Multicenter Study of Congenital Pulmonic Valve Dysfunction Studying the SAPIEN 3 THV With the Alterra Adaptive Prestent
Phase: NA
Conditions: Pulmonary Disease, Transcatheter Pulmonary Valve Replacement (TPVR), Tetralogy of Fallot, Congenital Heart Disease, Pulmonary Regurgitation
Sponsor: Edwards Lifesciences

 
 
 
 
ALTERRA 
 
Multicenter Study of Congenital Pulmonic Valve Dysfunction 
Studying the SAPIEN 3 Transcatheter Heart Valve with the Alterra 
Adaptive Prestent 
 
 
 
NCT03130777 
 
 
Dec 2021 

PROPRIETARY DATA: This document and the information contained herein may not be reproduced, used or 
disclosed without written permission from Edwards LLC 
Edwards Lifesciences, Edwards, Alterra, Edwards SAPIEN, Edwards SAPIEN XT, Edwards SAPIEN 3, Edwards 
SAPIEN 3 Pulmonic Delivery System, Edwards Commander, SAPIEN, SAPIEN XT, and SAPIEN 3 are trademarks of 
Edwards Lifesciences Corporation. 
Page 1 of 51 
 
 
 
ALTERRA 
 
Multicenter Study of Congenital Pulmonic Valve Dysfunction 
Studying the SAPIEN 3 Transcatheter Heart Valve with the 
Alterra Adaptive Prestent 
 
Clinical Protocol 
Study Number:  2016-04 
 
Version 7.0 
December 16, 2021 
 
 
 
Study Sponsor: 
Edwards Lifesciences LLC 
One Edwards Way 
Irvine, CA 92614 
USA 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 2 of 51 
TABLE OF CONTENTS 
LIST OF TABLES AND FIGURES ............................................................................................. 4 
PROTOCOL SYNOPSIS ........................................................................................................... 5 
INVESTIGATOR SIGNATURE PAGE ....................................................................................... 9 
1 
INTRODUCTION .................................................................................................................10 
1.1 
BACKGROUND ..............................................................................................................10 
2 
STUDY OBJECTIVE ...........................................................................................................11 
3 
STUDY DESIGN .................................................................................................................11 
4 
STUDY DEVICES ...............................................................................................................12 
4.1 
INVESTIGATIONAL DEVICE DESCRIPTIONS ......................................................................12 
4.1.1 
Edwards Alterra Adaptive Prestent ........................................................................................ 12 
4.1.2 
Edwards SAPIEN 3 THV ........................................................................................................ 13 
4.1.3 
Edwards Commander Delivery System ................................................................................. 13 
4.1.4 
Edwards SAPIEN 3 Pulmonic Delivery System ..................................................................... 14 
4.1.5 
Edwards Crimper ................................................................................................................... 15 
4.2 
INTENDED USE .............................................................................................................15 
5 
STUDY ENDPOINTS ..........................................................................................................15 
5.1 
PRIMARY ENDPOINT ......................................................................................................15 
5.2 
SECONDARY ENDPOINT ................................................................................................16 
5.3 
ADDITIONAL SAFETY AND EFFECTIVENESS OUTCOMES ...................................................16 
6 
STUDY POPULATION ........................................................................................................17 
6.1 
INCLUSION CRITERIA .....................................................................................................17 
6.2 
EXCLUSION CRITERIA ...................................................................................................17 
7 
STUDY PROCEDURES ......................................................................................................18 
7.1 
INFORMED CONSENT ....................................................................................................18 
7.2 
SCREENING/BASELINE ASSESSMENTS ...........................................................................18 
7.2.1 
Case Review .......................................................................................................................... 19 
7.3 
PROCEDURE ................................................................................................................19 
7.3.1 
Subject Enrollment ................................................................................................................. 19 
7.3.2 
Recommended Concomitant Medical Therapy ..................................................................... 19 
7.3.3 
Implant Procedure .................................................................................................................. 19 
7.4 
DISCHARGE ..................................................................................................................20 
7.5 
FOLLOW-UP ..................................................................................................................20 
7.5.1 
30 days................................................................................................................................... 20 
7.5.2 
6 months ................................................................................................................................ 21 
7.5.3 
12 months .............................................................................................................................. 21 
7.5.4 
Years 2 through 5, 7 and 10 .................................................................................................. 21 
7.5.5 
Years 6, 8 and 9 ..................................................................................................................... 22 
7.6 
IMAGING ASSESSMENTS ................................................................................................22 
7.7 
QUALITY OF LIFE QUESTIONNAIRES ...............................................................................22 
7.8 
MISSED VISITS / SUBJECT DISCONTINUATION .................................................................24 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 3 of 51 
7.8.1 
Missed Visits .......................................................................................................................... 24 
7.8.2 
Subject Discontinuation ......................................................................................................... 24 
8 
ADVERSE EVENTS ............................................................................................................25 
8.1 
ADVERSE EVENT DEFINITIONS .......................................................................................25 
8.2 
AE REPORTING REQUIREMENTS ....................................................................................26 
8.3 
INVESTIGATOR ASSESSMENT .........................................................................................27 
8.4 
SPONSOR ASSESSMENT................................................................................................27 
8.5 
DEVICE MALFUNCTIONS ................................................................................................27 
9 
RISK / BENEFIT ANALYSIS ..............................................................................................28 
9.1 
BENEFITS .....................................................................................................................28 
9.2 
RISKS ..........................................................................................................................28 
9.2.1 
Risk Minimization ................................................................................................................... 30 
10 STATISTICAL CONSIDERATIONS ....................................................................................31 
10.1 
SAMPLE SIZE CALCULATIONS ........................................................................................31 
10.2 
ANALYSIS POPULATIONS ...............................................................................................31 
10.3 
PRIMARY ENDPOINT ANALYSIS ......................................................................................32 
10.4 
CENTER POOLABILITY ...................................................................................................32 
10.5 
ENDPOINTS FOR LABELING ............................................................................................33 
10.5.1 Improvement in Total PR from Baseline to 30 Days .............................................................. 33 
10.6 
ADDITIONAL SAFETY AND EFFECTIVENESS OUTCOMES ...................................................33 
11 STUDY ADMINISTRATION ................................................................................................34 
11.1 
GENERAL STUDY ORGANIZATION ...................................................................................34 
11.2 
STEERING COMMITTEE ..................................................................................................34 
11.3 
CASE REVIEW BOARD ...................................................................................................34 
11.4 
DATA SAFETY MONITORING BOARD ...............................................................................34 
11.5 
CLINICAL EVENTS COMMITTEE.......................................................................................34 
11.6 
STUDY PROCEDURES....................................................................................................35 
11.6.1 Investigational Site Selection ................................................................................................. 35 
11.6.2 Training .................................................................................................................................. 35 
11.6.3 Echocardiography .................................................................................................................. 35 
11.6.4 Radiographic Imaging ............................................................................................................ 35 
11.6.5 Image Management ............................................................................................................... 35 
11.6.6 Histopathology ....................................................................................................................... 36 
11.7 
DEVICE MANAGEMENT ..................................................................................................36 
11.7.1 Study Devices ........................................................................................................................ 36 
11.7.2 Device Storage ...................................................................................................................... 36 
11.7.3 Device Accountability ............................................................................................................. 36 
11.8 
DATA MANAGEMENT .....................................................................................................36 
11.9 
MONITORING PROCEDURES ..........................................................................................36 
11.10 SITE DISCONTINUATION ................................................................................................37 
11.11 AUDITING .....................................................................................................................37 
11.12 PUBLICATION POLICY ....................................................................................................37 
12 ETHICAL AND REGULATORY CONSIDERATIONS .........................................................37 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 4 of 51 
12.1 
APPLICABLE PRINCIPLES AND REGULATIONS ..................................................................37 
12.2 
INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE .......................................................37 
12.3 
SUBJECT INFORMED CONSENT ......................................................................................38 
12.4 
CONFIDENTIALITY .........................................................................................................38 
12.5 
INVESTIGATOR RECORDS ..............................................................................................38 
12.6 
INVESTIGATOR REPORTS ..............................................................................................39 
12.7 
PROTOCOL AMENDMENTS .............................................................................................39 
12.8 
PROTOCOL DEVIATIONS ................................................................................................39 
APPENDIX A: ABBREVIATIONS .............................................................................................41 
APPENDIX B: DEFINITIONS ...................................................................................................43 
APPENDIX C: REFERENCES ..................................................................................................50 
 
 
LIST OF TABLES AND FIGURES 
Table 1: Alterra Device Sizing ...................................................................................................13 
Table 2: Recommended Concomitant Medical Therapy ............................................................19 
Table 3: Schedule of Events .....................................................................................................23 
 
Figure 1: Edwards Alterra Adaptive Prestent .............................................................................12 
Figure 2: Edwards Alterra Delivery System ...............................................................................13 
 
 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 5 of 51 
PROTOCOL SYNOPSIS 
Title 
ALTERRA 
Multicenter Study of Congenital Pulmonic Valve Dysfunction Studying the 
SAPIEN 3 Transcatheter Heart Valve with the Alterra Adaptive Prestent 
Purpose 
To demonstrate the safety and effectiveness of the Edwards Alterra Adaptive 
Prestent in conjunction with the Edwards SAPIEN 3 Transcatheter Heart 
Valve (THV) System in subjects with a dysfunctional right ventricular outflow 
tract/pulmonary valve (RVOT/PV) who are indicated for treatment of 
pulmonary regurgitation (PR) 
Study Devices 
• 
Edwards Alterra Adaptive Prestent and delivery system 
• 
Edwards SAPIEN 3 THV with the associated delivery systems 
Study Design 
Single arm, prospective, multicenter study.  A separate registry will be 
conducted to evaluate the Pulmonic Delivery System (PDS) for delivery of 
the SAPIEN 3 THV. 
Study 
Population 
The study population will be comprised of subjects with a dysfunctional 
RVOT/PV, who are indicated for treatment of moderate to severe PR. 
Sample Size 
Up to 60 subjects will be enrolled in the main cohort.  Subjects enrolled under 
earlier versions of the protocol (Early Feasibility Study versions 1.0 and 2.0) 
will count towards enrollment.  Twenty-five additional subjects will be 
enrolled in the PDS Registry. 
Study Sites 
Up to 25 participating sites in the US and Canada 
Assessment 
Schedule 
Screening/baseline, discharge, 30 days, 6 months, 12 months and annually 
thereafter through 10 years 
Primary 
Endpoint 
Main Cohort: 
THV dysfunction at 6 months.  THV dysfunction is defined as a non-
hierarchical composite of: 
• 
RVOT/PV reintervention 
• 
Moderate or greater total PR via Transthoracic Echocardiography 
(TTE) 
• 
Mean RVOT/PV gradient ≥ 35 mmHg via TTE 
 
