Prospective, Non-Randomized, Single Arm, Multicenter Clinical Evaluation of the Edwards Pericardial Aortic Bioprosthesis (Model 11000A) for Pulmonary Valve Replacement
Phase: NA
Conditions: Pulmonary Valve Insufficiency, Pulmonary Valve Degeneration, Congenital Pulmonary Valve Abnormality
Sponsor: Edwards Lifesciences

Edwards Lifesciences LLC 
One Edwards Way  Irvine, CA USA  92614 
Phone: 949.250.2500  Fax: 949.250.2525  www.edwards.com 
COMMENCE-P Trial 
COMMENCE Pulmonary: Clinical Evaluation of 
Edwards Pericardial Aortic Bioprosthesis (Model 
11000A) for Pulmonary Valve Replacement 
(COMMENCE-P)
NCT02656290
August 4, 2017

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VERSION B: 04 August 2017 
Page 1 of 57 
Protocol Number 2015-03 
CLINICAL INVESTIGATIONAL PLAN 
Version B 
04-Aug-17
Prospective, Non‐randomized, Single Arm, Multicenter Clinical 
Evaluation of the INSPIRIS RESILIA Pulmonary Valve  (Model 11500P) 
for Pulmonary Valve Replacement (2015-03 TRIAL) 
Trial Sponsor: 
Edwards Lifesciences LLC 
One Edwards Way 
Irvine, CA 92614 USA 
Edwards Lifesciences, the stylized E logo, Carpentier-Edwards, Magna Ease, PERIMOUNT, PERIMOUNT Magna, and 
ThermaFix are trademarks of Edwards Lifesciences Corporation

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PAGE 2 OF 57 
1. INVESTIGATOR SIGNATURE PAGE 
Trial Title: 
Prospective, Non‐randomized, Single Arm, Multicenter Clinical 
Evaluation of the INSPIRIS RESILIA Pulmonary Valve (Model 11500P) 
for Pulmonary Valve Replacement (2015-03 TRIAL) 
Protocol Number: 
2015-03 
Version Number: 
Rev. B 
Date: 
04 August 2017 
I have read this protocol 
s and agree to participate in the clinical investigation 
sponsored by Edwards Lifesciences LLC.  I agree to conduct this investigation in accordance with the study 
agreement, the investigational plan, the instructions for use, applicable FDA regulations and conditions of 
approval imposed by the reviewing Institutional Review Board.  I agree to supervise the use of all of the 
investigational devices at my institution and to ensure appropriate informed consent is obtained from all 
subjects prior to inclusion in this trial.  I further agree to maintain accurate, complete, and current records 
relating to my participation in this investigational trial as required by 21CFR812.140. 
 
 
 
 
INVESTIGATOR NAME 
 
DATE 
INVESTIGATOR SIGNATURE 
 
 
 
 
  
 
 
 
 

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2. TRIAL CONTACT PERSONNEL 
 SPONSOR CONTACTS 
 
TRIAL MANAGER 
 
TRIAL SITE PROJECT MANAGER 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
MEDICAL MONITOR 
 
SAFETY OFFICER 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 TRIAL CONTACTS  
 
NATIONAL PRINCIPAL INVESTIGATOR 
 
 
NATIONAL PRINCIPAL INVESTIGATOR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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NATIONAL COORDINATOR 
 
 
CLINICAL EVENTS COMMITTEE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
   
 
 
ECHOCARDIOGRAPHY CORE LAB 
 
DATA SAFETY MONITORING BOARD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3.   PROTOCOL SYNOPSIS 
Title: 
Prospective, Non‐randomized, Single Arm, Multicenter Clinical Evaluation of the 
INSPIRIS RESILIA Pulmonary Valve (Model 11500P) for Pulmonary Valve 
Replacement (2015-03 TRIAL) 
Protocol Number 
2015-03 
Trial Sponsor: 
Edwards Lifesciences 
One Edwards Way  
Irvine, CA 92614 
 
 
 
 
Trial Device: 
INSPIRIS RESILIA Pulmonary Valve, Model 11500P  
Study Indication: 
The INSPIRIS RESILIA Pulmonary Valve, Model 11500P, is indicated for pediatric 
and adult patients five years or older requiring replacement of their native or 
prosthetic pulmonary valve. 
Trial Objective: 
The objective of this trial is to assess the safety and effectiveness of the INSPIRIS 
RESILIA Pulmonary Valve, Model 11500P, in the pulmonary position in pediatric 
and adult subjects five years or older requiring replacement of their native or 
prosthetic pulmonary valve.    
Trial Design: 
Prospective, Non-Randomized, Single Arm, Multicenter study.  Up to one 
hundred (100) pulmonary valve replacement (PVR) subjects at up to ten (10) 
clinical sites will be enrolled. Clinical data will be collected from at least 3 centers 
with data available on patients who have completed the 1 year follow-up visit. 
Sites will not be allowed to implant more than 50% of total sample size.  
Trial Sites: 
Participating sites are chosen based on their experience in conducting clinical 
trials, their surgical experience implanting bioprosthetic valves, as well as their 
ability to maintain robust subject enrollment and follow-up. The investigational 
sites will be selected throughout the United States.  
Trial Duration: 
Total enrollment period for this trial is estimated to be 3 years.   

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PAGE 6 OF 57 
Subject participation begins with the enrollment of the first subject and ends 
after the last subject enrolled has completed the five (5) year follow up visit or 
has exited the trial.   
Overall trial duration is estimated to be 9 years.  This includes subjects being 
monitored, all outstanding data queries resolved and all trial sites closed to 
follow-up. 
Trial Assessment 
Visits: 
Visit 
Visit Window (Days) 
 
Screening/Baseline 
_____ 
 
Procedure 
_____ 
 
Discharge1 
_____ 
 
30 Days2 
+/- 7 days  
 
6 Months 
+/- 21 days 
 
Year 1 
+/- 30 days 
 
Year 2 
+/- 45 days 
 
Year 3 
+/- 45 days 
 
Year 4 
+/- 45 days 
 
Year 5 
+/- 45 days 
 
 
1 Subjects who are not discharged within 10 days post procedure must have an echocardiogram 
to assess performance of the trial valve. Those subjects will not require an additional 
echocardiogram at discharge. 
2May be Clinic or Telephone Visit  
Trial Endpoints:  
 
Primary Endpoint: 
 
 
Secondary Endpoint: 
Safety Endpoints  
• 
The primary safety endpoint for the trial is freedom from device or 
procedure-related death and/or reoperation at 1 year.  
The following safety endpoints will also be assessed: 
• 
All cause mortality 
• 
Structural valve deterioration 
• 
All/Major paravalvular leak  
• 
Non-structural valve deterioration 
• 
All/Major transvalvular leak 
• 
Trial valve-related mortality 
• 
Endocarditis 
• 
Valve thrombosis 
• 
Explant 
• 
All/Major valve-related bleeding 
• 
Thromboembolism 
• 
Valve-related reoperation 
• 
Hemolysis 
 
 
Effectiveness Endpoints: 
• 
Clinically acceptable hemodynamic performance confirmed by core lab 
evaluation of echocardiography 

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PAGE 7 OF 57 
• 
Functional improvement from baseline (NYHA/Modified Ross Heart Failure 
Classification) 
Subject Enrollment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion Criteria: 
Each subject is required to meet all of the following inclusion criteria: 
1. Has pulmonary valve disease requiring pulmonary valve replacement of 
their native or prosthetic valve 
2. Is greater than or equal to 5 years of age  
3. Subject and/or subject’s legal representative has provided written 
informed consent as approved and required by the respective institutional 
review board and agrees to its provisions.  NOTE: Written consent must 
be obtained prior to any research related test being performed.  
Exclusion criteria:  
A subject meeting any of the following criteria shall be excluded: 
1. Valve-in-conduit procedure 
2. Requires emergency surgery 
3. Has acute myocardial infarction (MI) within 30 days prior to screening 
date 
4. Has MRI or CT scan confirmed stroke, cerebrovascular accident (CVA) or 
transient ischemic attack (TIA) within 6 months (180 days) prior to 
screening date 
5. Has hemodynamic or respiratory instability requiring inotropic support, 
mechanical circulatory support, or mechanical ventilation within 30 days 
prior to screening date 
6. Has active endocarditis/myocarditis or endocarditis/myocarditis within 3 
months prior to screening date 
7. Has renal insufficiency as determined by creatinine (S-Cr) level ≥ 2.5 mg/dL 
within 60 days prior to screening visit or end-stage renal disease  
8. Has documented leukopenia (WBC < 3.5x 103/µL), acute anemia (Hgb < 
10.0 g/dL or 6 mmol/L), or thrombocytopenia (platelet count < 50x103/µL) 
accompanied by history of bleeding diathesis or coagulopathy within 60 
days prior to screening date 
9. Diagnosed with abnormal calcium metabolism and hyperparathyroidism 

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10. Echocardiographic evidence of an intra-cardiac mass, thrombus, or 
vegetation 
11. RVOT aneurysm unless treated during pulmonary valve replacement 
surgery 
12. Has prior organ transplant or is currently an organ transplant candidate 
13. Was previously implanted with INSPIRIS RESILIA Pulmonary valve 
14. Previously implanted with an aortic, mitral, or tricuspid bioprosthetic 
valve, mechanical valve, or annuloplasty ring  
15. Need for concomitant replacement of the aortic, mitral or tricuspid valves 
16. Has presence of non-cardiac disease limiting life expectancy to less than 
12 months 
17. Is currently or has recently participated (within 6 weeks) in another 
investigational drug or device trial  
18. Positive urine or serum pregnancy test in female subjects of child-bearing 
potential and/or nursing mothers, or planning to become pregnant 
within 1 year of study valve implant 
19. Has left ventricular ejection fraction ≤ 20% as validated by diagnostic 
procedure prior to screening date 
20. Currently incarcerated or unable to give voluntary informed consent 
21. Documented history of substance (drug or alcohol) abuse within the last 
5 years prior to screening date 
22. Patients with hypersensitivity to metal alloys that contain cobalt, 
chromium, nickel, molybdenum, manganese, carbon, beryllium and iron  
23. Patients with hypersensitivity to latex 
Intra-Op Exclusion Criterion: 
24. Significant injury to the heart upon entry defined as emergent 
cardiopulmonary bypass requiring femoral cannulation 

