 THV.  CE Mark approval was received in November 2018 for patients with 
severe aortic stenosis and at least intermediate surgical risk, and in March 2020 for patients at 
low surgical risk. 
This post-market study will further evaluate real-world outcomes for the SAPIEN 3 Ultra THV 
System in TAVI centres that are implementing minimalist periprocedural practices and facilitating 
early discharge home. 
3 STUDY DESIGN 
This is a prospective, observational, single-arm, multicentre post-market study.  Up to 500 
subjects who will undergo TAVI with the SAPIEN 3 Ultra THV will be enrolled at up to 50 centres 
predominantly in the European Union. 
Clinical data and imaging available from routine clinical assessments performed pre-procedure 
and through 1-year post-procedure will be collected. 
4 STUDY DEVICES 
The study will use the following commercially available devices: 
• 
Edwards SAPIEN 3 Ultra THV 
• 
Edwards Commander Delivery System 
• 
Edwards eSheath Introducer Set 
• 
Edwards Loader 
• 
Edwards Crimper and Crimp Stopper 
• 
Edwards Qualcrimp Crimping Accessory 
 
Descriptions of all study devices are provided in the respective Instructions for Use (IFU). 
 

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SAPIEN 3 Ultra EU Post-Market Observational Study 
 
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Study Number 2020-02 
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5 OUTCOME MEASURES 
The outcome measures for the study are as follows: 
• 
Death 
• 
Stroke 
• 
New requirement for permanent pacemaker 
• 
Aortic valve reintervention 
• 
Valve haemodynamics 
o Aortic regurgitation 
o Mean aortic valve gradient 
o Effective orifice area 
• 
Length of index hospitalization 
• 
Discharge location 
 
6 STUDY POPULATION 
6.1 
Inclusion Criteria 
Subjects must meet all of the following criteria to be included in the study: 
1. Will undergo TAVI with the Edwards SAPIEN 3 Ultra System as part of standard-of-care 
treatment 
2. Less than 80 years of age at time of the procedure 
3. Low surgical risk as determined by the Heart Team 
4. Meets clinical and procedural requirements for early discharge as determined by the 
Heart Team 
5. The subject has been informed of the nature of the study, agrees to its provisions and 
has provided written informed consent 
 
6.2 
Exclusion Criteria 
Subjects will be excluded from the study if any of the following conditions are present: 
1. Medical, social, or psychological conditions that preclude appropriate consent and 
follow-up, including subjects under guardianship 
2. Considered to be part of a vulnerable population 
3. Active SARS-CoV-2 infection (Coronavirus-19 [COVID-19]) or previously diagnosed with 
COVID-19 with sequelae that could confound endpoint assessments 
4. Cannot tolerate an anticoagulation/antiplatelet regimen 
5. Active bacterial endocarditis 

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SAPIEN 3 Ultra EU Post-Market Observational Study 
 
Edwards Lifesciences LLC 
Study Number 2020-02 
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6. Participating in a drug or device study that has not reached its primary endpoint.  Note: 
Participation in required national registries is not an exclusion. 
 
7 STUDY PROCEDURES 
7.1 
Informed Consent 
Eligible subjects who will undergo TAVI with the Edwards SAPIEN 3 Ultra THV System will be 
given an overview of the study.  If subjects are interested in participating and are willing to 
authorize the use of their data, they must sign the Ethics Committee (EC)-approved informed 
consent form (ICF) before data collection can commence. 
7.2 
Data Collection 
Clinical data and imaging available from routine clinical assessments performed pre-procedure 
and through 1-year post-procedure will be collected.  Imaging obtained during this time frame 
should be uploaded and information entered in the CRF.  It is expected that the sites' standard-
of-care for the management of subjects undergoing TAVI will be aligned and consistent with 
established guidelines and recommendations (e.g., 2017 ESC/EACTS Guidelines for the 
Management of Valvular Heart Disease 3, Valve Academic Research Consortium-2 Consensus 
Document 4, echocardiographic recommendations 5-7) and will include, but not be limited to, the 
following assessments: 
 Baseline/Pre-Procedure 
Data from the following assessments will be collected: 
• 
Medical history 
• 
Physical assessment (height and weight only) 
• 
Risk assessment 
• 
New York Heart Association (NYHA) functional class 
• 
Valve-related imaging (Cardiac computed tomography angiography (CTA), transthoracic 
echocardiogram (TTE), transoesophageal echocardiogram (TEE), etc) 
 