PDS Registry: 
Acute PDS Success, defined as a non-hierarchical composite of: 
• 
Single THV implanted in the desired location 
• 
Right ventricle to pulmonary artery (RV-PA) peak-to-peak gradient < 
35 mmHg post-THV implantation 
• 
Less than moderate total PR by discharge TTE (or earliest evaluable 
TTE) 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 6 of 51 
• 
Free of SAPIEN 3 / Alterra explant at 24 hours post-implantation 
Secondary 
Endpoints 
Main Cohort: 
The following secondary endpoint will be evaluated for labeling purposes: 
• 
Improvement in total PR from baseline to 30 days 
 
Additional 
Safety and 
Effectiveness 
Outcomes 
The following additional outcomes will be evaluated: 
Main Cohort: 
• 
Improvement in tricuspid regurgitation (TR) from baseline to 30 days 
and 6 months by TTE for subjects with TR of mild or greater at baseline 
• 
Major vascular complications at 30 days and 6 months 
• 
Life-threatening or disabling bleeding at 30 days and 6 months 
• 
Alterra embolization at 30 days and 6 months 
• 
THV embolization at 30 days and 6 months 
• 
Alterra fracture that led to reintervention at 30 days and 6 months 
• 
THV frame fracture that led to reintervention at 30 days and 6 months 
• 
All-cause mortality at 30 days and 6 months 
• 
Acute Device Success, defined as a non-hierarchical composite of: 
o Single Alterra deployed in the desired location 
o Single THV implanted in the desired location within Alterra (staged 
procedures allowed) 
o RV-PA peak-to-peak gradient < 35 mmHg post-THV implantation 
o Less than moderate total PR by discharge TTE (or earliest 
evaluable TTE) 
o Free of Alterra explant at 24 hours post-implantation 
 
PDS Registry: 
• 
Improvement in tricuspid regurgitation (TR) from baseline to 30 days by 
TTE for subjects with TR of mild or greater at baseline 
• 
Major vascular complications at 30 days 
• 
Life-threatening or disabling bleeding at 30 days 
• 
Alterra embolization at 30 days 
• 
THV embolization at 30 days 
 
Inclusion 
Criteria 
1. The candidate/candidate’s legal guardian has been informed of the 
nature of the study, agrees to its provisions and has provided written 
informed consent 
2. Weight is ≥ 20 kg (≥ 44 lbs) 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 7 of 51 
3. RVOT/PV with moderate or greater PR by TTE 
4. RVOT/PV proximal and distal landing zone diameter ≥ 27 mm and ≤ 38 
mm, and minimum of 35 mm from contractile tissue to lowest pulmonary 
artery takeoff 
Exclusion 
Criteria 
1. Active infection requiring current antibiotic therapy (if temporary illness, 
patient may be a candidate 2 weeks after discontinuation of antibiotics) 
2. History of or active endocarditis (active treatment with antibiotics) within 
the past 180 days 
3. Leukopenia (WBC < 2000 cells/µL), anemia (Hgb < 7 g/dL), 
thrombocytopenia (platelets < 50,000 cells/µL) or any known blood 
clotting disorder 
4. Inappropriate anatomy for introduction and delivery of Alterra or the 
SAPIEN 3 THV 
5. Need for concomitant atrial septal defect or ventricular septal defect 
closure or other concomitant interventional procedures other than 
pulmonary artery or branch pulmonary artery stenting or angioplasty 
6. Interventional/surgical procedures within 30 days prior to the Alterra or 
valve implant procedure 
7. Any planned surgical, percutaneous coronary or peripheral procedure to 
be performed within the 30-day follow-up from the Alterra or valve 
implant procedure 
8. History of or current intravenous drug use 
9. Major or progressive non-cardiac disease resulting in a life expectancy 
of less than one year 
10. Known hypersensitivity to aspirin or heparin and cannot be treated with 
other antiplatelet and/or antithrombotic medications 
11. Known hypersensitivity to nitinol, cobalt-chromium, nickel or contrast 
media that cannot be adequately pre-medicated 
12. 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 devices.] 
13. Positive urine or serum pregnancy test in female patients of child-bearing 
potential 
14. Renal insufficiency (creatinine > 3.0 mg/dL) and/or renal replacement 
therapy 
Statistical 
Methods 
Main Cohort: 
For the primary endpoint of THV dysfunction at 6 months, an exact binomial 
95% confidence interval (CI) for the percent of subjects with THV dysfunction 
will be calculated and compared to the performance goal of 25%.  If the 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 8 of 51 
upper bound of the CI is below 25% then the performance goal will be 
considered to be met. 
PDS Registry: 
Descriptive statistics will be provided; no formal hypothesis testing will be 
conducted. 
Study Principal 
Investigator 
Evan Zahn, MD, FACC, FSCAI 
Cedars-Sinai Heart Institute 
Sponsor 
Edwards Lifesciences  
One Edwards Way 
Irvine, CA 92614 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 9 of 51 
INVESTIGATOR SIGNATURE PAGE 
Protocol Title:  ALTERRA:  Multicenter Study of Congenital Pulmonic Valve Dysfunction Studying 
the SAPIEN 3 Transcatheter Heart Valve with the Alterra Adaptive Prestent 
 
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, Declaration of Helsinki, and all 
applicable regulatory requirements. 
 
Investigative Site Name 
 
 
Site Principal Investigator Name (print) 
 
 
 
 
Site Principal Investigator Signature 
 
Date 
 
 
 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 10 of 51 
1 
INTRODUCTION 
1.1 
Background 
Congenital heart defects (CHD) can be complex, involving structures of either the right and/or left 
heart and are reported in approximately eight of every 1000 newborns.  Right ventricular outflow 
tract (RVOT) defects such as pulmonary valve stenosis, Tetralogy of Fallot, and double outlet 
right ventricle are common in this population and may represent as many as 20% of those with 
CHD.  Initial surgical correction of these lesions often involves relief of RVOT obstruction often 
using a combination of muscular resection, pulmonary valvotomy/valvectomy and a transannular 
patch.  While surgical correction of these lesions has been performed safely for more than 50 
years, many of these operations result in pulmonary insufficiency.  For decades, it was believed 
that pulmonary insufficiency was a benign condition, as it is typically well tolerated throughout 
childhood and in many patients for several decades thereafter.  Recently, however, it has been 
widely recognized that chronic pulmonary regurgitation (PR) in this patient population is 
associated with a number of pathologic conditions including: right ventricular dilation, diminished 
ventricular systolic function, arrhythmia, decreased functional capacity, right heart failure and 
death (1).  Numerous surgical options exist for placing a competent valve in the pulmonic position 
(homografts, xenografts, bioprosthetic valves), however all of these options by definition require 
repeat open heart surgery and all of the attendant risks and morbidity associated with it (2).  
Furthermore, all currently available options for surgical pulmonary valve replacement are only 
temporizing in that essentially all of these valves will degenerate and need replacement (3, 4). 
The durability of these prostheses is variable and time to reoperation often depends on the chosen 
conduit material and/or biological tissue and age of the patient at the time of the initial surgery.  
Thrombosis, recurrent stenosis and conduit tissue/valve leaflet calcification with concomitant PR 
are the most commonly reported reasons for additional surgical reinterventions.  Patients 
receiving pulmonary xenografts are reported to have a mean time to reintervention of 10.3 years 
and for those implanted with a homograft 16 years.  Multiple reoperations over a patient’s lifetime 
are the current norm (3, 4). 
Transcatheter replacement of the pulmonary valve, currently designed only to be used in the 
setting of a previously placed failed right ventricle-pulmonary artery (RV-PA) conduit, provides a 
less invasive alternative to surgical replacement, which requires open-heart surgery, re-
sternotomy and cardiopulmonary bypass.  Treatment of this patient population with a 
transcatheter heart valve (THV) may provide both short and long-term relief of their symptoms, 
improved hemodynamic function, and a gradual, consistent improvement of their cardiac function, 
which may delay the need for future repeat open-heart surgeries and provide improved quality of 
life (5) and might reduce the number of operations needed over the total lifetime of patients with 
RV-PA conduits (1, 2). 
Currently there are two Food and Drug Administration (FDA) approved transcatheter pulmonic 
valves (TPV) for use as an adjunct to surgery in the management of patients with dysfunctional 
RVOT conduits.  The Medtronic Melody Transcatheter Pulmonary Valve was approved on 
January 27, 2015 for use as an adjunct to surgery in the management of patients with 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 11 of 51 
dysfunctional RVOT conduits.  Due to its use of a bovine jugular vein, the Melody device can only 
be manufactured in sizes ≤ 22 mm for treatment of RVOT conduits ranging from 16-20 mm.  The 
SAPIEN XT valve was approved in 2016 for use in the pulmonic position, also as an adjunct to 
surgery in patients with previously existing RV-PA conduits.  The SAPIEN XT valve comes in 
diameters of 23, 26 and 29 mm.  It is important to note that both of these devices are approved 
for use only in dysfunctional RV-PA conduits, not in patients who underwent other forms of RVOT 
surgery (e.g. pulmonary valvotomy, transannular patch repair).  It is estimated that only 15% of 
congenital heart patients with RVOT dysfunction have had a previously placed surgical conduit 
resulting in the vast majority of these patients currently not being candidates for TPV implantation 
(TPVI) (6). 
Currently there is no commercially-approved transcatheter valve available to treat patients with 
what is commonly referred to as a “native outflow tract”, meaning they have had their RVOT 
surgically addressed as described above (muscle resection, valvotomy/valvectomy and patch) 
but have not undergone conduit or other form of surgical pulmonary valve replacement.  This is a 
challenging anatomic substrate to design a TPV due to several factors including: large diameter 
of the RVOT, irregular shape of the RVOT, marked changes in RVOT dimensions during systole 
and diastole, compliant nature and unpredictable shape of the RVOT after transannular patch.  
Several novel approaches have been described utilizing existing technologies; however, the 
larger population remains untreatable.  Existing evidence suggests that if a proper “landing zone” 
can be created in the RVOT, one that reduces RVOT volume and creates a circular semi-rigid 
area to place a TPV, this patient population can be successfully treated and avoid repeated open 
heart surgery.  Phillips et al reported on 8 patients with native RVOT who underwent successful 
TPVI after using a novel hybrid approach to modify the RVOT (7). 
The Edwards Alterra Adaptive Prestent (Alterra) is designed to provide a simple and safe way to 
reduce the diameter of these large irregular RVOTs and provide a circular, semi-rigid landing 
zone to place an Edwards SAPIEN 3 THV (8). 
2 
Study Objective 
The objective of this study is to demonstrate the safety and effectiveness of the Edwards Alterra 
Adaptive Prestent in conjunction with the Edwards SAPIEN 3 THV System in subjects with a 
dysfunctional RVOT/pulmonary valve (PV) who are indicated for treatment of PR. 
3 
Study Design 
This is a single arm, prospective, multicenter study.  Up to 60 subjects will be enrolled in the main 
cohort at up to 25 sites in the US and Canada.  Twenty-five additional subjects will be enrolled in 
a separate registry to evaluate the Pulmonic Delivery System (PDS) for delivery of the SAPIEN 3 
THV.  No site will be allowed to enroll more than 35% of subjects (21 subjects in main cohort; 8 
subjects in PDS Registry).  Subjects will be assessed at the following intervals:  
screening/baseline, discharge, 30 days, 6 months, 12 months and annually thereafter through 10 
years. 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 12 of 51 
Subjects enrolled under EFS protocol versions 1.0 and 2.0 will count towards enrollment in the 
main cohort. 
4 
STUDY DEVICES 
The following devices will be used in this trial: 
• 
Edwards Alterra Adaptive Prestent, model 29AP4045 
• 
Edwards Alterra Adaptive Prestent delivery system 
• 
Edwards SAPIEN 3 THV, model 9600TFX in a 29 mm size 
• 
Edwards Commander Delivery System, model 9600LDS29 
• 
Edwards SAPIEN 3 Pulmonic Delivery System, model 9630PL29 
• 
Edwards Crimper, model 9600CR 
• 
Edwards Expandable Introducer Sheath Set, model 916ES 
• 
Edwards Balloon Catheter, model 9350BC25 (at physician’s discretion) 
• 
Inflation Devices 
 