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REV A: 29 MAY 2015 
 
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Page 9 of 57 
 
4. ABBREVIATIONS 
ACC 
American College of Cardiology 
AE 
Adverse Event 
AHA 
American Heart Association 
AS 
Aortic Stenosis 
ASD 
Atrial Septal Defect 
AVR 
Aortic Valve Replacement 
CABG 
Coronary Artery Bypass Graft 
CBC 
Complete Blood Count 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CO/CI 
Cardiac Output/Cardiac Index 
CRF 
Case Report Form 
CV 
Critical Value 
CVA 
Cerebrovascular Accident 
DIC 
Disseminated Intravascular Coagulation 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EOA 
Effective Orifice Area 
FDA 
Food and Drug Administration 
FMEA 
Failure Modes and Effects Analysis 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
HGB 
Hemoglobin 
HIPAA 
Health Insurance Portability & Accountability Act 
HCT 
Hematocrit 
HIT 
Heparin Induced Thrombocytopenia 
HOCM Hypertrophic Obstructive Cardiomyopathy 
ICF 
Informed Consent Form 
ICU 
Intensive Care Unit 
ID 
Index Diameter 
IDE 
Investigational Device Exemption 
IE 
Infective Endocarditis 
IFU 
Instructions for Use 
INR 
International Normalized Ratio 
INV 
Investigator 
IRB 
Institutional Review Board 
 
 
 
 
ISO 
International Standardization Organization  
LVOT 
Left Ventricular Outflow Tract 
MI 
Myocardial Infarction 
MOF 
Multi-system Organ Failure 
MR 
Magnetic Resonance 
MVR 
Mitral Valve Replacement 
NSVD Nonstructural Valve Dysfunction 
NYHA New York Heart Association 
OPC 
Objective Performance Criteria 
OUS 
Outside United States 
PFO 
Patent Foramen Ovale 
PI 
Pulmonary Insufficiency (see also pulmonary 
regurgitation)  
Principal Investigator 
PMA 
Premarket Approval  
PO 
Postoperative 
POD 
Postoperative Day 
PR 
Pulmonary Regurgitation 
PS 
Pulmonary Stenosis 
PT 
Prothrombin Time 
PTFE 
Polytetrafluoroethylene 
PTT 
Partial Thromboplastin Time 
PVL 
Paravalvular Leak 
PVR 
Pulmonary Valve Replacement 
QOL 
Quality of Life 
RBC 
Red Blood Cell  
REB 
Research Ethics Board 
RGA 
Returned Good Authorization 
SAE 
Serious Adverse Effect 
SAR 
Specific Absorption Rate 
SPVR 
Surgical Pulmonary Valve Replacement 
SF-12 Short Form 12 Health Survey 
SVD 
Structural Valve Deterioration 
TAD 
Tissue Annulus Diameter 
TEE 
Transesophageal Echocardiography 
TIA 
Transient Ischemic Attack 
TTE 
Transthoracic Echocardiography 
UADE Unanticipated Adverse Device Effect 
WBC 
White Blood Cell  

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REV A: 29 MAY 2015 
 
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REVISION B: 04 AUGUST 2017 
 
 
Page 10 of 57 
 
 
Table of Contents 
 
Section 
Page 
1. 
INVESTIGATOR SIGNATURE PAGE ........................................................................................... 2 
2. 
TRIAL CONTACT PERSONNEL .................................................................................................. 3 
 SPONSOR CONTACTS ...................................................................................................... 3 
 TRIAL CONTACTS ............................................................................................................ 3 
3. 
PROTOCOL SYNOPSIS ............................................................................................................. 5 
4. 
ABBREVIATIONS ..................................................................................................................... 9 
5. 
TRIAL OVERVIEW ................................................................................................................. 14 
 INTRODUCTION AND BACKGROUND ............................................................................. 14 
 REGULATORY HISTORY .................................................................................................. 18 
 PREVIOUS DEVICE ITERATION DESCRIPTION .................................................................. 19 
 CURRENT DEVICE ITERATION DESCRIPTION ................................................................... 19 
 REPORT OF PRIOR INVESTIGATIONS .............................................................................. 21 
6. 
BENEFITS AND RISKS ............................................................................................................ 23 
 BENEFITS ...................................................................................................................... 23 
 RISKS ............................................................................................................................ 23 
 MINIMIZING SUBJECT RISK ............................................................................................ 25 
7. 
TRIAL DESIGN ...................................................................................................................... 25 
 OBJECTIVE .................................................................................................................... 26 
 DESIGN ......................................................................................................................... 26 
 ENDPOINTS .................................................................................................................. 27 
 ADDITIONAL CLINICAL MEASURES ................................................................................. 28 
 NUMBER OF SUBJECTS .................................................................................................. 28 
 METHODS OF FOLLOW-UP ............................................................................................ 28 
8. 
TRIAL POPULATION .............................................................................................................. 30 
 INCLUSION CRITERIA: .................................................................................................... 30 
 EXCLUSION CRITERIA: ................................................................................................... 30 
 ENROLLED POPULATION ............................................................................................... 31 
 INDEX VALVE POPULATION ........................................................................................... 32 
 SUBJECT AND TRIAL DURATION ..................................................................................... 32 

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 SUBJECT TERMINATION OR WITHDRAWAL .................................................................... 32 
9. 
STATISTICAL METHODS ........................................................................................................ 32 
 ANALYSIS POPULATION ................................................................................................ 32 
 SAMPLE SIZE ................................................................................................................. 33 
 STATISTICAL ANALYSIS .................................................................................................. 33 
 ADDITIONAL MEASURES ............................................................................................... 34 
 POOLABILITY ................................................................................................................ 35 
 ANALYSIS OF COVARIATES ............................................................................................ 35 
 MISSING DATA .............................................................................................................. 35 
 FOLLOW-UP AND COMPLIANCE DATA ........................................................................... 36 
10. 
TRIAL PROCEDURES .............................................................................................................. 36 
  SUBJECT SCREENING .................................................................................................... 36 
  INFORMED CONSENT ................................................................................................... 36 
  SCREENING/BASELINE ASSESSMENT ............................................................................. 37 
  VALVE REPLACEMENT PROCEDURE ............................................................................... 38 
  POST INDEX VALVE IMPLANT ....................................................................................... 39 
  DISCHARGE .................................................................................................................. 39 
  POST DISCHARGE FOLLOW-UP ASSESSMENTS ............................................................... 40 
  MISSED FOLLOW-UP .................................................................................................... 41 
  STUDY EXIT .................................................................................................................. 42 
EXPLANT..................................................................................................................... 42 
11. 
ADVERSE EVENTS ................................................................................................................. 43 
 REPORTING .................................................................................................................. 43 
 NOTIFICATION OF UADE AND/OR SERIOUS DEVICE RELATED ADVERSE EFFECTS ............. 45 
 DEATH AND EXPLANTS .................................................................................................. 46 
 DATA MONITORING COMMITTEE .................................................................................. 46 
 CLINICAL EVENTS COMMITTEE (CEC) .............................................................................. 47 
12. 
TRIAL AND DATA MANAGEMENT ......................................................................................... 47 
 ECHOCARDIOGRAPHY CORE LAB ................................................................................... 47 
 DEVICE ACCOUNTABILITY .............................................................................................. 47 
 PROTOCOL DEVIATIONS ................................................................................................ 48 
 TRAINING AND MONITORING ....................................................................................... 49 

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 DOCUMENTATION REQUIREMENTS ............................................................................... 51 
 DATA COLLECTION ........................................................................................................ 52 
 DATA AND DOCUMENT RETENTION .............................................................................. 53 
 TRIAL PROTOCOL AMENDMENTS .................................................................................. 53 
 TRIAL COMPLETION ...................................................................................................... 53 
 FUTURE PLANS ........................................................................................................... 54 
13. 
STATEMENTS OF COMPLIANCE, CONFIDENTIALITY AND RESPONSIBILITIES ............................ 54 
 PROTECTION OF SUBJECT CONFIDENTIALITY .................................................................. 54 
 REGULATIONS AND GUIDELINES .................................................................................... 54 
 INVESTIGATOR RESPONSIBILITIES .................................................................................. 55 
 SPONSOR RESPONSIBILITIES .......................................................................................... 55 
14. 
PUBLICATIONS ..................................................................................................................... 55 
15. 
REFERENCES ........................................................................................................................ 56 
 

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5.   TRIAL OVERVIEW 
 INTRODUCTION AND BACKGROUND 
Congenital heart disease (CHD) is the most common congenital disorder in newborns. The reported 
prevalence of congenital heart disease (CHD) at birth ranges from 6 to 13 per 1000 live births. Survival of 
children with CHD has improved significantly and as a result increasing numbers of patients undergo 
pulmonary valve replacement (PVR). Surgical management of congenital heart disease (CHD) such as 
Tetralogy of Fallot (TOF) and pulmonary stenosis includes relief of right ventricular outflow tract (RVOT) 
obstruction using techniques that may result in pulmonary valve dysfunction and varying degrees of right 
ventricular (RV) volume and pressure overload.   Pulmonary regurgitation, a common sequelae, may 
initially be well tolerated but eventually leads to exercise intolerance, progressive RV dilation and 
dysfunction, ventricular and atrial tachycardia, congestive heart failure, and sudden cardiac death [1]. 
Implantation of a competent pulmonary valve is commonly undertaken to avoid these adverse clinical 
outcomes and preserve RV function.  The detrimental effects of pulmonary regurgitation are now widely 
accepted, which in turn, has led to earlier PVR in most instances before overt symptoms and 
cardiovascular decompensation develop. Delayed pulmonary valve replacement may contribute to higher 
perioperative mortality due to advanced right ventricular dysfunction. Therefore, timing and indications 
for replacement of an incompetent pulmonary valve are key issues.   
 
PULMONARY HEART DISEASE 
Congenital defects involving the right ventricular outflow tract require iterative surgical interventions 
and/or corrections throughout a patient’s growing years and young adulthood. Some of the defects 
include pulmonary atresia and pulmonary stenosis. Other defects that are more complex and require 
complex surgeries include transposition of the great arteries, Tetralogy of Fallot with or without 
pulmonary atresia, truncus arteriosus, or double outlet right ventricle.  
The occurrence of pulmonary insufficiency and/or pulmonary stenosis is not uncommon after surgery for 
congenital heart defects [1] [2] [3] [4]. Surgical repair of congenital heart disease such as Tetralogy of Fallot 
and pulmonary stenosis includes relief of right ventricular outflow tract obstruction using techniques that 
may result in significant pulmonary insufficiency [1].  Late morbidity and mortality following repair is 
predominantly secondary to the effects of progressive right heart failure and arrhythmias, to which 
pulmonary insufficiency (PI) contributes [5].  Patients require long-term follow-up, as they are at risk for 

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the chronic postoperative complications including arrhythmias including atrial tachycardia and ventricular 
tachycardia (VT), and sudden cardiac death.  Surgical pulmonary valve replacement may be necessary to 
restore pulmonary valve competence, improve right ventricular function and improve the symptoms.   
 