 Procedure 
The study devices will be used in accordance with the most current IFU. 
The valve implant procedure will be considered to have started when the first interventional 
access-related puncture/incision is established.  Subjects will be considered enrolled once the 
ICF is signed and the procedure has begun. 
Data from the following assessments will be collected: 
• 
Fluoroscopic imaging of valve deployment 

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• 
Post-deployment valve haemodynamics 
• 
Adverse events 
 
 Post-Procedure Follow-up 
The day of the procedure is considered Day 0 and one year is defined as 365 days. 
Data from the following assessments will be collected post-procedure through 1-year (+ 60 days): 
• 
Adverse events 
• 
Valve-related imaging (CTA, TTE, TEE, etc.) 
• 
Valve haemodynamics 
 
7.3 
Imaging Assessments 
Imaging performed during the study should follow current guidelines and recommendations, which 
are noted in the imaging reference guide supplied for this trial. 
7.4 
COVID-19 Assessments 
Results of all available SARS-CoV-2 (Coronavirus-19 [COVID-19]) testing should be recorded in 
the CRFs. 
7.5 
Subject Disposition 
The following categories of subject disposition have been defined for this study: 
Screen Failure:  Subjects who have provided informed consent will be considered a screen 
failure if they do not meet the eligibility criteria or do not have the procedure started. 
Enrolled:  Subjects will be considered enrolled once the ICF is signed and the procedure has 
begun. 
Discontinued:  Enrolled subjects will be considered discontinued for the following reasons: 
• 
Study Device Never Implanted:  Subjects considered enrolled but did not receive a 
study valve will be exited from the study. 
• 
Study Device Explanted:  Subjects who have a surgical reintervention where the study 
valve is explanted will be exited from the study. 
• 
Subject Withdrew Consent 
• 
Death 
If a subject discontinues, an exit form indicating the reason for discontinuation will be 
completed.  Subjects who discontinue will not be replaced. 
Complete:  Enrolled subjects will be considered complete when data through 1-year post-
procedure has been entered. 

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SAPIEN 3 Ultra EU Post-Market Observational Study 
 
Edwards Lifesciences LLC 
Study Number 2020-02 
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Table 3 summarizes the data that will be collected. 
Table 3. Data Collection Schedule 
Assessment 
Baseline/ 
Pre-procedure 1 
Procedure 1 
Post-procedure 
through 1 Year 1 
Informed Consent 
X 
 
 
Medical History 
X 
 
 
Physical Assessment 
X 
 
 
Risk Assessment 
X 
 
 
NYHA Functional Class 
X 
 
 
Valve-related Imaging 2 
X 
X 3 
X 
Valve Haemodynamics 
 
X 
X 
Adverse Events 
 
X 
X 
1. Results of all available SARS-CoV-2 (Coronavirus-19) testing should be recorded in the CRFs. 
2. All imaging (CTA, TTE, TEE, etc.) obtained from pre-procedure through 1 year (+ 60 days) should be uploaded 
and information entered in the CRF.   
3. Includes fluoroscopic imaging of valve deployment. 
 
 

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Study Number 2020-02 
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8 ADVERSE EVENTS 
8.1 
Definitions 
An Adverse Event (AE) is 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 study device or procedures involved and whether 
anticipated or unanticipated.  For users or other persons, this definition is restricted to events 
related to the study device. 
A Serious Adverse Event (SAE) is any adverse event that: 
• 
Led to death; 
• 
Led to serious deterioration in the health of the subject that either resulted in: 
o a life-threatening illness or injury; 
o a permanent impairment of a body structure or a body function including chronic 
diseases; 
o in-patient or prolonged hospitalization; 
o medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to body structure or a body function; 
• 
Led to foetal distress, foetal death. a congenital abnormality or birth defect including 
physical or mental impairment; 
NOTE 1:  Planned hospitalization for pre-existing condition, or a procedure required by the Clinical 
Investigation Plan, without a serious deterioration in health, is not considered a serious adverse event. 
NOTE 2:  Permanent impairment of a body structure or a body function - An AE, which results in a 
substantial disruption of a person’s ability to conduct normal life functions.  This does not pertain to minor 
events, but to serious events which result in a significant, persistent or permanent change, impairment, 
damage or disruption in the subject’s body function/structure, physical activities and/or quality of life. 
NOTE 3:  Life-threatening – an event in which the subject was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it were more severe. 
 