4.1 
Investigational Device Descriptions 
4.1.1 
Edwards Alterra Adaptive Prestent 
The prestent is used as a docking adaptor for the 29 mm SAPIEN 3 THV.  It is comprised of a 
self-expanding, radiopaque, nitinol frame assembly and polyethylene terephthalate (PET) fabric 
covering.  The prestent has designated inflow and outflow sides.  The proximal inflow section is 
identifiable by the presence of two triangular tabs that are attached to the catheter of the delivery 
system.  The distal outflow section is distinguished by the open cells for blood flow.  The PET 
fabric is attached by sutures to the inside surface of the frame to create a sealing at the inflow 
section and opening for the outflow.  Sutures are also used in the center to support the middle 
section when a SAPIEN 3 THV is implanted.  Refer to Table 1 for Alterra Device Sizing. 
Figure 1: Edwards Alterra Adaptive Prestent 
 
OD (Sealing) 
Height 
40 mm 
48 mm 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 13 of 51 
Table 1: Alterra Device Sizing 
Perimeter 
Perimeter Derived Diameter* 
Prestent Size 
THV Size 
84.9 mm-119.3 mm 
27-38 mm 
40 mm x 48 mm 
29 mm 
* Diameter range throughout cardiac cycle 
 
Edwards Alterra Delivery System 
The delivery system includes a handle which consists of a wheel that allows for deployment, two 
primary shafts with a flush port to flush the delivery system, and a long compliant tapered tip at 
the distal end to facilitate tracking through the vasculature.  The prestent is fully loaded in the 
delivery system.  A stylet is included within the guidewire lumen. 
Figure 2: Edwards Alterra Delivery System 
 
 
4.1.2 
Edwards SAPIEN 3 THV 
The SAPIEN 3 THV is a catheter-delivered heart valve that combines a balloon expandable stent 
and bioprosthetic valve technology. 
The SAPIEN 3 THV is comprised of a balloon-expandable, radiopaque, cobalt-chromium alloy 
frame, a tri-leaflet bovine pericardial tissue valve, a PET inner skirt, and a PET outer skirt.  The 
valve tissue is treated according to the Edwards ThermaFix process, packaged and terminally 
liquid sterilized in a buffered glutaraldehyde solution. 
The 29 mm SAPIEN 3 THV is intended to be implanted into the previously placed Alterra Adaptive 
Present within a dysfunctional RVOT. 
4.1.3 
Edwards Commander Delivery System 
The Edwards Commander Delivery System includes: 
• 
Edwards Commander Delivery System 
• 
Loader 
• 
Qualcrimp Crimping Accessory 
• 
2-piece Crimp Stopper 
 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 14 of 51 
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 RVOT.  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 RVOT.  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. 
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 Crimping Accessory 
The Qualcrimp crimping accessory is a non-patient-contacting device that is designed to protect 
the SAPIEN 3 THV tissue leaflets during the crimping process.  It is placed around the SAPIEN 3 
THV during the crimping process to facilitate displacement of the valve tissue between the valve 
frame struts and to prevent potential tissue damage. 
2-piece Crimp Stopper 
This component is discussed in Section 4.1.5. 
4.1.4 
Edwards SAPIEN 3 Pulmonic Delivery System 
The Edwards SAPIEN 3 Pulmonic Delivery System includes: 
• 
Edwards SAPIEN 3 Pulmonic Delivery System 
• 
24F Dilator 
• 
Qualcrimp Crimping Accessory 
• 
2-piece Crimp Stopper 
• 
Lock Clip 
 
The Edwards SAPIEN 3 Pulmonic Delivery System consists of an in-line sheath, balloon catheter 
for deployment of the Edwards SAPIEN 3 THV, and an outer shaft to cover the THV during 
insertion and tracking to the intended deployment location.  The delivery system includes a 
tapered tip to facilitate crossing of right heart structures.  A radiopaque Center Marker in the 
balloon is provided to help with valve positioning.  A stylet is included within the guidewire lumen 
of the delivery system. 
Dilator 
The 24F Dilator (packaged with the delivery system) is used to predilate the vessel prior to 
insertion of the delivery system, if necessary. 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 15 of 51 
Qualcrimp Crimping Accessory 
The Qualcrimp crimping accessory (packaged with the delivery system) is used during crimping 
of the THV. 
2-piece Crimp Stopper 
This component is discussed in Section 4.1.5. 
Lock Clip 
The Lock Clip (packaged with the delivery system) is used to maintain the position of the outer 
shaft during delivery system insertion. 
4.1.5 
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. 
4.2 
Intended Use 
The Edwards Alterra Adaptive Prestent, used in conjunction with the 29 mm Edwards SAPIEN 3 
THV, is intended for use in the treatment of moderate to severe PR in pediatric and adult patients 
with a dysfunctional RVOT/PV. 
5 
STUDY ENDPOINTS 
5.1 
Primary Endpoint 
Main Cohort: 
The primary endpoint is THV dysfunction at 6 months.  THV dysfunction is defined as a non-
hierarchical composite of: 
• 
RVOT/PV reintervention 
• 
Moderate or greater total PR via Transthoracic Echocardiography (TTE) 
• 
Mean RVOT/PV gradient ≥ 35 mmHg via TTE 
 
PDS Registry: 
The primary endpoint is Acute PDS Success, defined as a non-hierarchical composite of: 
• 
Single THV implanted in the desired location 
• 
RV-PA peak-to-peak gradient < 35 mmHg post-THV implantation 
• 
Less than moderate total PR by discharge TTE (or earliest evaluable TTE) 
• 
Free of SAPIEN 3 / Alterra explant at 24 hours post-implantation 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 16 of 51 
5.2 
Secondary Endpoint  
Main Cohort: 
The following secondary endpoint will be evaluated for labeling purposes: 
• 
Improvement in total PR from baseline to 30 days 
 
5.3 
Additional Safety and Effectiveness Outcomes 
The following additional outcomes will be evaluated: 
Main Cohort: 
• 
Improvement in tricuspid regurgitation (TR) from baseline to 30 days and 6 months by 
TTE for subjects with TR of mild or greater at baseline 
• 
Major vascular complications at 30 days and 6 months 
• 
Life-threatening or disabling bleeding at 30 days and 6 months 
• 
Alterra embolization at 30 days and 6 months 
• 
THV embolization at 30 days and 6 months 
• 
Alterra fracture that led to reintervention at 30 days and 6 months 
• 
THV frame fracture that led to reintervention at 30 days and 6 months 
• 
All-cause mortality at 30 days and 6 months 
• 
Acute Device Success, defined as a non-hierarchical composite of: 
• 
Single Alterra deployed in the desired location 
• 
Single THV implanted in the desired location within Alterra (staged procedures allowed) 
• 
RV-PA peak-to-peak gradient < 35 mmHg post-THV implantation 
• 
Less than moderate total PR by discharge TTE (or earliest evaluable TTE) 
• 
Free of Alterra explant at 24 hours post-implantation 
 
PDS Registry: 
• 
Improvement in tricuspid regurgitation (TR) from baseline to 30 days by TTE for subjects 
with TR of mild or greater at baseline 
• 
Major vascular complications at 30 days 
• 
Life-threatening or disabling bleeding at 30 days 
• 
Alterra embolization at 30 days 
• 
THV embolization at 30 days 
 
 
 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 17 of 51 
6 
STUDY POPULATION 
The study population will be comprised of subjects with a dysfunctional RVOT/PV, who are 
indicated for treatment of moderate to severe PR. 
6.1 
Inclusion Criteria 
Candidates for this study must meet all of the following inclusion criteria to be eligible: 
1. The candidate/candidate’s legal guardian has been informed of the nature of the study, agrees 
to its provisions and has provided written informed consent 
2. Weight is ≥ 20 kg (≥ 44 lbs) 
3. RVOT/PV with moderate or greater PR by TTE 
4. RVOT/PV proximal and distal landing zone diameter ≥ 27 mm and ≤ 38 mm, and minimum of 
35 mm from contractile tissue to lowest pulmonary artery takeoff 
 