SURGICAL OPTIONS FOR PULMONARY VALVE REPLACEMENT (PVR) 
There are no approved surgical options for pulmonary valve replacement.  As of January 27, 2015, the 
Medtronic Melody® Transcatheter Pulmonary Valve has been approved in the US as a catheter-delivered 
stent valve for use in a limited population. The transcatheter pulmonary valve replacement (TPVR) is 
approved as an adjunct to surgery in the management of pediatric and adult patients with 1) the existence 
of a full RVOT conduit equal to or greater than 16 mm in diameter when originally implanted and 2) 
dysfunctional RVOT conduit with a clinical indication for intervention: regurgitation ≥ moderate and/or 
mean RVOT gradient≥ 35 mmHg. It is available in two sizes: 16mm and 18mm (Source: FDA PMA 
Database).  
Not yet approved surgical options for pulmonary valve replacement include bioprostheses, homografts, 
and mechanical valves.  Controversy regarding the optimal valve in the pulmonary position remains. 
Bioprosthetic valves perform well hemodynamically but are prone to structural degeneration.  The 
homograft has a drawback of limited availability. Mechanical valves lead to a persistent need for 
anticoagulation; and despite positive reports in the literature have generally been associated with 
pulmonary thromboembolic complications [6]. Long-term data are available for bioprosthetic valve 
durability in the aortic position and these data are typically extrapolated to decision making and 
counseling for pulmonary valve replacement.   
The ideal pulmonary valve substitute has not yet been clearly defined but compared with mechanical, 
homograft and polytetrafluoroethylene valves, stented bioprosthetic valves in the pulmonary valve 
position have been shown to be a better option [4]. 
 
SURGICAL PULMONARY VALVE REPLACEMENT (PVR) 
Retrospective studies documented in literature have shown statistically significant improvements in 
performance following surgical pulmonary valve replacement (PVR). Significant improvements are seen  
in right ventricular end-diastolic volume or pressure [3] [6] [7] [8] [9], right ventricular end-systolic volume 
[8], right ventricular end-diastolic volume index [3], pulmonary regurgitation [4] [6] [10], pulmonary valve 
Doppler velocities [10], tricuspid regurgitation [3] [6], peak pulmonary valve gradient [3] [11], estimated 

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right ventricular pressure [3], cardiothoracic ratio on chest x-ray [8, 12], maximal oxygen uptake [10], QRS 
width [10] [12], left ventricular ejection fraction [9] [12], right ventricular enlargement [9], and right 
ventricular dysfunction [9] [13]. One study found statistically significantly fewer subjects with moderate 
or greater pulmonary stenosis and pulmonary insufficiency that were treated with porcine versus bovine 
valves [4]. However, the authors also noted that the follow-up duration was significantly shorter for the 
porcine group versus the bovine group (31.7 versus 55.7 months, P < 0.001). This study also found that 
subjects who received a PVR at an age greater than 15 years had significantly lower percentages of 
moderate or greater pulmonary stenosis and insufficiency. 
Retrospective review of New York Heart Association functional class of subjects that underwent PVR 
showed an improvement in function class postoperatively, with five studies reaching statistical 
significance [1] [6] [7] [9] [10] [11] [12] [13] [5]. 
Freedom from re-intervention/reoperation specific to patients who received the Carpentier-Edwards 
PERIMOUNT valve were 100% at 2.5 years [5], 50% and 97.7% at 5 years [14] [1], 74.7% at 7 years [8], and 
79% [15] and 94% at 10 years [11]. Risk factors found to be associated with increased risk for 
reintervention/reoperation in a multivariate analysis included younger age at PVR [4] [2] [9], underlying 
diagnosis of pulmonary atresia with ventricular septal defect [2], and use of stentless porcine valve [2].  
Six 
studies 
provided 
results 
on 
the 
freedom 
from 
structural 
valve 
deterioration/ 
failure/dysfunction/explant or freedom from moderate-severe or severe pulmonary insufficiency [3] [6] 
[2] [11] [1] [9]. The overall 5 year rates ranged from 74% to 92.2% and overall 10 year rates ranged from 
20.2% to 98%. Rates specific to patients who received the Carpentier-Edwards PERIMOUNT valve were 
89.1% [1] and 92% [6] at 5 years and 79% [15] and 98% [11] at 10 years. Lee et al (2011) also found that 
stented bovine valves had a statistically significantly higher freedom from valve failure and dysfunction 
rate than stentless porcine valves (p = 0.015), but valve-specific rates were not provided. Risk factors 
found to be associated with increased risk for structural valve deterioration or failure in a multivariate 
analysis included younger age at PVR [3], higher indexed valve internal diameter [3], and use of a 
homograft in the early phase (within 3 years of surgery) [15]. However, higher indexed valve ID at 
implantation, which is indicative of valve oversizing, was an independent predictor of SVD within younger 
patients.  

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Babu-Narayan et al conducted a retrospective study investigating the survival rate after repair of Tetralogy 
of Fallot at a single tertiary center. Mortality was the primary outcome measure. In total, 221 surgical 
pulmonary valve replacements were performed in 220 patients (130 male patients; median age, 32 years; 
range, 16–64 years). The article concluded that surgical pulmonary valve replacement (PVR) has a low and 
improving mortality, with low 10 year re-intervention rates. The more recently operated on patients 
(2005-2010) were less symptomatic and had better exercise capacity at the time of referral for surgical 
PVR compared with those in the earlier era (1993-2004). The trend of earlier PVR was associated with 
lower mortality [16]. 
Jang et al retrospectively reviewed surgical outcomes of 131 PVRs performed at a single center from 2001 
to 2010.   The mean age was 14.8 yrs + 6.7 years. There were no early or late mortality; the rate of freedom 
from reoperation at 10 years was 66.4+ 4.4%; implanted valve type; young age; and large sized valve 
implantation were risk factors for repeat PVR in the univariate analysis [8].  
Retrospective studies have shown use of stented bioprosthetic valves to treat pulmonary valvular disease 
has become a standard treatment in clinical practice with optimal rates of survival and freedom from re-
operation.  Tweddell’s retrospective comparative study of 122 subjects (median age 14.6; range 0.6-49 
yrs) concluded heterograft valves should be the first choice among patients with TOF requiring pulmonary 
valve replacement as there was no difference in survival or freedom from re-intervention and they have 
the potential advantages of lower cost and availability [17] .  Additionally, clinical data supporting the 
safety of the Carpentier-Edwards PERIMOUNT valve showed a good safety profile [5]. Neukamm’s case 
series assessed the largest published series of 90 patients who received the Carpentier-Edwards 
PERIMOUNT valve in the pulmonary position with excellent midterm results in small children as young as 
2 years old.  Results showed the Carpentier-Edwards PERIMOUNT valve had the least stenosis and 
insufficiency compared to Bicuspid, Contegra, Homograft, and Monocusp valves [18]. The availability, 
handling characteristics, and excellent early outcomes make the Edwards Pericardial Aortic Bioprosthesis 
a promising option for surgeons seeking to provide pulmonary valve competence to the previously 
repaired RVOT [5], but further follow up is needed to define long-term function and durability.  
 
A number of studies were identified in the literature that presented data on pulmonary valve 
replacements.  Although none of the studies were randomized controlled trials (RCT), these data are of 
acceptable quality and the studies represent an acceptable level of scientific rigor and objectivity.  The 

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use of bioprosthetic valves to treat pulmonary valvular disease, including Tetralogy of Fallot, has become 
a standard treatment in clinical practice and has been the subject of multiple publications. Data found in 
publications evaluating bioprosthetic valves to treat pulmonary valvular disease also supported the 
performance of the Carpentier-Edwards PERIMOUNT Aortic Bioprosthesis.   
Based on the results of the aortic pre-clinical data, the OUS clinical trial, the interim results of the 
COMMENCE trial and literature review, the use of the investigational valve is justified.  
The goal of this trial is to provide prospective, controlled data with limiting confounding factors on the 
use of the INSPIRIS RESILIA Pulmonary Valve, Model 11500P in children and adults requiring pulmonary 
valve replacement.  
 
CLINICAL TRIAL PURPOSE 
The objective of this trial is to assess the safety and effectiveness of the INSPIRIS RESILIA Pulmonary Valve, 
Model 11500P in the pulmonary position in pediatric and adult subjects five years or older requiring 
replacement of their native or prosthetic pulmonary valve.   
 REGULATORY HISTORY 
The INSPIRIS RESILIA Pulmonary Valve (model 11500P) is the same valve as the INSPIRIS RESILIA Aortic 
Valve (model 11500A). The Model 11500A is a surgical bioprosthetic heart valve that is a design 
modification to the Edwards Pericardial Aortic Bioprosthesis, Model 11000A.  
The Edwards Pericardial Aortic Bioprosthesis (model 11000A) received CE mark on April 24, 2012 for the 
replacement of native or prosthetic aortic heart valves.  
The model 11000A has not been commercially released in the EU, or in any other country or geographic 
region as of the date of this document.  
INSPIRIS RESILIA Aortic Valve (model 11500A) received CE mark on September 29, 2016 for the 
replacement of native or prosthetic aortic heart valves.  
INSPIRIS RESILIA Aortic Valve (model 11500A) is currently under PMA review (PMA # P150048) for the 
replacement of native or prosthetic aortic heart valves.  The PMA has been found to be approvable 
pending results of final inspections; Ref. FDA letter dated February 21, 2017. 
  