Adverse Device Effects (ADE) and Serious Adverse Device Effects (SADE) are AEs related 
to the use of a medical device. 
NOTE 1:  This includes any AE resulting from insufficiencies or inadequacies in the IFU, the deployment, 
the implantation, the installation, the operation, or any malfunction of the medical device. 
NOTE 2:  This includes any event that is a result of a use error or intentional abnormal use of the medical 
device. 
Anticipated AE means an effect, which by its nature, incidence, severity or outcome has been 
previously identified in the risk analysis report.  The potential AEs associated with the procedures 
involved and study devices are listed in the current IFU. 

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Unanticipated Serious Adverse Device Effect (USADE) is defined as any SADE, which by its 
nature, incidence, severity or outcome has not been identified in the current version of the risk 
analysis report or IFU. 
Device Deficiency is defined as an inadequacy of a medical device related to its identity, quality, 
durability, reliability, safety or performance.  This may include malfunctions, use error or 
inadequacy in the information supplied by the manufacturer, including labelling. 
A malfunction or deterioration is defined as the failure of a device to perform in accordance with 
its intended purpose when used in accordance with the manufacturer´s instructions.  The intended 
performance of a device refers to the intended use for which the device is labelled or marketed. 
Reporting conventions for device deficiencies that could result in an SAE are the same as those 
for an actual SAE. 
8.2 
Investigator Assessment of AEs 
For each AE, the Investigator will determine whether the event is related to the device and/or the 
implant procedure, whether it was anticipated or not anticipated (based on the list of potential 
risks provided in the IFU) and whether the event meets the definition of an SAE or USADE. 
The causal relationship of the event to the device and the implant procedure will be categorized 
as follows: 
1. Not related:  relationship to the device or procedures can be excluded when there is no 
temporal relationship, the event is not a known adverse effect of similar devices or procedures, 
it is not clinically plausible, or the event can be attributed to another cause. 
2. Possible:  the relationship with the use of the device is weak but cannot be ruled out 
completely.  Alternative causes are also possible (e.g. an underlying or concurrent illness/ 
clinical condition or/and an effect of another device, drug or treatment).  Cases where 
relatedness cannot be assessed, or no information has been obtained should also be 
classified as possible. 
3. Probable:  the relationship with the use of the device seems relevant and/or the event cannot 
reasonably be explained by another cause, but additional information may be obtained. 
 
4. Causal relationship:  the event is associated with the device or with procedures beyond 
reasonable doubt when there is a temporal relationship, the event is a known adverse effect 
of similar devices or procedures, it is clinically plausible, or the event cannot be attributed to 
another cause. 
 
 
 

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8.3 
AE Reporting Requirements 
All AEs will be captured from the time of enrolment until subject participation has ended (i.e. 
completion of study or discontinuation).  See Section 8.3.1 for events that are not required to be 
reported to Edwards. 
Pre-existing medical conditions or symptoms reported prior to subject enrolment 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 or study-related procedure, then an AE must be recorded. 
Death should not be recorded as an AE but should be reflected as an outcome to another specific 
AE. 
If known, the diagnosis for an AE should be recorded, rather than listing individual signs and 
symptoms. 
All AEs will be reported in subject medical records and the appropriate electronic case report form 
(eCRF) throughout the duration of the study, and will be followed until resolution, stabilization or 
study completion. 
All SAEs and Device Deficiencies that might have led to a SAE must be reported to Edwards 
immediately, but not later than 3 calendar days after site study personnel’s awareness of 
the event.  Other AEs must be reported to Edwards as soon as practical but no later than 10 
working days of awareness. 
AE information must be entered into the EDC.  When EDC system is not available/accessible, AE 
information must be reported directly via email to EUTHVSafety@edwards.com, copying the 
Safety Officer of the study. 
At the time of initial AE notification, the following minimal information must be provided: 
• 
Subject ID 
• 
AE term/diagnosis 
• 
AE onset date 
• 
AE seriousness 
• 
AE device and procedure relationships 
Source documentation may be requested by the Edwards Safety Officer for AEs and SAEs on a 
case-by-case basis (i.e., device deficiencies, device- and procedure-related events, USADEs, 
etc.). 
The AEs will be reviewed by the Edwards Safety Officer.  Each AE will be assessed as to its 
relationship to the study device and/or implant procedure, whether it was anticipated or not 
anticipated, and whether it qualifies as an SAE or USADE. 