6.2 
Exclusion Criteria 
Candidates will be excluded from the study if any of the following conditions are present: 
1. Active infection requiring current antibiotic therapy (if temporary illness, patient may be a 
candidate 2 weeks after discontinuation of antibiotics) 
2. History of or active endocarditis (active treatment with antibiotics) within the past 180 days 
3. Leukopenia (White Blood Cell (WBC) < 2000 cells/µL), anemia (Hemoglobin (Hgb) < 7 g/dL), 
thrombocytopenia (platelets < 50,000 cells/µL) or any known blood clotting disorder 
4. Inappropriate anatomy for introduction and delivery of Alterra or the SAPIEN 3 THV 
5. Need for concomitant atrial septal defect or ventricular septal defect closure or other 
concomitant interventional procedures other than pulmonary artery or branch pulmonary 
artery stenting or angioplasty 
6. Interventional/surgical procedures within 30 days prior to the Alterra or valve implant 
procedure 
7. Any planned surgical, percutaneous coronary or peripheral procedure to be performed within 
the 30-day follow-up from the Alterra or valve implant procedure 
8. History of or current intravenous drug use 
9. Major or progressive non-cardiac disease resulting in a life expectancy of less than one year 
10. Known hypersensitivity to aspirin or heparin and cannot be treated with other antiplatelet 
and/or antithrombotic medications 
11. Known hypersensitivity to nitinol, cobalt-chromium, nickel or contrast media that cannot be 
adequately pre-medicated 
12. 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 devices.] 
13. Positive urine or serum pregnancy test in female patients of child-bearing potential 
14. Renal insufficiency (creatinine > 3.0 mg/dL) and/or renal replacement therapy 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 18 of 51 
7 
STUDY PROCEDURES 
7.1 
Informed Consent 
The study investigator(s) and support staff will approach patients with a dysfunctional RVOT/PV 
who are indicated for treatment of PR.  They will 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, they must sign the Institutional 
Review Board (IRB) / Ethics Committee (EC)-approved informed consent form (ICF) and 
screening will commence.  Informed consent must be obtained prior to performing screening 
procedures or baseline tests that are not standard of care. 
For those subjects whose initial consent was obtained from the legal guardian, a new consent 
must be obtained once the subject reaches adult age (if study participation is on-going), as 
determined by state and/or local laws.  If the subject refuses to sign a new ICF, they will be 
withdrawn from the study. 
All candidates being considered for study inclusion should be entered into the electronic 
database; the reasons for screen failure will be documented. 
7.2 
Screening/Baseline Assessments 
The following data will be collected for all subjects ≤ 30 days before the Alterra implant procedure, 
unless otherwise noted: 
• 
Medical history 
• 
Physical examination (blood pressure, heart rate, height, weight only) 
• 
Medications – Antithrombotics (anticoagulants, antiplatelets, thrombolytics), 
antiarrhythmics, heart failure medications and antibiotics only 
• 
New York Heart Association (NYHA) functional class 
• 
Short form (SF)-36 health survey 
• 
12-lead electrocardiogram (ECG) 
• 
TTE – Qualifying TTE must be performed within 90 days prior to the Alterra implant 
procedure. 
• 
Gated computed tomography angiography (CTA) for general assessment of RVOT/PV, 
pulmonary artery and right heart anatomic parameters.  CTA must be performed within 1 
year prior to the Alterra implant procedure and meet the defined parameters within the 
applicable Core Lab Manual of Operations. 
• 
Cardiac magnetic resonance imaging (cMRI) for general assessment of RVOT/PV and 
right heart function.  cMRI must be performed within 1 year prior to the Alterra implant 
procedure and meet the defined parameters within the applicable Core Lab Manual of 
Operations. 
• 
WBC, Hgb, hematocrit (Hct) and platelet count 
• 
Serum creatinine 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 19 of 51 
• 
Urine or serum pregnancy test for all females of childbearing potential 
• 
International Normalized Ratio (INR), if subject is taking Warfarin (or other Coumadin 
derivative) 
 
7.2.1 
Case Review 
All candidates being considered for participation must be approved by the Case Review Board.  
Before a case is submitted for review, the site will screen the candidate for initial enrollment 
criteria.  Once fully screened and deemed an appropriate candidate, the site will submit the case 
for review and approval consideration by the Case Review Board. 
Edwards will maintain a record of the case presentation and case review notes. 
7.3 
Procedure 
7.3.1 
Subject Enrollment 
Subjects will be considered enrolled in the study after informed consent has been obtained and 
the Alterra procedure has begun (defined as the time of vascular access – incision or puncture).  
If these criteria are not met, the candidate will be considered a Screen Failure. 
7.3.2 
Recommended Concomitant Medical Therapy 
Table 2 outlines the recommended concomitant medical therapy.  It is expected that specific 
agents and dosing regimens may vary from site to site.  It is strongly recommended that study 
subjects be treated prophylactically with antibiotics for endocarditis per the recommendation of 
the American Heart Association (9). 
Table 2: Recommended Concomitant Medical Therapy 
Pre-procedure 
Aspirin: 
At least 81 mg within 24 hours prior to procedure 
Intra-procedure 
Antibiotics: 
1st dose prior to or at time of procedure 
Heparin: 
To achieve/maintain activated clotting time (ACT) ≥ 250 sec 
Post-procedure 
Antibiotics: 
2nd dose 8 hours after first dose 
 
3rd dose 8 hours following the 2nd dose 
Prophylaxis for life 
Aspirin: 
At least 81 mg once daily for life 
 
7.3.3 
Implant Procedure 
It is strongly encouraged that the Alterra procedure be performed within 14 days of case review 
approval. 
Alterra may be implanted during the same procedure as the THV or in a separate, staged 
procedure.  If staged, the valve implant procedure should take place no more than 3 months after 
the Alterra procedure. 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 20 of 51 
The Instructions for Use (IFU) will be included with each shipment of the investigational devices.  
Study devices and accessories will be used per the most current labeling at all times.  Only 
physicians appropriately trained to the use of the device and identified on the Delegation of 
Authority (DoA) log on file with Edwards may perform the implant procedures in study subjects. 
Pre-implantation, the following assessments should be performed: 
• 
Angiogram to evaluate coronary artery patency and aortic root configuration 
• 
Intracardiac echocardiography (ICE) to assess native valve function, regurgitation, and 
native leaflet location and length (if present) 
Post-implantation, the following assessments should be performed: 
• 
Angiogram: 
o Evaluate deployment and positioning of the Alterra 
o Evaluate THV function and position within Alterra 
• 
Invasively measure RV-PA peak-to-peak gradient, pulmonary artery pressure (PAP) and 
right atrium pressure (RAP) 
• 
ICE to assess THV function, regurgitation, and native leaflet location and length (if 
present) 
 
7.4 
Discharge 
The following data will be collected for all subjects at discharge or within 48 hours prior to 
discharge, unless noted otherwise: 
• 
Medications:  Antithrombotics, antiarrhythmics, heart failure medications, antibiotics only 
• 
12-Lead ECG 
• 
TTE 
• 
Gated CTA:  Must be performed after the valve implant procedure but prior to the end of 
the 30 days follow up period 
• 
Chest X-Ray (CXR) 
• 
Adverse events assessment 
 
7.5 
Follow-up 
The day of the valve implant procedure will be considered Day 0 and will be used to schedule all 
subsequent visits and calculate visit windows.  Six months is defined as 180 days; one year is 
defined as 365 days. 
7.5.1 
30 days 
The following assessments will be conducted at 30 days post-procedure (+ 14 days): 
• 
Medications:  Antithrombotics, antiarrhythmics, heart failure medications and antibiotics 
only 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 21 of 51 
• 
NYHA Functional Class 
• 
SF-36 health survey 
• 
12-lead ECG 
• 
TTE 
• 
Gated CTA:  Must be performed after the valve implant procedure but prior to the end of 
the 30 days follow up period 
• 
CXR 
• 
Adverse events assessment 
 
7.5.2 
6 months 
The following assessments will be conducted at 6 months post-procedure (+ 14 days): 
• 
Medications:  Antithrombotics, antiarrhythmics, heart failure medications and antibiotics 
only 
• 
NYHA Functional Class 
• 
12-lead ECG 
• 
TTE 
• 
Fluoroscopy 
• 
Adverse events assessment 
 
7.5.3 
12 months 
The following assessments will be conducted at 12 months post-procedure (+ 30 days): 
• 
Medications:  Antithrombotics, antiarrhythmics, heart failure medications and antibiotics 
only 
• 
NYHA Functional Class 
• 
SF-36 health survey 
• 
TTE 
• 
cMRI 
• 
Fluoroscopy 
• 
Adverse events assessment 
 
7.5.4 
Years 2 through 5, 7 and 10 
The following assessments will be conducted at years 2 through 5, 7 and 10 (+ 45 days): 
• 
Medications:  Antithrombotics, antiarrhythmics, heart failure medications and antibiotics 
only 
• 
NYHA Functional Class 
• 
TTE 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 22 of 51 
• 
CXR or fluoroscopy.  For subjects with a previously identified device fracture, 
fluoroscopy must be performed. 
• 
Gated CTA – at years 5 and 10 only 
• 
Adverse events assessment 
 
7.5.5 
Years 6, 8 and 9 
The following assessments will be conducted by telephone or office visit at years 6, 8 and 9 (+ 
45 days): 
• 
Medications:  Antithrombotics, antiarrhythmics, heart failure medications and antibiotics 
only 
• 
Adverse events assessment 
 
7.6 
Imaging Assessments 
Imaging performed during the course of the study (TTE, CTA, cMRI, ICE, CXR, fluoroscopy) 
should follow the applicable Core Lab Manual of Operations. 
If CXR reveals potential device fracture, fluoroscopy should be completed for confirmation.  If 
another radiographic assessment (CT, fluoroscopy) has been performed by which fracture can 
be assessed, then CXR does not need to be performed. 
7.7 
Quality of Life Questionnaires 
QoL will be measured through the following standard survey: 
• 
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. 
Study sites will be provided with paper QoL questionnaires.  Questionnaires will be IRB/EC-
approved prior to use.  Study site personnel will administer questionnaires to subjects at the 
required time points.  Study sites should retain the completed questionnaire in the subjects’ 
medical record. 
 