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 PREVIOUS DEVICE ITERATION DESCRIPTION 
Edwards Pericardial Aortic Bioprosthesis, Model 11000A  
The Edwards Pericardial Aortic Bioprosthesis, Model 11000A (also referred to as the Model 11000A) is a 
bioprosthesis comprised of bovine pericardium. It is based on the same design as the Carpentier-Edwards 
PERIMOUNT Magna Ease Pericardial Aortic Bioprosthesis, Model 3300TFX, which was approved under 
P860057/S042 on 07 May 2009.  
The physical structure and design of the Model 11000A is identical to the Model 3300TFX, except for tissue 
processing, sterilization and packaging. The Edwards Pericardial Aortic Bioprosthesis, Model 11000A, is a 
trileaflet bioprosthesis comprised of treated bovine pericardium that is mounted on a flexible frame. It is 
available in sizes 19, 21, 23, 25, 27, and 29 mm.  The bioprosthesis is stored in non-aqueous packaging, 
and does not require rinsing prior to implantation. 
The wireform is made of a cobalt-chromium alloy and is covered with a woven polyester fabric. A cobalt-
chromium alloy/polyester film laminate band surrounds the base of the wireform frame. A silicone sewing 
ring that is covered with a porous polytetrafluoroethylene (PTFE) cloth is attached to the wireform frame. 
The sewing ring has three, equally spaced black silk suture markers at the cusp centers to aid in 
bioprosthesis orientation and suture placement. 
The Model 11000A valve is treated with a new tissue process that builds on Edwards’ existing tissue 
process, ThermaFix (TFX). The new process allows the valve to be stored in non-aqueous packaging and 
the valve is ethylene oxide sterilized. 
The Model 11000A, is being evaluated as part of the COMMENCE trial (ClinicalTrials.gov # NCT01757665, 
Protocol Number 2012-02) to confirm safety and effectiveness in subjects who require replacement of 
their native or prosthetic aortic.  Safety and performance for the Edwards Pericardial Aortic Bioprosthesis, 
Model 11000A and Edwards Pericardial Mitral Bioprosthesis, Model 11000M is supported by the interim 
clinical data from the COMMENCE trial, see section 5.4.2. 
 CURRENT DEVICE ITERATION DESCRIPTION 
INSPIRIS RESILIA Pulmonary Valve, Model 11500P 
 
 
 

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The INSPIRIS RESILIA Pulmonary Valve, Model 11500P, incorporates two novel features (available on sizes 
19 – 25 mm only) designed for potential future valve-in-valve (ViV) procedures: fluoroscopically visible 
size markers and an expandable cobalt chromium alloy band. 
As in the Edwards Pericardial Aortic Bioprosthesis, Model 11000A, a thin cobalt-chromium alloy band and 
polyester support band surround the base of the valve beneath the wireform frame providing structural 
support for the orifice.  
In the INSPIRIS RESILIA Pulmonary Valve, model 11500P which is the same valve as model 11500A, the 
ends of the cobalt-chromium alloy band are secured by a polyester shrink sleeve on the sizes 19 – 25 mm 
(Figure 1a) to allow the internal orifice of the valve to expand. The polyester support band allows 
expansion at each commissure when subjected to radial forces. The expandable cobalt-chromium alloy 
band does not impact suture placement or implant technique. Valves with expandable bands (sizes 19 – 
25 mm) will maintain a stable diameter at implant and under intracardiac conditions, which was 
demonstrated during compression resistance testing and accelerated wear testing. 
In the sizes 27 and 29 mm (Figure 1b), the free ends of the cobalt-chromium alloy band are permanently 
secured using a weld joint.  
Similar to other Edwards’ bioprosthetic valves, the cobalt-chromium alloy wireform in the model 11500P 
can be identified on fluoroscopy. The fluoroscopically visible size marker is designed to aid the clinician 
in surgical valve size identification after implantation. A representation of the commissure size markers 
for the sizes 19 – 25 mm is shown in Figure 1c. 
Figure 1a (Sizes 19 – 25 mm Cobalt Chromium Alloy Band) 
Figure 1b (Sizes 27 and 29 mm Cobalt Chromium Alloy Band) 
 
 
 
 
 
 
 
 
 
 
Size Markings 
Area of Expansion 
Weld Joint 

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Figure 1c (Sizes 19 – 25 mm Size Markers) 
 
 
19 mm 
 
21 mm 
 
23 mm 
 
25 mm 
 
   5.4.1 
   DEVICE INDICATION FOR USE 
The INSPIRIS RESILIA Pulmonary Valve, Model 11500P, is indicated for pediatric and adult patients five 
years or older requiring replacement of their native or prosthetic pulmonary valve.  
   5.4.2    CONTRAINDICATION 
Do not use the bioprosthesis if the surgeon believes use is contrary to the best interests of the patient. 
The decision for or against use of this bioprosthesis remains with the surgeon who must evaluate all the 
various risks involved, including the anatomy and pathology observed at the time of surgery. 
5.4.3 
DEVICE TRAINING 
Sponsor will present formal device training to applicable study personnel prior to performing first 
implant.  Formal device training will further enhance training per the Instructions for Use (IFUs) provided 
in the protocol.  
 REPORT OF PRIOR INVESTIGATIONS 
   5.5.1 
        EUROPEAN STUDY INFORMATION- CLINICAL TRIAL OF THE EDWARDS 
AORTIC  BIOPROSTHESIS, MODEL 11000 
A prior confirmatory clinical trial (ClinicalTrials.gov #NCT01651052, Protocol #2010-03) initiated in Europe 
in July 2011 is also underway to gather data on the Model 11000A. This is a prospective, non-randomized 
clinical trial of the trial valve for subjects undergoing aortic valve replacement (AVR). The trial enrolled 

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and successfully implanted one hundred thirty-three (133) subjects at two sites in Poland. Enrollment for 
this trial was closed as of 19 February 2013. Follow-up compliance of 100% (131/131) at discharge, 99.2% 
(129/130) at 3-months, 97.6% (122/125) at 1-year, 92.5% (111/120) at 2-years, 93.8% (105/112) at 3-
years, 92.7% (101/109) at 4-years, and 100% (17/17) at 5-years has been achieved for all eligible subjects 
as of 07 April 2017. Follow-up is ongoing until all subjects complete the 5 year follow-up.  
To date, three (3) early (≤30 POD) and sixteen (16) late deaths have occurred in the enrolled cohort. One 
(1) early and three (3) late deaths were adjudicated by the CEC as study valve related including one death 
attributed to late study valve thrombosis. One (1) study valve explant has occurred on POD 234 due to 
endocarditis. One (1) incident of late non-structural valve dysfunction has been reported: the 2-year 
follow-up echocardiogram demonstrated high gradients which had worsened from the 1-year follow-up 
due to patient prosthesis mismatch, as adjudicated by the CEC. There have been no reports involving 
unanticipated adverse device effects or structural valve deterioration. 
5.5.2 
U.S. STUDY INFORMATION- PROSPECTIVE, NON-RANDOMIZED, MULTICENTER CLINICAL 
EVALUATION OF THE EDWARDS PERICARDIAL AORTIC AND MITRAL BIOPROSTHESES 
(MODELS 11000A AND 11000M) WITH A NEW TISSUE TREATMENT PLATFORM 
The objective of the COMMENCE trial (protocol 2012-02, NCT#01757665) is to confirm that tissue 
processing, valve sterilization and packaging used in the Model 11000A and Model 11000M do not raise 
any new questions of safety and effectiveness in subjects who require replacement of their native or 
prosthetic aortic or mitral valve. IRB or EC approval of the investigational plan has been obtained at thirty-
five (35) investigational sites in the US, Canada, and Europe. Enrollment was completed in the aortic arm 
in March 2016, and completed in the mitral arm in July 2016.  Six hundred ninety-four (694) subjects were 
enrolled in the aortic cohort across twenty-seven (27) investigational sites and eighty three (83) subjects 
were enrolled in the mitral cohort across seventeen (17) investigational sites. Of the enrolled population, 
six hundred eighty nine (689) subjects were treated and successfully implanted with Model 11000A and 
eighty two (82) subjects with the Model 11000M.  
For the aortic cohort, follow-up compliance of 100% at discharge, 97.2% at 3-months, 97.0% at 1-year, 
92.8% at 2-years, and 88.5% at 3-years has been achieved for all eligible implanted subjects. To date, nine 
(9) early (≤ 30 POD) deaths and twenty eight (28) late deaths have occurred. Ten (10) deaths, three (3) 
early and seven (7) late, were considered related to the study valve per CEC adjudication. Three (3) study 
valve explants have occurred, due to endocarditis. There have been no reported incidences of valve 

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thrombosis, structural valve deterioration, and all other complications fall within accepted performance 
criteria. 
For the mitral cohort, follow-up compliance of 100% at discharge, 95% at 3-months, 100% at 1-year, and 
100% at 2-years has been achieved for all eligible implanted subjects. To date, one (1) early death and 
seven (7) late deaths have occurred, of which one (1) early and one (1) late death were considered to be 
related to the study valve per CEC adjudication. No explants have occurred to date. Two (2) late events of 
structural valve deterioration have been site reported due to worsening central regurgitation.  
Safety and performance for the Edwards Pericardial Aortic Bioprosthesis, Model 11000A and Edwards 
Pericardial Mitral Bioprosthesis, Model 11000M is supported by the early clinical data. Continued subject 
follow-up will confirm that the new tissue process modifications do not raise new safety and effectiveness 
questions. 
6.   BENEFITS AND RISKS 
 BENEFITS 
The benefits of the trial valve are the same as other bioprosthetic valves including improved valvular 
function, acute alleviation of symptoms related to valve stenosis or insufficiency, and/or improved 
morbidity and mortality.  
The anticipated additional benefits are to eliminate the need for rinsing the bioprosthesis prior to 
implantation, less exposure to the risks of glutaraldehyde, and elimination of hazardous waste requiring 
special disposal.  Additionally, the V-fit technology (available on sizes 19 – 25 mm) incorporates two novel 
features designed for potential future valve-in-valve (ViV) procedures: fluoroscopically visible size markers 
and an expandable cobalt chromium alloy band 
. 
 RISKS 
As with all prosthetic heart valves, serious complications, including death may be associated with the use 
of tissue valves. Complications due to individual subject reaction to an implanted device, or to physical or 
chemical changes in the components, particularly those of biological origin, may occur at varying intervals 
(hours or days) necessitating reoperation and replacement of the prosthetic device. Some or all of the 
risks listed below could require a reoperation or explant, and/or they may lead to permanent disability or 
death. 