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Depending on the local requirements or following agreement between both parties, Edwards or 
the Principal Investigator will be responsible for performing safety reporting to the EC according 
to the relevant local regulatory requirements. 
Edwards will be responsible for reporting to the National Competent Authority according to 
national requirements and in line with MEDDEV 2.7/3 (Serious Adverse Event Reporting) and/or 
MEDDEV 2.12-1 (Medical Devices Vigilance System), as applicable. 
 Events that do not require reporting to Edwards 
For purposes of this study, the following events will not be required to be reported as AEs to 
Edwards, because they are normally expected to occur in conjunction with transcatheter valve 
implantation or are associated with customary, standard care of subjects undergoing THV 
implantation: 
• 
Post-operative pain. 
• 
Post-anaesthesia emesis, nausea or headache (within 24 hours of procedure). 
• 
Electrolyte imbalance without clinical sequelae following procedure, even if requiring 
correction. 
• 
Low grade temperature increase (≤ 101°F or 38.5°C). 
• 
Elevated white blood count, outside the standard laboratory normal value, without signs 
and symptoms of infection. 
• 
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 should be reported. 
• 
Hyperglycaemia – The use of insulin in the post-operative period does not constitute 
hyperglycaemia 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 hyperglycaemia. 
• 
Expected, non-clinically significant events such as non-significant lab variances. 
• 
Dizziness: imprecise term commonly used to describe various symptoms such as 
faintness, giddiness, imbalance, light-headedness, unsteadiness or vertigo without signs 
of TIA or stroke. 
In addition, pre-planned future surgical procedures not associated with the study procedure or 
device and not due to worsening of an existing condition, do not need to be reported. 
 
 

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9 RISK AND BENEFIT ANALYSIS 
Subjects participating in this observational study will undergo TAVI with the SAPIEN 3 Ultra THV 
System as part of their standard-of-care treatment for severe AS.  No study-specific procedures 
will be performed.  There are no increased risks related to the participation in this study.  There 
are potential risks related to the overall procedure (standard cardiac catheterization, valvuloplasty 
and use of anaesthesia) as well as potential risks associated with the TAVI procedure, the 
bioprosthesis, and the use of its associated devices and accessories; risks are summarized in the 
IFU. 
10 STATISTICAL CONSIDERATIONS 
10.1 Analysis Populations 
As Treated (AT) Population:  Will consist of all subjects that were enrolled in the trial. 
Valve Implant (VI) Population:  Will consist of all enrolled subjects who receive and retain the 
study valve upon leaving the procedure room. 
10.2 Statistical Analyses 
No statistical inference will be performed, and only descriptive statistics will be presented.  
Descriptive statistics include number of subjects and frequencies in percentage for categorical 
variables and mean and standard deviation/standard error for continuous variables.  Kaplan-Meier 
estimates will be used for time-to-event measures and where appropriate for adverse event 
outcomes. 
11 STUDY ADMINISTRATION 
11.1 General Study Organization 
Edwards is the Sponsor and has the overall responsibility for the conduct of the study, including 
assurance that the study meets applicable regulatory requirements. 
Edwards will be responsible for obtaining appropriate approvals prior to study commencement, 
selecting investigators, and conducting clinical site monitoring to ensure that subjects are being 
properly consented and the study is being conducted according to the plan.  Edwards will notify 
investigative sites of enrolment closure. 
11.2 Steering Committee 
A Steering Committee will be selected to provide oversight and medical expertise to the study.  
Steering Committee activities are defined in the Steering Committee Charter. 
11.3 Echocardiographic Core Lab 
An independent echocardiographic core lab will review and analyse echocardiographic images.  
A manual of procedures describing current guidelines and recommendations will be provided to 