 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 23 of 51 
An overview of study procedures is summarized in the Schedule of Events in Table 3. 
Table 3: Schedule of Events 
 
Screening/ 
Baseline 
Procedure 
Discharge 
Follow-up 
30 Day 
(+ 14 days) 
6 Month 
(+ 14 days) 
12 Month 
(+ 30 days) 
2-5, 7, 10 Years 
(+ 45 days) 
6, 8 and 9 Years 
(+ 45 days) 11 
Informed Consent 
X 
 
 
 
 
 
 
 
History & Physical 
X 
 
 
 
 
 
 
 
Medications 1 
X 
X 
X 
X 
X 
X 
X 
X 
NYHA Functional Class 
X 
 
 
X 
X 
X 
X 
 
SF-36 Health Survey 
X 
 
 
X 
 
X 
 
 
12-lead ECG 
X 
 
X 
X 
X 
 
 
 
TTE 
X 2 
 
X 
X 
X 
X 
X 
 
Gated CTA 
X 3 
 
X 7 
 
 
X 9 
 
cMRI 
X 4 
 
 
 
 
X 
 
 
CXR 8 
 
 
X 
X 
 
 
X 10 
 
Fluoroscopy 
 
 
 
 
X 
X 
X 10 
 
WBC, Hgb, Hct, Platelets 
X 
 
 
 
 
 
 
 
Serum Creatinine 
X 
 
 
 
 
 
 
 
Pregnancy test 5 
X 
 
 
 
 
 
 
 
INR, if taking Warfarin 
X 
 
 
 
 
 
 
 
Case Review 
X 
 
 
 
 
 
 
 
Alterra Procedure 
 
X 
 
 
 
 
 
 
THV Implant Procedure 6 
 
X 
 
 
 
 
 
 
Pre- and Post-implantation 
Assessments 
 
X 
 
 
 
 
 
 
Adverse Event Assessment 
 
X 
X 
X 
X 
X 
X 
X 
1. 
Antithrombotics, antiarrhythmics, heart failure medications and antibiotics only 
2. 
Must be performed within 90 days prior to the Alterra implant procedure 
3. 
General assessment of RVOT/PV, pulmonary artery and right heart anatomic parameters.  Must be performed 
within 1 year prior to the Alterra implant procedure and meet the defined parameters within the applicable Core 
Lab Manual of Operations. 
4. 
General assessment of RVOT/PV and right heart function.  Must be performed within 1 year prior to the Alterra 
implant procedure and meet the defined parameters within the applicable Core Lab Manual of Operations. 
5. 
If female of childbearing potential only (either urine or serum are acceptable) 
6. 
This may be done in a two-stage approach 
7. 
Must be performed after the valve implant procedure but prior to the end of the 30 days follow up period 
8. 
If CXR reveals potential device fracture, fluoroscopy should be completed for confirmation.  If another 
radiographic assessment (CT, fluoroscopy) has been performed by which fracture can be assessed, then CXR 
does not need to be performed. 
9. 
At years 5 and 10 only 
10. CXR or fluoroscopy.  For subjects with a previously identified device fracture, fluoroscopy must be performed. 
11. Telephone or office visit 
 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 24 of 51 
7.8 
Missed Visits / Subject Discontinuation 
7.8.1 
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, multiple attempts to contact the subject should be 
made and details recorded in source documentation 
7.8.2 
Subject Discontinuation 
Every subject should remain in the study until completion of the required follow-up period; 
however, a subject’s participation may be discontinued.  Should this occur, the reason for 
discontinuation should be documented in the subject’s medical record.  Potential reasons for 
discontinuation may include, but are not limited to the following: 
• 
Subject Withdrawal:  Subject participation in a clinical trial is voluntary and the subject 
may discontinue participation (refuse all subsequent testing/follow-up) at any time 
without loss of benefits or penalty. 
• 
Investigator Termination:  The investigator may terminate the subject’s participation 
without regard to the subject’s consent if the investigator believes it is medically 
necessary 
• 
Investigational Device Never Implanted:  Subjects considered enrolled but the Alterra 
Adaptive Prestent was never implanted will be followed for 30 days or until resolution of 
any adverse events related to the study implant procedure, whichever is later, and then 
exited from the study. 
• 
Investigational Device Explanted:  Subjects who have the study valve explanted (e.g., 
valve replaced due to endocarditis or subject growth requiring larger valve) will be 
followed for 30 days post-explant or until resolution of any adverse events related to the 
procedure, whichever is later, and then exited from the study. 
• 
Lost-to-Follow-up:  A subject is not considered lost-to-follow up until the full 10 years of 
follow-up have elapsed. 
 
Subjects that have valvuloplasty or valve-in-valve procedure will continue to be followed for the 
duration of the study. 
Subjects who discontinue prematurely will be included in the analysis of results and will not be 
replaced. 
For subjects that are lost-to-follow-up or withdraw early, Edwards may request the site to search 
the Social Security Death Index and/or other death registries and may request the site to obtain 
the death certificate, if applicable. 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 25 of 51 
8 
ADVERSE EVENTS 
8.1 
Adverse Event 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 investigational medical device. 
AEs may be volunteered by subjects, elicited by the Investigator or designee, the Clinical Events 
Committee (CEC), safety team, monitoring team, or collected via observation by the Investigator.  
In addition, subjects should be instructed to contact the investigator, and/or study coordinator if 
any significant AEs occur between study visits. 
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 if it meets serious criteria.  If it is determined that an 
AE has occurred, the investigator should obtain all the information required to complete the AE 
electronic Case Report Form (eCRF). 
A Serious Adverse Event (SAE) is any AE that: 
• 
led to death 
• 
led to a 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 
o in-patient or prolonged hospitalization, or 
o medical or surgical intervention to prevent life threatening illness or injury or 
permanent impairment to a body structure or a body function 
• 
led to fetal distress, fetal death or a congenital abnormality or birth defect 
• 
Important medical event:  Important medical events that do not meet the above criteria 
may still be considered an SAE if they seriously jeopardize the subject and require 
immediate medical or surgical intervention to prevent one of the aforementioned 
outcomes. 
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 subjects. 
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 due to 
the device or study related procedure, then an AE must be recorded. 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 26 of 51 
Death should not be recorded as an AE, but should only be reflected as an outcome to another 
specific AE. 
8.2 
AE Reporting Requirements 
All AEs will be captured from the time of enrollment until subject participation has ended (i.e. 
completion of study or subject discontinuation).  AEs must be followed until resolution, 
stabilization or study completion.  Expected, non-clinically significant events such as non-
significant lab variances are not required to be reported. 
AE information must be entered into the EDC.  When EDC system is not available/accessible, AE 
information must be reported directly via email to THV_Safety@edwards.com, copying the Safety 
Officer of the study. 
At the time of initial notification, the following minimal information must be provided: 
• 
Study site 
• 
Subject ID 
• 
AE description 
• 
Causal relationship to device and implant procedure 
• 
Aware date 
 
The site Principal Investigator is responsible for informing the IRB/EC of SAEs, UADE and/or AEs, 
as required.  A copy of this report should be provided to Edwards Lifesciences (or designee). 
Enrolling sites must provide to the Sponsor at a minimum an index hospitalization admission 
history and physical, implant procedure report, discharge summary, and relevant 
echocardiographic reports for all enrolled subjects.  This will be done irrespective of subject 
having any AE/SAE. 
The site will provide a copy of supporting documentation (example: admission H&P, index 
procedure reports, anesthesia records, discharge summary, echocardiogram and ECG reports, 
laboratory results, etc.) for all endpoint-related events, device and procedure-related events, and 
UADEs to Edwards Lifesciences (or designee).  Source documentation may be requested by the 
Edwards Safety Officer for other AEs that may meet potential complaint reporting criteria or in 
order to verify that events are being assessed appropriately. 
All AEs must be reported to Edwards Lifesciences within 10 working days of the site becoming 
aware of the event. 
Edwards Lifesciences will notify FDA, all participating investigators and participating IRBs/ECs of 
all UADEs that occur during this study within 10 working days of the Sponsor becoming aware of 
the event.  Investigators are responsible for reviewing information received about UADEs. 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 27 of 51 
8.3 
Investigator Assessment 
For each AE, the investigator will determine whether the event is related to the device and/or the 
procedure, and whether the event meets the definition of a SAE or UADE as outlined in Section 
8.1. 
The causal relationship of the event to the device and the procedure will be categorized as follows: 
• 
None:  The event is not associated with the device or procedure.  There is no relation 
between the event and the device or procedure. 
• 
Possibly Related:  The temporal sequence between the device or procedure and the 
event is such that the relationship is not unlikely or there is no contradicting evidence 
that can reasonably explain the study subject’s condition.  There is a possibility of any 
relation between the event and the device or 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 
subject’s condition or comorbidities.  The event is related or most likely associated with 
the device or procedure. 
 
8.4 
Sponsor Assessment 
All AEs will be reviewed by the Edwards Safety Officer.  Each AE will be assessed as to its 
relationship to the study device and/or procedure, whether it was anticipated or not anticipated, 
based on the list of anticipated events provided in Section 9.2, and whether it qualifies as an SAE 
and/or UADE. 
8.5 
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.  Device malfunctions may or may not be associated with an 
AE. 
Any clinical events or sequelae resulting from fractures of either the SAPIEN 3 THV or Alterra 
Adaptive Prestent will be recorded as an AE. 
Device malfunctions should be reported to Edwards Lifesciences within 10 working days of the 
site becoming aware of the event. 
 
 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 28 of 51 
9 
RISK / BENEFIT ANALYSIS 
9.1 
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 Alterra Adaptive Prestent and SAPIEN 3 THV are not known at the 
present time.  Alternative treatments include palliative medical therapy, commercially available 
percutaneous pulmonic valve implantation and surgical pulmonic valve replacement. 
9.2 
Risks 
The potential risks associated with this study can be grouped into two categories.  There are the 
potential risks associated with anesthesia and interventional procedures used to deliver and 
deploy the devices.  There are the additional potential risks uniquely associated with the use 
of the Alterra Adaptive Prestent, SAPIEN 3 THV and the delivery systems. 
Potential risks associated with the overall procedure including access, cardiac catheterization, 
balloon-sizing, local and/or general anesthesia include but are not limited to: 
• 
Allergic reaction to anesthesia, contrast media, antithrombotic therapy, device materials 
• 
Anemia 
• 
Angina 
• 
Arrhythmia 
• 
Arteriovenous fistula 
• 
Atelectasis 
• 
Blood loss requiring transfusion 
• 
Cardiac failure 
• 
Cardiovascular or vascular injury, such as perforation or damage (dissection) of vessels, 
myocardium, or valvular structures including rupture of the pulmonary RVOT that may 
require intervention 
• 
Conduction system injury 
• 
Death 
• 
Deep vein thrombosis 
• 
Dislodgement of previously implanted devices (i.e. pacing lead) 
• 
Electrolyte imbalance 
• 
Embolic event: air, calcific material, thrombus 
• 
Exercise intolerance or weakness 
• 
Fever 
• 
Hematoma or ecchymosis 
• 
Hypertension or hypotension 
• 
Infection including incisional site infection, septicemia and endocarditis 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 29 of 51 
• 
Inflammation 
• 
Myocardial infarction 
• 
Pain 
• 
Pericardial effusion/cardiac tamponade 
• 
Pleural effusion 
• 
Pneumothorax 
• 
Pulmonary edema 
• 
Radiation Injury 
• 
Renal insufficiency or renal failure 
• 
Respiratory insufficiency or respiratory failure 
• 
Stroke/transient ischemic attack 
• 
Syncope 
• 
Systemic or peripheral ischemia 
• 
Systemic or peripheral nerve injury 
 
In addition to the risks listed above, additional potential risks associated with the use of Alterra, 
SAPIEN 3 THV, the delivery systems and/or accessories include, but may not be limited to, the 
following: 
• 
Aortic root distortion 
• 
Cardiac arrest 
• 
Cardiogenic shock 
• 
Chest pain/discomfort 
• 
Coronary flow obstruction/transvalvular flow disturbance 
• 
Device dysfunction (regurgitation and/or stenosis) 
• 
Device embolization 
• 
Device fracture 
• 
Device migration or malposition 
• 
Device thrombosis  
• 
Dyspnea 
• 
Embolic event: device fragments 
• 
Emergent and non-emergent reintervention 
• 
Endocarditis 
• 
Hemolysis/hemolytic anemia 
• 
Injury to tricuspid valve/chordae resulting in tricuspid regurgitation 
• 
Mechanical failure of the delivery system and/or accessories 
 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 30 of 51 
9.2.1 
Risk Minimization 
Product handling and 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. 
A complete regimen of testing has been conducted on the Alterra Adaptive Prestent model 
29AP4045, delivery system, and accessories to verify the performance of the devices and to 
demonstrate adequate safety and effectiveness for their use in the trial.  Testing was performed 
in accordance with applicable international standards, relevant FDA guidance documents, and 
specifications based on clinical relevance. 
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 transcatheter aortic valve replacement in the US and countries that honor the CE 
mark. 
 