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Known/potential risks associated with stented bioprosthetic heart valves include but not limited to: 
 Angina 
 Bleeding diatheses (coagulopathy) related to 
anticoagulant therapy 
 Cardiac arrhythmias 
 Cardiac failure 
 Coronary ostial blockage 
 Endocarditis 
 Hemolysis/Hemolytic anemia 
 Hemorrhage 
 Immunological response 
 Leaflet entrapment (impingement) 
 Myocardial infarction 
 Nonstructural valve dysfunction 
 Paravalvular/Perivalvular/Transvalvular or 
Valvular Leaking 
 Malfunctions of valve due to distortion at 
implant, fracture of wireform, physical and or 
chemical deterioration of valve components 
 Patient prosthetic mismatch (PPM) 
 Regurgitation/insufficiency  
 Stenosis 
 Thromboembolism/stroke 
 Tissue deterioration including infection, 
calcification, thickening, perforation, 
degeneration, suture abrasion, instrument 
trauma, and or leaflet detachment 
 Transient ischemic attack (TIA) 
 Valve pannus 
 Valve thrombosis 
 Valve dislodgement/instability 
 
Potential risks associated with pulmonary valve replacement surgery include but not limited to: 
 Allergic reaction 
 Annular dissection 
 Atelectasis 
 Pulmonary artery (damage, dissection, tear) 
 Bleeding, anticoagulant related  
 Bleeding, procedural  
 Bleeding, post‐procedural  
 Cardiac arrest 
 Cardiogenic shock 
 Disseminated intravascular coagulation 
(DIC) 
 Esophageal rupture 
 Ventricular dysfunction/Heart failure 
 Hematoma 
 Heparin induced thrombocytopenia (HITs) 
 Hypotension 
 Hypertension 
 Coronary artery compression 
 Hypoxemia 
 Infection, local or wound 
 Infection, systemic (septicemia) 
 Myocardial infarction 
 Multi-system organ failure (MOF) 
 Pericardial effusion 
 Pericardial tamponade 
 Pleural effusion 
 Pneumothorax 
 Pulmonary edema 
 Pneumonia 
 Renal dysfunction 
 Respiratory failure 
 Thromboembolism 
– Venous, peripheral or central 
– Arterial, peripheral or central 
– Pulmonary, thrombus or other 
 Tricuspid valve insufficiency 
 
 

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Risks associated with trial valve are anticipated to be the same as those listed above for other pulmonary, 
aortic or mitral bioprosthetic valves and valve replacement surgery.  Based on the results of the aortic 
pre-clinical data, the OUS clinical trial, and the interim results of the COMMENCE trial it is not anticipated 
that any new risks associated with the trial valve tissue process, sterilization method, or packaging will be 
observed. 
Risks associated with stand-alone balloon pulmonary valvuloplasty procedures are pulmonary valve 
incompetence, and with valve-in-valve procedures, are instability / migration / embolization for the 
transcatheter device anchored within. Specific risk information related to the band expansion is provided 
in the device Instructions for Use. 
 MINIMIZING SUBJECT RISK 
Several safeguards are incorporated into the trial to minimize subject risk.  All pre-clinical device testing 
for the implantable valve is performed in accordance with FDA regulations, ISO 5840 and recognized 
standards.  All test results have passed the required specifications supporting reasonable safety for this 
clinical product. 
This clinical trial is conducted under the direction of qualified physicians experienced with cardiac surgery 
including pulmonary valve replacement and the use of investigational devices. All participating 
investigators and sites are screened and qualified. They must be experienced in conducting clinical 
research and have adequate personnel to assure compliance to the trial protocol. All clinical investigators 
performing the implant procedure will receive training specific to the trial valve procedure.  The 
Instructions for Use 
 provides detailed instructions on the 
proper handling and implantation of these investigational valves.  
Clinical outcomes for all trial subjects will be routinely monitored by the Sponsor during the course of the 
trial.  
7. TRIAL DESIGN 
The trial design methodology is based on the primary safety endpoint of freedom from device or 
procedure-related death and/or reoperation at 1 year as discussed in Sections 7.3 and 9.   
A number of studies were identified in the literature that presented data on pulmonary valve 
replacements.  Although none of the studies were randomized controlled trials (RCT), these data are of 
acceptable quality and the studies represent an acceptable level of scientific rigor and objectivity.  The 

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use of bioprosthetic valves to treat pulmonary valvular disease, including Tetralogy of Fallot, has become 
a standard treatment in clinical practice and has been the subject of multiple publications. Data found in 
publications evaluating bioprosthetic valves to treat pulmonary valvular disease also supported the 
performance of the Carpentier-Edwards PERIMOUNT Aortic Bioprosthesis.   
Based on the results of the aortic pre-clinical data, the OUS clinical trial, the interim results of the 
COMMENCE trial and literature review, the use of the investigational valve is justified.  
 OBJECTIVE 
The objective of this trial is to assess the safety and effectiveness of the INSPIRIS RESILIA Pulmonary Valve, 
Model 11500P, in the pulmonary position in pediatric and adult subjects five years or older requiring 
replacement of their native or prosthetic pulmonary valve.   
 DESIGN 
Prospective, Non-Randomized, Single Arm, Multicenter study.  Up to one hundred (100) pulmonary valve 
replacement (PVR) subjects at up to ten (10) clinical sites will be enrolled. Clinical data will be collected 
from at least 3 centers with data available on patients who have completed the 1 year follow-up visit. 
Sites will not be allowed to implant more than 50% of total sample size.  
 
The trial design includes methods to minimize bias.  Efficacy endpoints will be independently evaluated 
by an independent Echo Core Lab.  Members will be independent from the Sponsor, the Investigators, or 
trial staff involved in the medical care of the study subjects. 
 
Study oversight includes a Data Monitoring Committee (DMC) and a Clinical Events Committee (CEC). The 
DMC and CEC are independent from the Sponsor, the Investigators, or anyone involved in the medical 
care of the study subjects. Member will not have conflict of interest related to the Sponsor. Committee 
Members must sign a non-conflict of interest statement in this regard.  
 
The Data Monitoring Committee (DMC) will review aggregate safety data during the enrollment period to 
determine if the trial is being conducted safely and will decide if the clinical investigation should be 
modified, suspended and/or stopped.  The Clinical Events Committee (CEC) evaluates the adverse events 
that are endpoint related as well as those resulting in death. The CEC adjudicates early and late events for 
their relatedness to the investigational device and/or the valve implant procedure. 

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 ENDPOINTS 
Safety and effectiveness data will be compared to available, control data published in articles in the 
prosthetic heart valve literature. 
 
SAFETY 
The primary safety endpoint for the trial is freedom from device or procedure-related death and/or 
reoperation at 1 year. The null hypothesis is that the rate of device or procedure-related death and/or 
reoperation at 1 year is greater than 25%. The alternative hypothesis is that this rate is less than 25%.  
 
The following safety endpoints will also be assessed: 
• 
All cause mortality 
• 
Structural valve deterioration 
• 
All/Major paravalvular leak  
• 
Non-structural valve deterioration 
• 
All/Major transvalvular leak 
• 
Trial valve-related mortality 
• 
Endocarditis 
• 
Valve thrombosis 
• 
Explant 
• 
All/Major valve-related bleeding 
• 
Thromboembolism 
• 
Valve-related reoperation 
• 
Hemolysis 
 
 
EFFECTIVENESS 
Effectiveness endpoints include the following:  
• 
Clinically acceptable hemodynamic performance confirmed by echocardiography and core lab 
evaluation which will include the following parameters: 
• 
Mean gradient 
• 
Peak gradient 
• 
Valvular regurgitation 
• 
TR gradient 
 
• 
Peak Velocity 
• 
Doppler Velocity Index (DVI) 
• 
Transvalvular VTI 
 
• 
Functional improvement from baseline: 
− 
NYHA for subjects older than 12 years 
− 
Modified Ross Heart Failure Classification for subjects 12 years and under 

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 ADDITIONAL CLINICAL MEASURES 
– 
White Blood Cell Count 
– 
Red Blood Cell Count 
– 
Hemoglobin 
– 
Hematocrit 
– 
Platelet Count 
– 
Plasma free hemoglobin or haptoglobin or serum LDH 
– 
INR/PTT 
– 
Urine urobilinogen (if necessary for subjects 12 years and under) 
 
 NUMBER OF SUBJECTS 
Clinical data will be collected from at least 3 centers with data available on patients who have completed 
the 1 year follow-up visit. Sites will not be allowed to implant more than 50% of total sample size. Up to 
one hundred (100) pulmonary valve replacement (PVR) subjects at up to ten (10) clinical sites will be 
enrolled.  
 METHODS OF FOLLOW-UP 
All subjects undergo a pre-operative echocardiogram to document the function of their current valve prior 
to surgery. Evaluation of the echocardiogram (echo) is performed by a qualified cardiologist at the site 
and over-read by an independent core lab. Other baseline exams include physical assessment, recording 
of pertinent medical history, electrocardiogram (ECG), NYHA or Modified Ross Heart Failure Classification, 
and selected hematological variables.  
Sponsor allows standard of care tests to be used for screening/baseline data collection provided they are 
performed within 60 days before implant date and there are no significant changes in subject’s condition 
that would invalidate the results.  Standard of care tests are performed for all valve patients scheduled 
for valve replacement surgery whether or not being considered for the trial. If the patient agrees to 
participate in the trial, they are then consented and any trial related tests are performed post consent.  
During the procedure, a transesophageal echo (TEE) will be completed. In addition, follow-up will occur 
at or prior to hospital discharge where physical assessment, ECG, echo and evaluation of selected 
hematological variables will occur. A post-op echocardiogram must be completed on or prior to post-
operative Day 10.  A telephone follow-up visit is conducted at POD 30 to document anti-thromboembolic 
therapy (medications), adverse events and determine NYHA or Modified Ross Heart Failure Classification. 
At 6 month follow-up visit, a physical assessment, NYHA or Modified Ross Heart Failure Classification, ECG, 

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echocardiogram, and selected hematological variables will be evaluated. The subsequent follow-up visits 
will be made annually thereafter up to 5 years.  Table 1 lists the follow-up visit time points and visit 
windows. 
Adverse events and anti-thromboembolic therapy/cardiac medications are collected from the time of the 
index procedure until the subject exits the clinical trial.  
Table 1.  Visit Follow-Up Schedule 
Visit 
Visit Window (Days) 
Timing from Implant (Day 0) 
Screening/Baseline 
_____ 
Day -60 to Day 0 
Index Procedure 
_____ 
Day 0 
Discharge1 
_____ 
Prior to Discharge to Day 10 
POD 302 
+/- 7 days 
              Day 23 to 37 
6 Months 
+/- 21 days 
Day 162 to Day 204 
Year 1 
+/- 30 days 
Day 335 to Day 395 
Year 2 
+/- 45 days 
Day 685 to Day 775 
Year 3 
+/- 45 days 
Day 1050 to Day 1140 
Year 4 
+/- 45 days 
Day 1415 to Day 1505 
Year 5 
+/- 45 days 
Day 1780 to Day 1870 
1 Subjects who are not discharged within 10 days post procedure must have an echocardiogram to assess performance of the 
trial valve. Those subjects will not require an additional echocardiogram at discharge. 
2 May be Clinic or Telephone Visit 
All subjects will be followed until five (5) year follow-up visit is completed and the last subject enrolled 
exits the trial. 
   