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the study sites prior to study initiation. 
11.4 Image Management 
An image transfer vendor will receive, maintain and provide angiographic and echocardiographic 
images to the appropriate personnel for analysis. 
Instructions for image upload will be provided to study site personnel prior to study initiation.  
Study site personnel should make every reasonable effort to upload all images to the image 
transfer vendor within 5 business days of image acquisition.  Any unscheduled imaging performed 
related to the safety or performance of the device should also be uploaded. 
11.5 Histopathology 
Histopathology will be performed on all explanted valves.  Explants will be prepared, preserved 
and shipped to the Histopathology Core Lab per instructions provided by Edwards. 
11.6 Study Site Personnel Training 
Training by Edwards or its designee is required for study site personnel in accordance with the 
roles outlined in the DoA log.  Training may include review of the clinical investigation plan, 
identification of eligible subjects, and instructions on data collection and entry. 
Ongoing training may be provided by Edwards or by already trained site staff.  Retraining may be 
performed for sites who have demonstrated protocol or implant procedure compliance issues. 
Documentation of study site personnel qualifications and training will be maintained in the site’s 
study files with copies sent to Edwards. 
11.7 Data Management 
This study will use a secure, password protected electronic data capture (EDC) system accessible 
via the Internet.  A unique Subject ID will be assigned for each subject enrolled in the study.  All 
pertinent data will be entered by the study site and core lab personnel into the eCRFs. 
Every reasonable effort should be made to complete data entry within 5 business days of data 
collection.  Data review by Edwards 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 provide his/her electronic signature on the appropriate eCRFs at regular 
intervals during the study, as requested by Edwards.  If changes are made to data previously 
signed-off, a new electronic signature will be required to acknowledge/approve the changes. 
11.8 Monitoring Procedures 
All study sites will be monitored periodically by Edwards or designee to ensure compliance with 

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the plan and the Investigator’s Agreement, and that all study subjects have been properly 
consented.  The monitor will ensure that the completed eCRFs match the medical records and 
work with the site to resolve differences through queries or formal action items. 
11.9 Site Discontinuation 
Edwards has the right to discontinue an Investigator or study site for the following reasons: 
• 
Failure of the Investigator to enrol subjects into the study at an acceptable rate 
• 
Failure of the Investigator to comply with pertinent regulations of appropriate regulatory 
authorities 
• 
Insufficient adherence to plan requirements 
• 
Submission of knowingly false information from the research facility to Edwards, Study 
Monitor, EC or appropriate regulatory authority. 
If a study site is discontinued, subjects enrolled prior to discontinuation will continue to be followed 
per the plan. 
11.10 Auditing 
The study site may be subject to a quality assurance audit by Edwards or a designee, as well as 
inspection by appropriate regulatory authorities.  It is important that the Investigator and relevant 
study site 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 as soon as possible. 
11.11 Publication Policy 
Publication or presentation of the overall clinical study results and/or site-specific results requires 
prior written approval of Edwards.  If Edwards 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 will provide statistical support for the publication process. 
Results from this study will be made publicly available. 
 
 

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12 ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 Applicable Principles and Regulations 
The study will be performed in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki (as updated in Fortaleza Brazil in 2013). 
The following regulations and guidelines will be followed, as applicable: 
• 
ISO 14155: 2020 Clinical Investigation of Medical Devices for Human Subjects - Good 
Clinical Practice 
• 
Medical Device Regulation 2017/745 (MDR) 
• 
MDCG 2020-10/1 guidance 
• 
General Data Protection Regulation 2016/679 
• 
Specific country regulations will be fulfilled, as applicable. 
 
12.2 Ethics Committee 
This plan, the proposed ICF, other written subject information and any proposed advertising 
material for subject recruitment must be submitted to the EC for written approval.  A copy of the 
written EC approval of the plan and ICF must be received by Edwards before recruitment of 
subjects into the study. 
The Investigator must submit and, where necessary, obtain approval from the EC for all 
subsequent plan amendments and changes to the ICF. 
The Investigator is responsible for obtaining annual EC approval and renewal throughout the 
duration of the study.  Copies of the Investigator’s reports and the EC continuance of approval 
must be sent to Edwards. 
12.3 Informed Consent 
Edwards will provide a sample ICF to the Investigator to prepare for use at his/her site.  The site-
specific ICF, and any subsequent modifications, must agree with current regulations and 
guidelines and must be approved by Edwards prior to submission to the EC.  The reviewing EC 
must approve the ICF before use at the site. 
Before participating in the study, each subject must give written Informed Consent after the 
context of the study has been fully explained in a language that is easily understood by the 
subject.  The subject must also be given sufficient time to read and understand the ICF per local 
regulations, as applicable, as well as the opportunity to ask questions and have those questions 
answered to his/her satisfaction. 
A copy of each subject’s signed and dated consent form must be maintained by each Investigator 
in a designated clinical study administrative file.  A signed copy of the consent form must be given 