 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 31 of 51 
10 STATISTICAL CONSIDERATIONS 
10.1 Sample Size Calculations 
The primary safety and effectiveness endpoint for the main cohort is THV dysfunction at 6 months.  
THV dysfunction is defined as a non-hierarchical composite of the following events: 
• 
RVOT/PV reintervention 
• 
Moderate or greater total PR via TTE 
• 
Mean RVOT/PV gradient ≥ 35 mmHg via TTE 
 
The observed percentage of subjects with THV dysfunction at 6 months and a two-sided exact 
binomial 95% confidence interval (CI) will be calculated. 
If the true rate of THV dysfunction is 7.4% or less and the performance goal is set to 25%, then a 
sample of 38 subjects will yield at least 85% power to detect this difference at a one-sided 
significance level of 0.025 (i.e. the upper limit of the two-sided 95% CI is less than the performance 
goal, 25%).  The total enrolled sample size will be up to 60 subjects to account for trial 
contingencies. 
Power 
Enrolled 
Sample Size 
Observable 
Sample Size 
Performance 
Goal 
True 
Rate 
Target 
Alpha 
Alpha 
Beta 
0.8531 
60 
38 
0.2500 
0.0740 
0.0250 
0.0235 
0.1469 
 
Sample size calculations were performed using PASS 13’s power analysis of one proportion using 
an exact test and a one-sided alternative (11). 
10.2 Analysis Populations 
The All Treated (AT) population is defined to include all enrolled subjects.  Subjects will be 
considered enrolled in the study after informed consent has been obtained and the Alterra 
procedure has begun (defined as the time of vascular access – incision or puncture). 
The Attempted Implant (AI) population is defined as all AT subjects who had an attempted implant 
of the Alterra.  Subjects will be considered to have an attempted implant at the time in which the 
introducer sheath for vascular delivery of the Alterra is inserted. 
The Valve Implant (VI) population will consist of all AI subjects who received and retained the 
SAPIEN 3 THV upon leaving the catheterization laboratory/hybrid suite. 
 
 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 32 of 51 
10.3 Primary Endpoint Analysis 
Main Cohort: 
The primary endpoint is THV dysfunction at 6 months.  THV dysfunction is defined as a non-
hierarchical composite of: 
• 
RVOT/PV reintervention 
• 
Moderate or greater total PR via TTE (as assessed by Echo Core Lab) 
• 
Mean RVOT/PV gradient ≥ 35 mmHg via TTE 
 
The observed proportion with THV dysfunction and a two-tailed exact binomial 95% CI will be 
calculated for the composite endpoint as well as each of the individual components. 
A performance goal of 25% was pre-specified for the 6-month rate.  The hypothesis for the primary 
endpoint is as follows: 
H0: πAlterra ≥ 25% 
HA: πAlterra < 25% 
 
Where πAlterra represents the proportion of subjects with THV dysfunction at 6 months.  If the upper 
95% confidence limit for the composite event is less than 25%, the performance goal will have 
been met. 
The primary endpoint will be evaluated on the VI population. 
PDS Registry: 
The primary endpoint is Acute PDS Success, defined as a non-hierarchical composite of: 
• 
Single THV implanted in the desired location 
• 
RV-PA peak-to-peak gradient < 35 mmHg post-THV implantation 
• 
Less than moderate total PR by discharge TTE (or earliest evaluable TTE) 
• 
Free of SAPIEN 3 / Alterra explant at 24 hours post-implantation 
 
No formal hypothesis testing will be conducted.  Data will be analyzed by descriptive summary 
tables only. 
10.4 Center Poolability 
The center effect and center-poolability will be evaluated using a Fisher’s exact test on the 
contingency table of main cohort primary endpoint by center at alpha level of 0.15.  Once 
confirmed that there is no qualitative center effect, data from all centers will be combined for 
analysis. 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 33 of 51 
10.5 Endpoints for Labeling 
A hierarchical gatekeeping approach will be used to control the overall type I error between the 
primary endpoint and the secondary endpoint analyses.  If the null hypothesis for the primary 
endpoint is rejected, testing of the endpoint for labeling will proceed using a one-sided α=0.025.  
If the primary endpoint’s null hypothesis is not rejected, testing the endpoint for labeling will not 
occur. 
10.5.1 Improvement in Total PR from Baseline to 30 Days 
Total PR at baseline and 30 days will be presented.  The change in total PR from baseline to 30-
days will be tested using a Wilcoxon Signed Rank Test using the following hypothesis: 
H0: DPR ≥ 0 
HA: DPR < 0 
 
Where DPR represents the difference in total PR from baseline to 30 days.  In order to calculate 
the difference, a numerical value will be assigned to each level. 
0 = None 
1 = Trace 
2 = Mild 
3 = Moderate 
4 = Severe 
 
For each subject, the difference between the value at baseline and 30 days will be calculated (30-
days - baseline).  Evaluation of the null hypothesis will be done using a Wilcoxon signed rank test 
on the VI population and the p-value will be presented. 
10.6 Additional Safety and Effectiveness Outcomes 
All clinically relevant baseline and follow-up variables will be tabulated.  Descriptive statistics will 
be used for continuous variables (e.g., mean, standard deviation, sample size, minimum, and 
maximum) and frequency tables or proportions for discrete variables.  Kaplan-Meier (KM) 
estimates will be performed at the pre-specified follow-up times to project the estimates for time-
related safety endpoints. 
 
 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 34 of 51 
11 STUDY ADMINISTRATION 
11.1 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 appropriate regulatory requirements. 
Edwards Lifesciences will be responsible for obtaining Investigational Device Exemption (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 subjects 
are being properly consented and the study is being conducted according to the protocol.  
Edwards will notify investigative sites of enrollment closure. 
As appropriate, Edwards Lifesciences will submit changes in the Investigational Plan to the FDA 
and investigators to obtain FDA/IRB/EC re-approval. 
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 investigator list, annual progress reports, recall information, final reports and protocol 
violations. 
11.2 Steering Committee 
A Steering Committee will be selected to provide oversight and medical expertise to the study. 
11.3 Case Review Board 
The Case Review Board will be comprised of a subset of Investigators who are participating in 
the study.  The role of the Case Review Board is to review submitted cases to determine if the 
subject is an appropriate candidate for the study, with a focus on confirming appropriate anatomy 
for device size and vascular access, and any relevant clinical factors impacting enrollment 
eligibility. 
11.4 Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will review study data, evaluate trends in 
reported AEs and any potential changes in risk assessment, and make recommendations to 
Edwards regarding safety issues and risks to research subjects as well as the continuing validity 
and scientific merit of the study.  DSMB oversight will occur minimally through enrollment 
completion.  DSMB activities are defined in the DSMB Charter. 
11.5 Clinical Events Committee 
An independent CEC will adjudicate endpoint events and device- and procedure-related AEs as 
determined by site and/or Edwards Safety Officer.  The CEC will include cardiologists and 
cardiothoracic surgeons with experience in the field of CHD pulmonary homografts who are not 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 35 of 51 
involved in the study and have no significant conflict of interest.  CEC activities will be defined in 
the CEC Charter. 
11.6 Study Procedures 
11.6.1 Investigational Site Selection 
Edwards Lifesciences will select investigators based on training and experience.  Up to 25 
investigational sites in the US and Canada will enroll subjects. 
11.6.2 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 device IFU, study protocol, case 
review process, identification of eligible subjects, instructions on data collection, standardized 
image acquisition, 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 with copies sent to Edwards. 
Training may be provided in one of the following formats: in-person training sessions, 
teleconference, online meeting applications, or read and review.  Retraining may be performed 
for sites who have demonstrated protocol or implant procedure compliance issues. 
11.6.3 Echocardiography 
An independent echocardiographic core lab will review and analyze echocardiographic images.  
A standardized protocol for acquiring images and training will be provided to the clinical sites prior 
to enrollment start. 
11.6.4 Radiographic Imaging 
A central lab will independently review and analyze CTA, cMRI, CXR and fluoroscopic images.  
Analysis will include an assessment of RVOT/PA anatomy, ventricular function, PR, possible 
fracture of either the SAPIEN 3 valve or the Alterra Adaptive Prestent.  Standardized protocols 
for acquiring images and training will be provided to the clinical sites prior to enrollment start. 
11.6.5 Image Management 
A image transfer vendor will receive, maintain, and provide echocardiographic and radiographic 
images to the core labs for analysis. 
Instructions for image uploads will be provided to investigative staff prior to enrollment start.  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. 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 36 of 51 
11.6.6 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. 
11.7 Device Management 
11.7.1 Study Devices 
All products will be supplied by Edwards.  Each Alterra Adaptive Prestent and SAPIEN 3 THV will 
have a unique identifier, which should be recorded in the subject’s medical file. 
11.7.2 Device Storage 
All components should be stored in a secure location where only study personnel can access the 
device for use. 
11.7.3 Device Accountability 
The study site will maintain detailed records of the receipt and disposition of all investigational 
devices.  Device disposition will be verified by the clinical monitor periodically throughout the 
study.  The Investigator will return unused devices to the Sponsor at completion of enrollment.  
Use of the investigational devices and accessories provided for use in the study is prohibited 
outside of this protocol. 
11.8 Data Management 
This study will use a secure, password protected 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 one week 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 must ensure the accuracy and completeness of the recorded data 
and then 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. 
11.9 Monitoring Procedures 
All 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 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. 
 