 
 

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8. TRIAL POPULATION 
 INCLUSION CRITERIA: 
Each subject is required to meet all of the following inclusion criteria: 
1. Has pulmonary valve disease requiring pulmonary valve replacement of their native or prosthetic 
valve 
2. Is greater than or equal to 5 years of age  
3. Subject and/or subject’s legal representative has provided written informed consent as approved and 
required by the respective institutional review board and agrees to its provisions.  NOTE: Written 
consent must be obtained prior to any research related test being performed. 
 EXCLUSION CRITERIA:  
A subject meeting any of the following criteria shall be excluded: 
1. Requires valve-in-conduit procedure 
2. Requires emergency surgery 
3. Has acute myocardial infarction (MI) within 30 days prior to screening date 
4. Has MRI or CT scan confirmed stroke, cerebrovascular accident (CVA) or transient ischemic attack 
(TIA) within 6 months (180 days) prior to screening date 
5. Has hemodynamic or respiratory instability requiring inotropic support, mechanical circulatory 
support, or mechanical ventilation within 30 days prior to screening date 
6. Has active endocarditis/myocarditis or endocarditis/myocarditis within 3 months prior to screening 
date 
7. Has renal insufficiency as determined by creatinine (S-Cr) level ≥ 2.5 mg/dL within 60 days prior to 
screening visit or end-stage renal disease  
8. Has documented leukopenia (WBC < 3.5x 103/µL), acute anemia (Hgb < 10.0 g/dL or 6 mmol/L), or 
thrombocytopenia (platelet count < 50x103/µL) accompanied by history of bleeding diathesis or 
coagulopathy within 60 days prior to screening date 
9. Diagnosed with abnormal calcium metabolism and hyperparathyroidism 
10. Echocardiographic evidence of an intra-cardiac mass, thrombus, or vegetation 
11. RVOT aneurysm unless treated during pulmonary valve replacement surgery 
12. Has prior organ transplant or is currently an organ transplant candidate 
13. Was previously implanted with INSPIRIS RESILIA Pulmonary valve 

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14. Previously implanted with an aortic, mitral, or tricuspid bioprosthetic valve, mechanical valve or 
annuloplasty ring  
15. Need for concomitant replacement of the aortic, mitral or tricuspid valves 
16. Has presence of non-cardiac disease limiting life expectancy to less than 12 months 
17. Is currently or has recently participated (within 6 weeks) in another investigational drug or device trial  
18. Positive urine or serum pregnancy test in female subjects of child-bearing potential and/or nursing 
mothers,  or planning to become pregnant within 1 year of study valve implant 
19. Has left ventricular ejection fraction ≤ 20% as validated by diagnostic procedure prior to screening 
date 
20. Currently incarcerated or unable to give voluntary informed consent 
21. Documented history of substance (drug or alcohol) abuse within the last 5 years prior to screening 
date 
22. Patients with hypersensitivity to metal alloys that contain cobalt, chromium, nickel, molybdenum, 
manganese, carbon, beryllium and iron  
23. Patients with hypersensitivity to latex 
Intra-Op Exclusion Criterion: 
24. Significant injury to the heart upon entry defined as emergent cardiopulmonary bypass requiring 
femoral cannulation 
 
 ENROLLED POPULATION 
Subjects will be included in the enrolled population after signing the informed consent, meeting all the 
enrollment criteria, and after the surgeon assesses the subject’s anatomy, sizes the annulus, and 
determines that the trial valve can be implanted. If the surgeon is unable to complete the implant 
procedure, the subject is considered “intent to treat” and will be followed for 30 days or until any device 
related adverse events experienced by subject are resolved.   
Each investigator or qualified designee screens subjects for potential inclusion into the trial. Screening 
results are used to make a final determination as to subject suitability for enrollment. Subjects must meet 
all applicable inclusion criteria and no pre-operative exclusion criteria at the time of enrollment evaluation 
in order to participate. 

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 INDEX VALVE POPULATION 
The investigational valve population includes all enrolled subjects that receive and retain the index valve. 
The analysis of the effectiveness endpoints and of the primary safety endpoint will be based on the 
investigational valve population. 
 SUBJECT AND TRIAL DURATION 
Total enrollment period for this trial is estimated to be 3 years.   
Subject participation begins with the enrollment of the first subject and ends after the last subject enrolled 
has completed the five (5) year follow up visit or has exited the trial.   
 
Overall trial duration is estimated to be 9 years.  This includes subjects being monitored, all outstanding 
data queries resolved and all trial sites closed to follow-up. 
 SUBJECT TERMINATION OR WITHDRAWAL 
Once enrolled, subjects may discontinue participation at any time by withdrawing informed consent or 
meeting the requirement for termination. Participation in the trial is entirely voluntary. Subject 
participation for any explanted patient will be terminated at either 30 days post-explant or when all post-
explant adverse events are resolved (whichever comes last). If the surgeon is unable to complete the 
implant procedure and/or subject meets intra-op exclusion criteria (see section 8.2), those subjects are 
considered enrolled as “intent to treat” and will be followed for 30 days or until any adverse events 
experienced by this cohort are resolved and then will be exited from the trial. 
9.   STATISTICAL METHODS 
 ANALYSIS POPULATION 
The analysis populations will include the enrolled population and the investigational valve population. The 
index valve population will include all subjects who meet enrollment criteria, provide written informed 
consent, meet intraoperative eligibility criteria and who receive the index valve.  The enrolled population 
will include the index valve population and the “intent to treat” population1.  For the enrolled population, 
the number of patients enrolled per site will be reported. Summaries of baseline and procedural data will 
 
1 If the surgeon is unable to complete the implant procedure, those subjects are considered enrolled as “intent to 
treat” and will be followed for 30 days or until any adverse events experienced by this cohort are resolved and 
then will be exited from the trial. 

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be based on the enrolled population. The analysis of mortality and all safety data shall in general be based 
on the investigational valve population. For the investigational valve population, the number of subjects 
implanted per site will be reported, stratified by valve size. 
 SAMPLE SIZE 
Up to 100 implanted subjects at up to 10 US sites will compromise the subject group.  See below for a 
power analysis.  
 STATISTICAL ANALYSIS 
 
SAFETY ANALYSIS 
9.3.1.1 
Primary Safety Endpoint 
The primary safety endpoint for the trial is freedom from device or procedure-related death and/or 
reoperation at 1 year. Survival probabilities and standard errors will be estimated using the Kaplan Meier 
method. Time to event will be calculated in days and freedom from death and reoperation at 1 year will 
be estimated at 365 days from the Kaplan Meier survival curve. Standard errors will use the Greenwood 
algorithm. If we let p denote the probability that an implanted subject will experience device or 
procedure-related death and/or reoperation at 1 year, then the null and alternative hypotheses for the 
primary safety endpoint are: 
H0: p > 25% 
Ha: p ≤ 25% 
The statistical test of the null hypothesis for the primary safety endpoint is based on a one-sided, upper 
95% confidence limit for device or procedural related death and/or reoperation at 1 year. If the upper 
95% confidence limit is less than 25%, the acceptance criterion for the primary safety endpoint will have 
been met.  
Based on a simulation, the power of the confidence interval above to reject the null hypothesis is 90% for 
the sample size of 100 patients receiving the 1-year visit.  For the purposes of power calculation, the 
simulation assumes an exponential survival model with a constant hazard rate of device or procedure-
related death or reoperation at 1 year of 15%; if a smaller rate is assumed, the power of the statistical test 
would be higher.  
Reoperation is defined as any operation that repairs, alters or replaces the study valve, which occurs after 
the completion of the procedure and the transfer out of the procedure room. 
9.3.1.2 
Secondary Safety Endpoints 
The secondary safety endpoints listed in 7.3 will be analyzed using the investigational valve population. 
Early adverse events within 30 days of procedure will be reported as the number of events divided by the 

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number of enrolled subjects.  Percentages for the early events will also be calculated for all other 
complications observed in the trial, including reoperation and/or death. 
Actuarial rates based on the method of Kaplan - Meier will be calculated for the primary safety endpoint, 
and for each of the safety events in Section 7.3 at each of the follow-up time points; the number of 
subjects at risk of the event will be reported at each of these intervals. 
A sub-analysis for patients receiving valve-in-valve procedures will be made via descriptive method. 
 
EFFECTIVENESS ANALYSIS 
The following effectiveness endpoints will be analyzed using the investigational valve population.  
The following parameters will be summarized at baseline and at each follow-up visit for all subjects in 
the investigational valve population: 
• 
Peak pressure gradient  
• 
Mean pressure gradient  
• 
TR gradient 
• 
Valvular regurgitation 
 
• 
Peak Velocity 
• 
Doppler Velocity Index (DVI) 
• 
Transvalvular VTI 
 
Valvular regurgitation will be summarized by the number and percentage of subjects in each level of 
regurgitation.  All other parameters will be summarized by N, mean, and standard deviation, and a 95% 
confidence interval. These summaries will be stratified by valve size. 
 
NYHA CLASS 
A comparison of preoperative and postoperative NYHA functional class (presented as the percentage of 
subjects in each class at baseline, at each follow-up time-point, and as the percentage of subjects at each 
follow-up time-point who improved, worsened, or did not change in class) will be presented for all 
subjects greater than 12 years old.  This comparison will be based on the investigational valve population.  
Additionally, a cross-tabulation of baseline vs. POD 390 NYHA will be presented for all subjects in the 
investigational valve population with both baseline and POD 390 NYHA data. Additionally, the summaries 
described above will be presents using the Modified Ross Heart Failure Classification for subjects aged 12 
and under.   
 ADDITIONAL MEASURES 
 
BLOOD DATA 
For all measured blood parameters, individual results will be compared to documented normal ranges.  
The Investigator will determine for each parameter that is out-of-range whether the value is not clinically 
significant and summary statistics will be provided.   