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to each subject.  The consent process must be documented in the subject’s medical record; the 
documentation should minimally include that consent was obtained prior to participation in the 
study, the date consent was obtained, and confirmation that a copy of the consent was given to 
the subject. 
12.4 Confidentiality 
The Investigator is responsible for maintaining confidentiality throughout the clinical study.  All 
data used in the analysis and reporting of this evaluation will be without identifiable reference to 
the subject.  Authorized personnel assigned by Edwards will have access to the confidential files 
and will have the right to inspect and copy all records pertinent to this study. 
12.5 Investigator Records 
Records to be maintained by the Investigator include, but are not limited to, the following: 
• 
Study plan and all amendments 
• 
Signed Clinical Trial Agreement and any amendments 
• 
EC approval letters, including continuing reviews and all amendments/changes 
• 
EC-approved informed consent documents 
• 
Relevant correspondence with another study site, EC, Edwards, monitor, including 
required reports 
The following records must be maintained for each subject enrolled in the study: 
• 
Signed ICF 
• 
All relevant source documentation  
• 
Supporting documentation of any AEs 
All clinical sites will maintain the study records according to their country-specific record retention 
requirements. 
12.6 Plan Amendments 
The plan can be altered only by written amendments made by Edwards.  The amended plan will 
be submitted to the EC before being distributed to sites.  Each site must obtain EC approval and 
complete required training (if any, and as required by Delegation of Authority role) before 
implementing the amended plan. 
12.7 Plan Deviations 
Each deviation from the plan must be documented with the date and reason for the deviation and 
reported to Edwards as soon as possible, and to the EC per local guidelines and government 
regulations. 
 
 

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APPENDIX A ABBREVIATIONS 
Abbreviation 
Full Term 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AT 
As Treated 
CTA 
Computed Tomography Angiography 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ICF 
Informed Consent Form 
IFU 
Instructions for Use 
NYHA 
New York Heart Association 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
STS 
Society of Thoracic Surgeons 
TAVI 
Transcatheter Aortic Valve Implantation 
THV 
Transcatheter Heart Valve 
TEE 
Transoesophageal Echocardiogram 
TTE 
Transthoracic Echocardiogram 
USADE 
Unanticipated Serious Adverse Device Effect 
VI 
Valve Implant 
 
 

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APPENDIX B DEFINITIONS 
Term 
Definition 
Reference/ 
Justification 
Arrhythmia / 
Conduction 
System Injury 
(Defect) 
Arrhythmia: an irregular heart rate (increased > 100 beats/min or 
decreased < 60 beats/min) or abnormal rhythm resulting in symptoms 
or requiring medical intervention. 
Conduction system defect: an impairment of the electrical pathways 
and specialized muscular fibres that conduct impulses through the 
heart (ex. bundle branch block, heart block, internodal fibres, Bundle 
of His, Purkinje fibres, etc.). 
Sponsor 
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 
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 

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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 parameters b 
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 
a  Not well-validated and may overestimate the severity compared with the quantitative 
Doppler.  Circumferential extent of PVR best not to be used alone, but in combination 
with vena contracta width and/or area. 
b  For LVOT >2.5 cm, significant stenosis criteria is <0.20. 
VARC-2 
Prosthetic 
Aortic Valve 
Stenosis 
Criteria a 
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 index c 
>0.35 
0.35-0.25 
<0.25 
Effective orifice area d 
>1.1 cm2 
>1.1-0.8 cm2 
<0.8 cm2 
Effective orifice area e 
>0.9 cm2 
>0.9-0.6 cm2 
<0.6 cm2 
a  In conditions of normal or near normal stroke volume (50–70 mL). 
b  These parameters are more affected by flow, including concomitant aortic 
regurgitation. 
c  For LVOT >2.5 cm, significant stenosis criteria is <0.20. 
d  Use in setting of BSA ≥1.6 cm2 (note: dependent on the size of the valve and the size 
of the native annulus). 
e  Use in setting of BSA <1.6 cm2. 
VARC-2 
Reintervention 
Any intervention that repairs, alters or replaces a previously implanted 
or operated valve, which occurs 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 

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Term 
Definition 
Reference/ 
Justification 
Stroke / 
Transient 
Ischemic 
Attack (TIA) 
Diagnostic Criteria 
Acute episode of a focal or global neurological deficit with at least one 
of the following: 
• 
change in level of consciousness 
• 
hemiplegia 
• 
hemiparesis 
• 
numbness or sensory loss affecting one side of the body  
• 
dysphasia or aphasia 
• 
hemianopia 
• 
amaurosis fugax 
• 
or other neurological signs or symptoms consistent with stroke 
Duration of a focal or global neurological deficit >24 h; OR <24 h, if 
available neuroimaging documents a new haemorrhage or infarct; OR 
the neurological deficit results in death 
 