 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 37 of 51 
11.10 Site Discontinuation 
Edwards has the right to discontinue an Investigator or study site for the following reasons: 
• 
Failure of the Investigator to enroll patients into the study at an acceptable rate 
• 
Failure of the Investigator to comply with pertinent regulations of appropriate regulatory 
authorities 
• 
Insufficient adherence to protocol requirements 
• 
Submission of knowingly false information from the research facility to the Sponsor, 
Study Monitor, or appropriate regulatory authority. 
If a study site is discontinued, subjects enrolled prior to discontinuation will continue to be followed 
per the protocol. 
11.11 Auditing 
The study may be subject to a quality assurance audit by Edwards Lifesciences or a designee, 
as well as inspection by 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. 
11.12 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. 
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) and in compliance with Title 21 
Code of Federal Regulations (CFR) Parts 11, 50, 54, 56, 812 and Good Clinical Practices. 
12.2 Institutional Review Board/Ethics Committee 
This protocol, the proposed ICF, other written subject information and any proposed advertising 
material must be submitted to the IRB/EC for written approval.  A copy of the written IRB/EC 
approval of the protocol and ICF must be received by Edwards Lifesciences before recruitment 
of subjects 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. 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 38 of 51 
The investigator is responsible for obtaining annual IRB/EC approval and renewal throughout the 
duration of the study.  Copies of the investigator’s reports and the IRB/EC continuance of approval 
must be sent to Edwards Lifesciences. 
12.3 Subject 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 Title 21 CFR Part 50 and current GCP 
guidelines.  Edwards Lifesciences must approve the site-specific ICF prior to submission to the 
IRB/EC; the reviewing IRB/EC must approve the ICF before use at that site.  The ICF documents 
should be translated into the languages understandable to potential subject populations. 
Before participating in the clinical trial, each subject/ subject’s legal guardian 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/ subject’s legal guardian.  The subject/ subject’s legal guardian 
must also be given the opportunity to ask questions and have those questions answered to his/her 
satisfaction. 
A copy of each subject’s signed consent form must be maintained by each investigator.  A signed 
copy of the consent form must be given to each subject/ subject’s legal guardian.  The consent 
process must be documented in the subject’s medical chart; at minimum, the documentation 
should include that consent was obtained prior to participation in the study, date consent was 
obtained, and confirmation that a copy of the consent was given to the subject. 
Any modifications to the site-specific ICF must be approved by Edwards Lifesciences and the 
IRB/EC. 
Once the subject reaches 18 years of age (or adult age as defined by state or local laws), a new 
ICF must be obtained (if study participation is on-going).  If the subject refuses to sign a new ICF, 
they will be withdrawn from the study. 
12.4 Confidentiality 
All data used in the analysis and reporting of this evaluation will be without identifiable reference 
to the subject.  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. 
12.5 Investigator Records 
Records to be maintained by the investigator include, but are not limited to, the following: 
• 
Clinical trial protocol and all amendments 
• 
Signed Clinical Trial Agreement and any amendments 
• 
IRB/EC approval letters, including continuing reviews and all amendments/changes 
• 
IRB/EC-approved informed consent documents 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 39 of 51 
• 
All correspondence with another Investigator, IRB/EC, Edwards, monitor or FDA, 
including required reports 
• 
Records of receipt, use or disposition of a device 
 
The following records must be maintained for each subject enrolled in the trial: 
• 
Signed ICF 
• 
All relevant source documentation for study visits and study-related procedures 
• 
Supporting documentation of any AEs 
 
All enrolling sites will maintain the study records for a period of two years after the latter of the 
following two dates:  The date on which the investigation is terminated or completed, or the date 
that the records are no longer required for purposes of supporting a premarket approval 
application. 
12.6 Investigator Reports 
AE reporting requirements are discussed in Section 8.2. 
Withdrawal of IRB/EC approval.  Within 5 working days, the Principal Investigator will report to 
Edwards Lifesciences a withdrawal of approval by the reviewing IRB/EC 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/EC within 5 
working days after the issue is identified. 
Progress Reports.  The Principal Investigator will submit progress reports on the investigation to 
Edwards Lifesciences and the IRB/EC 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/EC as required by the regulations.  The 
report must be submitted within 3 months of completion or termination of the trial. 
12.7 Protocol Amendments 
The protocol can be altered only by written amendments made by Edwards.  The amended 
protocol will be submitted to the required regulatory agencies, as applicable, before being 
distributed to sites.  Each site must obtain IRB/EC approval and complete required training (if any, 
and as required by DoA role). 
12.8 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 do not require 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 40 of 51 
prior approval but must be reported to Edwards Lifesciences and the reviewing IRB/EC within 5 
days of the incident. 
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/EC per local guidelines 
and government regulations. 
 
 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 41 of 51 
APPENDIX A: Abbreviations 
Abbreviation 
Full Term 
ACT 
Activated Clotting Time 
AE 
Adverse Event 
AI 
Attempted Implant 
AT 
All Treated 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CHD 
Congenital Heart Defects 
CI 
Confidence Interval 
cMRI 
Cardiac Magnetic Resonance Imaging 
CTA 
Computed Tomography Angiography 
CXR 
Chest X-Ray 
DoA 
Delegation of Authority 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
Echo 
Echocardiogram 
FDA 
Food and Drug Administration 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
ICE 
Intracardiac Echocardiogram 
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption 
IFU 
Instructions for Use 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
KM 
Kaplan-Meier 
NYHA 
New York Heart Association 
PA 
Pulmonary Artery 
PAP 
Pulmonary Artery Pressure 
PDS 
Pulmonic Delivery System 
PET 
Polyethylene Terephthalate 
PR 
Pulmonary Regurgitation 
PV 
Pulmonary Valve 
RAP 
Right Atrium Pressure 
RV 
Right Ventricle 
RVOT 
Right Ventricular Outflow Tract 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 42 of 51 
Abbreviation 
Full Term 
SAE 
Serious Adverse Event 
SF 
Short Form 
THV 
Transcatheter Heart Valve 
TIA 
Transient Ischemic Attack 
TPV 
Transcatheter Pulmonic Valve 
TPVI 
Transcatheter Pulmonic Valve Implantation 
TR 
Tricuspid Regurgitation 
TTE 
Transthoracic Echocardiogram 
UADE 
Unanticipated Adverse Device Effect 
VARC 
Valve Academic Research Consortium 
VI 
Valve Implant 
WBC 
White Blood Cell 
 
 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 43 of 51 
APPENDIX B: Definitions 
Term 
Definition 
Reference 
Acute Kidney 
Injury 
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) 
compared with baseline, within 48 days of the index procedure 
VARC-2 
(12) 
Access Site 
Any location (arterial or venous) traversed by a guidewire, a catheter 
or a sheath  
VARC-1  
(13) 
Access site 
related 
complication 
Any adverse clinical consequence possibly associated with any of the 
access sites used during the procedure 
VARC-1  
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 
Aortic Root 
Compression 
Aortic Root Compression (ARC) can occur during balloon sizing of the 
RVOT or during coronary compression testing (BS/CCT) prior to TPVI, 
causing aortic valve dysfunction and/or root distortion with or without 
coronary compression. 
(14) 
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 
Bleeding Event 
Bleeding, including, but not limited to fatal bleed, bleeding associated 
with transfusion, drop in Hgb or visible sign of blood loss 
Sponsor 
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 
Cardiopulmonary 
bypass (CPB) 
Bypass of the function of the heart and lungs as in open heart surgery 
Sponsor 
Conversion to 
open surgery 
Any conversion to complete TPVI procedure secondary to any 
procedure-related complications  
Sponsor 
Coronary artery 
compression 
Angiographic or echocardiographic evidence of a new, partial or 
complete, compression of a coronary artery, associated with the TPVI 
procedure 
Sponsor 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 44 of 51 
Term 
Definition 
Reference 
Device Fracture 
 