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Summary statistics (N, mean, and standard deviation) will be calculated preoperatively and post-
operatively.  In addition, the percentage of patient within the normal range preoperatively and post-
operatively will be calculated.  The percentage of patients within the normal range post-operatively will 
be reported separately for patients within and without the normal range preoperatively and for all 
patients combined. 
 POOLABILITY 
Subject baseline risk will be statistically compared among centers for the enrolled population.  Chi-square 
tests will be used to compare categorical risk factors while analysis of variance will be used to compare 
continuous risk factors.  Comparisons will be based on the following demographic and pre-operative 
variables: age, sex, and pre-operative NYHA or Modified Ross Heart Failure Classification.   
Early and late adverse event rates for the investigational valve population will be compared between the 
sites for each of the adverse events listed in the Safety Endpoints Section 7.3.1.  Early event rates will be 
compared with a logistic regression model; late event rates will be compared with an exponential hazards 
regression model.   
 ANALYSIS OF COVARIATES 
A hazard regression analysis will be performed to test for the effect of gender, age at implant, pre-
operative NYHA functional classification or Modified Ross Heart Failure Classification, previous valve 
surgery, right ventricular function, BMI, and implant size on survival. This analysis will be performed by 
using a Cox proportional hazards model and will be based on the enrolled population. Additionally, the 
rate for each of the adverse events listed in the Safety Endpoints Section 7.3.1 will be compared between 
the genders via a Cox regression analysis.  
Finally, the effect of gender on each of the following effectiveness endpoints at POD 390 (1 year) will be 
investigated with a linear regression model: peak gradient, mean gradient, and TR gradient.  These linear 
regression models will be adjusted by BSA (to adjust for the effect of body size), and by valve size.  The 
effect of gender on all valvular regurgitation at POD 390 (1 year) will be investigated via a proportional 
odds model; this model also will be adjusted by BSA, and by valve size. 
 MISSING DATA 
All statistical tests on the effectiveness endpoints will be performed using only those subjects with 
available data required for endpoint analysis.  No missing value imputation will be performed. 

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 FOLLOW-UP AND COMPLIANCE DATA 
The number of valve population subjects followed to 390 days post-implant will be reported stratified by 
site and valve size; follow-up duration information, including mean follow-up, standard deviation and 
range of follow-up, and cumulative follow-up in subject-years will be reported for the valve population. 
Subject compliance will be calculated and reported as the following four percentages:  the number of 
subjects a) having completed follow-up visits; b) with NYHA functional classification or Modified Ross 
Heart Failure Classification data; c) with echocardiographic data; and d) with clinical laboratory results at 
each follow-up time-point, divided by the total number of implanted subjects available (i.e., who have not 
died or had their valve explanted) and eligible (i.e., who have reached the given time-point) for follow-up 
at that particular time-point.  Compliance will be reported for each follow-up visit and will be based on 
the investigational valve population. 
10. TRIAL PROCEDURES 
The following section provides a summary of the tests and measurements to be conducted at 
baseline/screening, operatively, prior to discharge, and during follow-up.  
 
. 
 
SUBJECT SCREENING 
All subjects requiring pulmonary valve replacement as assessed by cardiac surgeon participating in this 
clinical trial should be screened for eligibility. Subjects who may meet eligibility requirements will be asked 
to participate.  
A “Screening Log” is provided to the investigational sites to maintain a cumulative log of all screened 
subjects. For subjects who are ineligible for participation in the clinical investigation, a reason supporting 
the disqualification of the subject must be entered on the Screening Log. Any subject deemed ineligible 
due to active or recent endocarditis, acute anemia, pregnancy, or participation in another clinical 
investigation may be re-screened later. Re-screened subjects will be assigned another unique subject ID 
number and must be re-entered on the Screening Log. 
 
INFORMED CONSENT 
Written informed assent and/or consent, in accordance with FDA and IRB regulations shall be obtained 
from each subject and/or or the subject’s legal representative prior to research related procedures. The 

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investigator retains a copy of the signed informed consent document in each subject’s record, and 
provides a copy to the subject.  
The Investigator or designee (identified in Delegation of Authority Log) must obtain the written informed 
consent of all subjects, and must not allow any subject to participate in the investigation prior to obtaining 
governing institutional review board (IRB) approval. Before starting the trial, the investigator provides trial 
Sponsor with a copy of the sample Informed Consent document approved by the IRB with documented 
evidence that the IRB approved the protocol and the informed consent. 
 
 
 
 
 
 
SCREENING/BASELINE ASSESSMENT 
Sponsor allows standard of care tests to be used for screening/baseline data collection provided they are 
performed within 60 days before implant date and there are no significant changes in subject’s condition 
that would invalidate the results.  Standard of care tests are performed for all valve patients scheduled 
for valve replacement surgery whether or not being considered for the trial. If the patient agrees to 
participate in the trial, they are then consented and any trial related tests are performed post consent.  
The following baseline data is obtained as noted in Table 2 below. This data includes physical assessment, 
demographic and medical history, 12-lead electrocardiogram (ECG), echocardiogram, blood studies, an 
assessment of NYHA or Modified Ross Heart Failure Classification, and INR or PTT.  

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Table  2. Screening/Baseline Assessment 
Clinical/Physical Assessment 
Blood Studies 
Echocardiography (TTE 
or TEE) 
Date of Assessment 
Date of Birth 
Sex/Gender 
Height 
Weight 
Heart Rate 
Blood Pressure  
Cardiac Rhythm (12-lead 
ECG) 
NYHA Classification or 
Modified Ross Heart Failure 
Classification  
Anti-thromboembolic 
Therapy 
(cardiac medications)  
Cardiovascular Risk Factors 
Cardiovascular Conditions 
Previous Procedures / 
Interventions 
Non-Cardiovascular 
Conditions 
Pregnancy Test* 
 
* negative urine or serum 
pregnancy test  ≤ 7 days 
prior to procedure in female 
patients of child bearing 
potential is required 
Blood Draw Date 
White Blood Cell Count 
Red Blood Cell Count 
Hemoglobin 
Hematocrit 
Platelet Count 
Plasma Free Hemoglobin or 
 Haptoglobin or Serum LDH 
Serum Creatinine 
INR/PTT* 
 
*INR/PTT will be determined 
for subjects on anticoagulant 
therapy only. 
 
Date of Exam 
 
 
REFER TO ECHO 
MANUAL 
 
 
 
VALVE REPLACEMENT PROCEDURE 
All procedures are performed in an operating room, or a surgical suite having cardiac surgery and 
anesthesia services. The surgical approach used is at the discretion of the Investigator’s routine surgical 
practice. TEE will be performed unless contraindicated (e.g., in the event of esophageal varices) to assess 
valve placement and function, including PVL.   
Note: The INSPIRIS RESILIA Pulmonary Valve, Model 11500P does not require rinsing prior to implant. 
Note: If the valve is rinsed prior to implant, it must be kept hydrated with sterile physiological solution 
throughout the remainder of the surgical procedure. Rinsing every 1-2 minutes is recommended. Caution: 
Contact of the leaflet tissue with any articles or sources of particulate matter should be avoided. 
Procedural information, findings, results and device identification information to be recorded are 
identified in Table 3. 

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Table  3.  Procedural Information 
General Information 
Clinical Information 
Device Information 
Echocardiography (TEE) 
Date of Admission 
Date of Procedure 
Implanting Surgeon 
Adverse Events 
 
Etiology 
Diagnosis for Replacement 
Valve Implant/ Valve Position 
Sizing 
Condition of the Native Valve 
Concomitant Procedures 
Intra-operative Adverse 
Events 
 
Valve Size and Serial 
Number 
Valve Performance 
 
Post-operative TEE  
REFER TO ECHO MANUAL 
 
 
POST INDEX VALVE IMPLANT 
At the discretion of the investigator, bioprosthetic heart valve recipients should be maintained on 
antithrombotic therapy (except when contraindicated) after implant, in accordance with current 
American College of Cardiology/American Heart Association (ACC/AHA) Guidelines/ American College of 
Chest Physicians (ACCP) Guidelines. Therefore, the appropriate antithrombotic therapy must be 
determined by the physician on an individual basis. Additionally, bioprosthetic heart valve recipients 
should have antibiotic prophylaxis at the time of all dental procedures per current AHA Guidelines. 
Patients should be encouraged to carry their Patient Identification Card at all times and to inform their 
healthcare providers that they have an implant when seeking care. 
 
DISCHARGE 
The medical information and clinical evaluation of trial subjects at discharge is identified in Table 4. 
Subjects not discharged within 10 days post procedure must have an echocardiogram completed, before 
or on day 10, to assess placement and performance of the index valve. This echocardiogram is required 
to complete the evaluation of short-term valve function. Those subjects will not require an additional 
echocardiogram on the day of discharge. 
 
 

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Table  4.  Discharge Information 
Clinical/Physical Assessment 
Blood Studies 
Echocardiography (TTE) 
Date of Discharge 
Weight 
Heart Rate 
Blood Pressure  
Cardiac Rhythm (12-lead ECG) 
Anti-thromboembolic Therapy 
(cardiac medications) 
Adverse Events 
Blood Draw Date 
White Blood Cell Count 
Red Blood Cell Count 
Hemoglobin 
Hematocrit 
Platelet Count 
Plasma Free Hemoglobin or 
   haptoglobin or serum LDH 
INR/PTT* 
 
*INR/PTT will be determined for 
subjects on anticoagulant therapy 
only. 
 
Blood Labs and INR/PTT may be 
omitted (if not clinically indicated) in 
children (subjects 12 years and under) 
but must be substituted with spot 
urine urobilinogen for hemolysis 
evaluation.  
Date of Exam 
 
REFER TO ECHO MANUAL 
 
 
POST DISCHARGE FOLLOW-UP ASSESSMENTS 
Post-procedure clinical evaluation is performed on all trial subjects at the investigational site. Information 
to be recorded at scheduled visits is further detailed in Table 5.  
During each postoperative follow-up visit, the investigator(s) will determine the subject's availability for 
future follow-up visits. If any subject needs to be seen at a time other than a regularly scheduled follow-
up visit, the required data collection would be the same as the 6 month follow-up evaluation and the data 
recorded as an interim visit.  
 