No other readily identifiable nonstroke cause for the clinical 
presentation (e.g., brain tumour, trauma, infection, hypoglycaemia, 
peripheral lesion, pharmacological influences) to be determined by or 
in conjunction with designated neurologist* 
 
Confirmation of the diagnosis by at least one of the following#: 
• 
Neurology or neurosurgical specialist 
• 
Neuroimaging procedure (MR or CT scan) 
• 
Clinical presentation alone  
Stroke definitions†: 
• 
Non-disabling: a mRS score of less than 2 at 90 days or the last 
available clinical visit with evaluable data or one that does not 
result in an increase of at least one mRS category from an 
individual’s pre-stroke baseline 
• 
Disabling: a mRS score of 2 or more at 90 days or the last 
available clinical visit with evaluable data and an increase of at 
least one mRS category from an individual’s pre-stroke baseline 
Stroke classification: 
• 
Haemorrhagic: an acute episode of focal or global cerebral or 
spinal dysfunction caused by intraparenchymal, intraventricular, or 
subarachnoid haemorrhage. 
• 
Ischemic: an acute symptomatic episode of focal cerebral, spinal, 
or retinal dysfunction caused by an infarction of the central 
nervous system tissue 
• 
Undetermined: stroke with insufficient information to allow 
categorization as ischemic or haemorrhagic. 
Transient Ischemic Attack (TIA) 
Duration of focal or global neurological deficit <24 h, any variable 
neuroimaging does not demonstrate a new haemorrhage or infarct 
*Subjects with non-focal global encephalopathy will not be reported as a stroke without 
unequivocal evidence based upon neuroimaging studies. 
#If a stroke is reported without evidence of confirmation of the diagnosis by one of these 
methods, the event may still be considered a stroke based on the clinical presentation 
alone. 
†Modified Rankin score assessments should be made by qualified individuals according 
to a certification process. 
VARC-2 

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Term 
Definition 
Reference/ 
Justification 
Vulnerable 
Population 
Individuals who are unable to fully understand all aspects of the 
investigation that are relevant to the decision to participate, or who 
could be manipulated or unduly influenced as a result of a 
compromised position, expectation of benefits or fear of retaliatory 
response 
ISO 
14155:2020 
 
 
 

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APPENDIX C REFERENCES 
1. 
Barbanti M, Baan J, Spence MS, et al. Feasibility and safety of early discharge after 
transfemoral transcatheter aortic valve implantation–rationale and design of the FAST-
TAVI registry. BMC cardiovascular disorders. 2017;17(1):259. 
2. 
Wood DA, Lauck SB, Cairns JA, et al. The Vancouver 3M (Multidisciplinary, 
Multimodality, But Minimalist) Clinical Pathway Facilitates Safe Next-Day Discharge 
Home at Low-, Medium-, and High-Volume Transfemoral Transcatheter Aortic Valve 
Replacement Centers. JACC: Cardiovascular Interventions. 2019;12(5):459. 
3. 
Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management 
of valvular heart disease. European Heart Journal. 2017;38(36):2739-2791. 
4. 
Kappetein AP, Head SJ, Genereux P, et al. Updated standardized endpoint definitions 
for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 
consensus document (VARC-2). Eur J Cardiothorac Surg. 2012;42(5):S45-60. 
5. 
Zamorano JL, Badano LP, Bruce C, et al. EAE/ASE recommendations for the use of 
echocardiography in new transcatheter interventions for valvular heart disease. Eur J 
Echocardiogr. 2011;12(8):557-584. 
6. 
Zoghbi WA, Adams D, Bonow RO, et al. Recommendations for Noninvasive Evaluation 
of Native Valvular Regurgitation. Journal of the American Society of Echocardiography. 
2017;30(4):303-371. 
7. 
Baumgartner H, Hung J, Bermejo J, et al. Recommendations on the echocardiographic 
assessment of aortic valve stenosis: a focused update from the European Association of 
Cardiovascular Imaging and the American Society of Echocardiography. European Heart 
Journal-Cardiovascular Imaging. 2016;18(3):254-275.