Type I 
Wire fracture(s) without loss of frame integrity1 or 
hemodynamic dysfunction2 
Type IIa 
Wire fracture(s) resulting in loss of frame integrity1 
without hemodynamic dysfunction2 or embolization  
Type IIb 
Wire fracture(s) resulting in loss of frame integrity1 
resulting in hemodynamic dysfunction2 without 
embolization 
Type IIIa 
Wire fracture(s) with fragment separation resulting in 
embolization without hemodynamic dysfunction2 
Type IIIb 
Wire fracture(s) with fragment separation resulting in 
embolization and hemodynamic dysfunction2 
1 Significant deformation (e.g., partial collapse, in-folding, fragmentation, etc.) or 
instability of a stent segment resulting in an increased risk of future hemodynamic 
dysfunction and/or embolization (Type IIa) or hemodynamic dysfunction (Type IIb) 
2 Increase in mean gradient ≥10 mmHg resulting in mean gradient ≥35 mmHg, or new 
occurrence or increase of ≥1 grade of total pulmonary regurgitation resulting in ≥ 
moderate pulmonary regurgitation as compared to most recent echocardiographic 
assessment prior to stent fracture 
Sponsor 
Device Success 
Device Success is defined as a composite of: 
• 
Single Alterra deployed into the desired location and 
• 
Single THV implanted in the desired location within the 
Alterra (staged procedures allowed) and 
• 
Right ventricle to pulmonary artery (RV-PA) peak-to-
peak gradient < 35 mmHg post-THV implantation and 
• 
Less than moderate total PR by discharge TTE (or 
earliest evaluable TTE) and 
• 
Free of explant at 24 hours post-implantation 
Sponsor 
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 
Embolism 
Embolism is defined as a free-flowing blood clot or lesion material that 
is located in the systemic or pulmonary circulation that occurs in the 
absence of infection after immediate perioperative period. 
Pulmonary embolic event is an operative, autopsy or clinically 
documented embolus that produces symptoms from complete or 
partial obstruction of a pulmonary or bronchial artery 
STS 
alignment 
Explant 
Removal of the Alterra for any reason 
Sponsor 
Index Procedure 
Placement of Alterra Adaptive present study device and/or additional 
procedures (ex. placement of Sapien 3 valve) occurring in the catheter 
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.) 
Sponsor 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 45 of 51 
Term 
Definition 
Reference 
Mortality 
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 
VARC-2 
Non-cardiovascular mortality 
Any death in which the primary cause of death is clearly related to 
another condition (e.g. trauma, cancer, suicide) 
Myocardial 
Infarction 
An acute ischemic event that is associated with documented and 
clinically significant myocardial necrosis. 
STS 
New York Heart 
Association 
Classification 
(NYHA) 
Class I: Patients with cardiac disease but resulting in no limitation of 
physical activity 
Class 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 
Class III: Patients with cardiac disease resulting in marked limitation 
of physical activity.  They are comfortable at rest.  Less than 
ordinary physical activity causes fatigue, palpitation, 
dyspnea, or anginal pain 
Class 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 increases 
NYHA 
Other TPVI-
Related 
Complications 
Conversion to open surgery 
Conversion to open sternotomy during the TPVI procedure secondary 
to any procedure-related complications 
VARC-2 
alignment 
Unplanned use of cardiopulmonary bypass (CPB) 
Unplanned use of CPB for hemodynamic support at any time during 
the TPVI procedure. 
VARC-2 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 46 of 51 
Term 
Definition 
Reference 
Coronary artery compression 
Angiographic or echocardiographic evidence of a new, partial or 
complete, compression of a coronary artery, associated with the TPVI 
procedure 
Aligned from VARC-2 definition for Coronary Obstruction 
VARC-2 
alignment 
Ventricular septal perforation 
Angiographic or echocardiographic evidence of a new septal 
perforation during or after the TPVI procedure 
VARC-2 
alignment 
Tricuspid valve apparatus damage or dysfunction 
Angiographic or echocardiographic evidence of new damage 
(chordae papillary muscle, or to the leaflet) to the tricuspid valve 
apparatus or dysfunction (e.g. restrictions due to the THV) of the 
tricuspid valve during or after the TPVI procedure 
VARC-2 
alignment 
Cardiac tamponade 
Evidence of a new pericardial effusion associated with hemodynamic 
instability and clearly related to the TPVI procedure 
VARC-2 
alignment 
Endocarditis 
Any one of the following: 
• 
Fulfillment of the Duke endocarditis criteria (15) 
• 
Evidence of abscess, paravalvular leak, pus, or 
vegetation confirmed as secondary to infection by 
histological or bacteriological studies during a re-
operation 
• 
Findings of abscess, pus, or vegetation involving a 
repaired or replaced valve during an autopsy 
VARC-2 
Pulmonary 
Hypertension 
Resting mean PA pressure of greater than 25 mmHg and greater than 
30 mmHg during exercise or when the pulmonary vascular resistance 
is greater than 4 woods units. 
(16) 
Severe:  Primary or secondary pulmonary hypertension with PA 
systolic pressures greater than 2/3 of systemic pressure 
VARC-2 
Pulmonary 
Regurgitation 
Regurgitation of blood through (transvalvular) and/or around 
(paravalvular) the pulmonary valve 
ASE (17) 
Criteria for Defining Pulmonary Regurgitation by TTE 
Grade 
Jet Width at its Origin 
(Diameter of Pulmonary Annulus) 
None/Trace 
Not quantifiable or within the error of the methods 
Mild 
5-30 % 
Moderate 
30-64 % 
Severe 
≥ 65 % 
Echo Core 
Lab 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 47 of 51 
Term 
Definition 
Reference 
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 pulmonary valvuloplasty 
• 
Transcatheter pulmonic valve implantation 
• 
Surgical pulmonary valve replacement 
• 
Valve in valve 
• 
Paravalvular leak closure 
Sponsor 
RVOT Stenosis/ 
Obstruction 
Narrowing of the pulmonary artery and/or valve leading to diminished 
blood flow.  Pulmonary stenosis is rated on the severity of the stenosis 
based on the following criteria: 
RVOT obstruction is defined as a peak gradient > 45 mmHg and/or 
right ventricle pressure to systemic pressure ratio of more than 70%: 
Criteria for Defining Pulmonary Stenosis 
Severity 
Peak Gradient (mmHg) 
Mild 
≤ 30 
Moderate 
31-45 
Severe 
> 45 
ACC/AHA 
Congenital
, (18) 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 48 of 51 
Term 
Definition 
Reference 
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 
• 
Stroke – Duration of a focal or global neurological 
deficit ≥24 h; OR <24 h if available neuroimaging 
documents a new hemorrhage or infarct; OR the 
neurological deficit results in death 
• 
TIA – Duration of a focal or global neurological deficit 
<24 h, any variable neuroimaging does not 
demonstrate a new hemorrhage or infarct 
• 
No other readily identifiable non-stroke cause for the 
clinical presentation (e.g. brain tumor, trauma, 
infection, hypoglycemia, 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: 
o Neurologist or neurosurgical specialist 
o Neuroimaging procedure (CT scan or brain 
MRI), but stroke may be diagnosed on clinical 
grounds alone 
VARC-2 
Stroke Classification: 
• 
Ischemic – An acute episode of focal cerebral, spinal, 
or retinal dysfunction caused by infarction of central 
nervous system tissue 
• 
Hemorrhagic – An acute episode of focal or global 
cerebral or spinal dysfunction caused by 
intraparenchymal, intraventricular or subarachnoid 
hemorrhage 
• 
A stroke may be classified as undetermined if there is 
insufficient information to allow categorization as 
ischemic or hemorrhagic 
* Patients with non-focal global encephalopathy will not be reported 
as a stroke without unequivocal evidence of cerebral infarction-based 
upon neuroimaging studies (CT scan or Brain MRI). 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 49 of 51 
Term 
Definition 
Reference 
Syncope 
A temporary loss of consciousness due to generalized cerebral 
ischemia 
 
Vascular injury  
Injury that may be caused by a guidewire, vascular sheath, delivery 
catheter, or any balloon used for pulmonic 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/Stent 
malpositioning 
Valve/Stent migration 
• 
After initial correct positioning, the valve or stent 
prosthesis moves upward or downward >4 mm within 
the landing zone from its initial position, with or without 
consequences 
Valve/Stent embolization 
• 
The valve or stent prosthesis moves during or after 
deployment such that it loses contact with the landing 
zone 
Ectopic valve/stent deployment 
• 
Permanent deployment of the valve or stent prosthesis 
in a location other than the intended location in the 
pulmonary artery 
Sponsor/ 
VARC-2 
 
 
 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 50 of 51 
APPENDIX C: References 
 
1. 
Lurz P, Coats L, Khambadkone S, Nordmeyer J, Boudjemline Y, Schievano S, et al. 
Percutaneous pulmonary valve implantation: impact of evolving technology and learning 
curve on clinical outcome. Circulation. 2008;117(15):1964-72. 
2. 
Bonhoeffer P, Boudjemline Y, Qureshi SA, Le Bidois J, Iserin L, Acar P, et al. 
Percutaneous insertion of the pulmonary valve. Journal of the American College of 
Cardiology. 2002;39(10):1664-9. 
3. 
Tweddell JS, Pelech AN, Frommelt PC, Mussatto KA, Wyman JD, Fedderly RT, et al. 
Factors affecting longevity of homograft valves used in right ventricular outflow tract 
reconstruction for congenital heart disease. Circulation. 2000;102(suppl 3):Iii-130. 
4. 
Homann M, Haehnel JC, Mendler N, Paek SU, Holper K, Meisner H, et al. Reconstruction 
of the RVOT with valved biological conduits: 25 years experience with allografts and 
xenografts. European journal of cardio-thoracic surgery. 2000;17(6):624-30. 
5. 
Cribier A, Eltchaninoff H, Bash A, Borenstein N, Tron C, Bauer F, et al. Percutaneous 
transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first 
human case description. Circulation. 2002;106(24):3006-8. 
6. 
Capelli C, Taylor AM, Migliavacca F, Bonhoeffer P, Schievano S. Patient-specific 
reconstructed anatomies and computer simulations are fundamental for selecting medical 
device treatment: application to a new percutaneous pulmonary valve. Philosophical 
Transactions of the Royal Society A: Mathematical,  
 
 
 
Physical and 
Engineering Sciences. 2010;368(1921):3027. 
7. 
Phillips AB, Nevin P, Shah A, Olshove V, Garg R, Zahn EM. Development of a novel hybrid 
strategy for transcatheter pulmonary valve placement in patients following transannular 
patch repair of tetralogy of fallot. Catheterization and cardiovascular interventions : official 
journal of the Society for Cardiac Angiography & Interventions. 2016;87(3):403-10. 
8. 
Zahn EM, Chang JC, Armer D, Garg R. First human implant of the Alterra Adaptive 
Prestent(TM) : A new self-expanding device designed to remodel the right ventricular 
outflow tract. Catheterization and cardiovascular interventions : official journal of the 
Society for Cardiac Angiography & Interventions. 2018;91(6):1125-9. 
9. 
Dajani AS, Taubert KA, Wilson W, Bolger AF, Bayer A, Ferrieri P, et al. Prevention of 
bacterial endocarditis: recommendations by the American Heart Association. Circulation. 
1997;96(1):358-66. 
10. Food and Drug Administration. Melody Transcatheter Pulmonary Valve Summary of Safety 
and Effectiveness 2017 [Available from: 
https://www.accessdata.fda.gov/cdrh_docs/pdf14/p140017s005b.pdf. 
11. Hintze J. PASS 13. www.ncss.com ed. Kaysville, Utah, USA: NCSS, LLC; 2014. 
12. Kappetein AP, Head SJ, Genereux P, Piazza N, van Mieghem NM, Blackstone EH, et al. 
Updated standardized endpoint definitions for transcatheter aortic valve implantation: the 
Valve Academic Research Consortium-2 consensus document (VARC-2). European 
journal of cardio-thoracic surgery : official journal of the European Association for Cardio-
thoracic Surgery. 2012;42(5):S45-60. 
13. Leon MB, Piazza N, Nikolsky E, Blackstone EH, Cutlip DE, Kappetein AP, et al. 
Standardized endpoint definitions for Transcatheter Aortic Valve Implantation clinical trials: 

ALTERRA – Protocol Number 2016-04 
Edwards Lifesciences 
 
Version 7.0, December 16, 2021 
CONFIDENTIAL 
Page 51 of 51 
a consensus report from the Valve Academic Research Consortium. J Am Coll Cardiol. 
2011;57(3):253-69. 
14. Lindsay I, Aboulhosn J, Salem M, Levi D. Aortic root compression during transcatheter 
pulmonary valve replacement. Catheterization and cardiovascular interventions : official 
journal of the Society for Cardiac Angiography & Interventions. 2016;88(5):814-21. 
15. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: 
utilization of specific echocardiographic findings. Duke Endocarditis Service. The American 
journal of medicine. 1994;96(3):200-9. 
16. Nihill MR. Clinical management of patients with pulmonary hypertension. Moss and Adams 
heart disease in infants, children, and adolescents Baltimore: Williams & Wilkins. 
1995:1695-711. 
17. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, et al. 
Guidelines for the echocardiographic assessment of the right heart in adults: a report from 
the American Society of Echocardiography: endorsed by the European Association of 
Echocardiography, a registered branch of the European Society of Cardiology, and the 
Canadian Society of Echocardiography. Journal of the American Society of 
Echocardiography. 2010;23(7):685-713. 
18. Allen HD, Beekman RH, Garson A, Hijazi ZM, Mullins C, O’Laughlin MP, et al. Pediatric 
therapeutic cardiac catheterization: a statement for healthcare professionals from the 
Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 
1998;97(6):609-25. 
19. Nordmeyer J, Khambadkone S, Coats L, Schievano S, Lurz P, Parenzan G, et al. Risk 
stratification, systematic classification, and anticipatory management strategies for stent 
fracture after percutaneous pulmonary valve implantation. Circulation. 2007;115(11):1392-
7.