 

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Table 5.  Follow-Up Information at all Post-Discharge Visits 
Visit 
Clinical/Physical 
Assessment 
Blood Studies 
Echocardiography (TTE) 
30 Day Follow Up Visit 
NYHA Classification or 
Modified Ross Heart Failure 
Classification  
Anti-thromboembolic Therapy 
(cardiac medications) 
Adverse Events 
Not required 
*only if clinically indicated  
 
 
Each visit at 6 mos and 
annual visits 
  
Weight 
Heart Rate 
Blood Pressure  
Cardiac Rhythm (12-lead ECG) 
NYHA Classification or 
Modified Ross Heart Failure 
Classification  
Anti-thromboembolic Therapy 
(cardiac medications) 
Adverse Events 
Blood Draw Date 
White Blood Cell Count 
Red Blood Cell Count 
Hemoglobin 
Hematocrit 
Platelet Count 
Plasma Free Hemoglobin or 
   haptoglobin or serum LDH 
INR/PTT* 
 
*INR/PTT will be determined 
for subjects on anticoagulant 
therapy only. 
 
Blood Labs and INR/PTT may 
be omitted (if not clinically 
indicated) at Day 30 in 
children (subjects 12 years 
and under) but must be 
substituted with spot urine 
urobilinogen for hemolysis 
evaluation. 
REFER TO ECHO MANUAL 
All efforts should be taken by the Investigator and the research staff to encourage subjects to return for 
required follow-up visits.  If a subject cannot return for follow-up visits, all attempts will be made to collect 
the protocol-specified data from outside hospitals or clinics. 
 
 
 
 
 
MISSED FOLLOW-UP 
The Investigator(s) will make every attempt to follow the subjects. All subjects will be encouraged by the 
Investigator(s) to report any address or telephone number changes to the trial site. Subjects should be 
informed of the importance of returning for scheduled follow-up visits, even if they are not having any 
medical issues. 
If a subject cannot be reached for a follow-up visit, the site will document on the CRF, the efforts 

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undertaken to contact the subject or the subject’s primary health care provider. These efforts should 
include three (3) attempts of telephone contact (telephone attempts should include next of kin or care 
giver if available) at least one month apart and a registered letter sent before the end of the follow-up 
window. Subjects who miss two (2) sequential follow-up visits will be considered lost to follow-up at the 
second missed visit and exit from the trial.  After the subject is exited from the trial, the 
Investigator/designee will attempt to determine if the subject is alive, including searching national 
mortality registries as permitted by local laws. 
 
STUDY EXIT 
Trial subjects exit the trial when no additional follow-up visits, procedures, or data collection are required. 
A subject is exited from the trial in the following instances: 
 Fails enrollment criteria after written consent 
 Is Lost-to-follow-up (LTFU) 
 Voluntarily withdraws from the trial  
 Death 
 Explant  
 Valve-in-Valve* 
 Does not retain trial valve after attempt to implant 
 Completes five (5) year follow-up visit (at POD 1825) 
 Investigator withdraws the subject from the trial 
* Enrolled subjects implanted with the study valve requiring valve‐in‐valve (ViV) reoperation will be 
 assessed at day 30 post ViV procedure date for assessment of device related events.  Subjects will be 
monitored up to 90 days post ViV procedure. 
• 
If no device related adverse events are observed per CEC determination, patients will be 
exited from the trial at day 90 post ViV.  
• 
If there are device related adverse events observed per CEC determination, subjects will be 
continued to be followed until resolution of event(s).  
Valve‐in‐valve data will be captured as part of the Case Report Form process. 
 
EXPLANT 
Implantation of the investigational valve is considered complete once proper placement of the valve is 

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confirmed and patient leaves the procedure room.  Proper placement of the valve will be confirmed by 
surgeon and echocardiologist by means of an intra-op transesophageal echocardiogram (TEE) confirming 
normal leaflet mobility and clinically acceptable study valve regurgitation.  If removal is required from this 
point forward, it will be considered an explant.  
In the event a valve is explanted, a copy of the procedure report must be provided to the trial Sponsor. 
Information on the cause of explant and its relationship to the valve will be provided by the investigator(s). 
Explanted valves must be returned to the trial Sponsor for analysis. Return kits for devices will be provided 
by the trial Sponsor. 
11. ADVERSE EVENTS 
 
REPORTING 
Adverse event (AE) information is reported throughout the clinical investigation.  AEs are reported from 
the time of the valve implant procedure (index procedure) until subject participation has ended (study 
exit).  At each evaluation, the Investigator will determine whether any adverse events (AEs) have occurred. 
For the purpose of this protocol, an adverse event is any undesirable medical occurrence in a subject. This 
definition does not depend on a causal relationship with the device or the protocol requirements. Adverse 
events are followed until they are adequately resolved.   
Adverse events may be volunteered by subjects, elicited from questioning or collected via observation. 
The Investigator or designee will determine whether or not the event is related to the device and/or 
procedure, and whether or not the event meets seriousness criteria. If it is determined that an AE has 
occurred, the Investigator should obtain all the information required to complete the AE Case Report 
Form.  In addition, subjects will be instructed to contact the Investigator, and/or study coordinator if any 
significant adverse events occur between study evaluation visits. 
Each event shall be assessed for severity using the definition of a serious adverse event (SAE) or not and 
SAE (see section 11.1.1).  Each event shall be assessed for causality (see section 11.1.2) and if the event is 
anticipated or unanticipated, as described in section 11.1.3 and 11.1.4. 
Pre-existing medical conditions or symptoms reported prior to device implantation will not be recorded 
as an AE. In the event there is a change in the pre-existing medical condition or symptoms due to the 
device or related procedure, then an AE must be recorded. 

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Multiple events of the same complication in the same subject will be counted as a single event if the 
complication does not resolve. For example, if a subject experiences multiple TIAs in a two-week period, 
only one event will be included in the linearized rate, although all events will be reported as a cluster.  
If, however, a subject has a stroke and then 6 months later experiences another stroke, both events will 
be included in the calculation of the linearized stroke rate. 
 SERIOUS ADVERSE EVENTS 
An Adverse Event is considered serious if the event results in or is: 
• 
Death 
• 
Life‐threatening 
• 
Hospitalization or prolonged hospitalization 
• 
Disability or permanent damage 
• 
Congenital anomaly or birth defect 
• 
Intervention to prevent permanent impairment or damage 
• 
Other serious or  important medical events – medical or surgical intervention to prevent one of 
the above outcomes 
Investigational sites report all applicable serious adverse events in accordance with the reviewing 
IRB’s requirements.  
  
 CAUSALITY 
For the adverse events reported from the sites, the causal relationship to the device and the procedure 
should be rated as follows: 
• 
Related: Evidence exists that the trial device or procedure caused the adverse event.  There is a 
temporal relationship between the event onset and trial device or procedure.  The subject’s clinical 
state and concomitant therapies are ruled out as a cause. 
• 
Not Related: There is no relationship between the event and the device or procedure. Evidence exists 
that the adverse event definitely has a cause other than the trial procedure or device (e.g., pre-existing 
condition or underlying disease, intercurrent illness, or concomitant medication) and does not meet 
any other criteria listed.   
• 
Undetermined: There is no evidence or relevant data available to assess the relationship between the 
event and the device or procedure. 

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 ANTICIPATED ADVERSE EVENTS 
Anticipated adverse events are AEs that have been identified as possible adverse events associated with 
the investigational device, or procedure. 
 
 
 
 UNANTICIPATED ADVERSE DEVICE EFFECTS 
An unanticipated adverse device effect (UADE) is any serious adverse effect (SAE) on health or safety or 
any life threatening problem or death caused by or associated with the device, if that effect, problem, or 
death was not previously identified in nature, severity, degree of incidence in this Investigational Plan 
(including a supplementary plan or application)- see Risk Section 6.2 and IFU for a list of anticipated 
events.  Additionally, an unanticipated adverse event includes any other unanticipated serious problem 
associated with the device that relates to the rights, safety, or welfare of subjects.   
Investigator(s) are required to submit to the reviewing IRB and the trial Sponsor a report of any 
unanticipated adverse device effect (UADE) occurring during this investigation as soon as possible, but 
in no event later than ten (10) business days after the investigator(s) first learns of the event (21CFR 
812.150(a)(l)).  The trial Sponsor must immediately conduct an evaluation of an UADE, and must report 
the results of the evaluation to FDA, all reviewing IRB/REB/ECs, and participating investigators within ten 
(10) business days after the trial Sponsor first receives notice of the event (21CFR 812.46(b), 
812.150(b)(l)). 
If it is determined that an UADE occurred, the trial Sponsor will notify the Data Monitoring Committee 
(DMC) within five (5) business days after the trial Sponsor or its designee first receives notice of the event. 
If the trial Sponsor and/or the DMC determines an event or event rate presents an unreasonable risk to a 
subject, all investigations or parts of investigations presenting that risk are terminated, as soon as 
possible. All trial subjects enrolled at the time the trial is terminated, will be followed by the Clinical 
Investigator for a period of five (5) years from the date of enrollment. 
 
NOTIFICATION OF UADE AND/OR SERIOUS DEVICE RELATED 
ADVERSE EFFECTS 
Notification of UADE and serious device related adverse effects should be done via RDC entry and phone 
call to Trial Manager. 

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DEATH AND EXPLANTS 
 DEATHS 
The site will send the Sponsor copies of an autopsy report, if available, and/or a death summary. The 
Investigator/designee will provide information about the cause of death and will determine relationship 
to the clinical investigational device. Deaths and UADEs will be reported to the DMC within five (5) 
business days after Edwards Lifesciences or its designee first receives notice of the event. The Clinical 
Events Committee (CEC) will also adjudicate each death for device relatedness and procedure relatedness.  
If explant of a device occurs during autopsy, return the device to the Sponsor for analysis. Return kits for 
explanted devices will be provided upon request by the clinical site manager. 
 EXPLANT REPORTING 
In the event a trial valve is explanted in the intra-operative or early post-operative period (i.e., while the 
subject is hospitalized at the investigational center), a copy of the procedure report must be provided to 
the Sponsor. Information on the cause of the explant and its relationship to the valve will be determined 
by the Investigator/designee. Explanted trial valves during this period must be returned to the Sponsor 
for analysis. Return kits for explanted devices will be provided upon request by the clinical site 
manager. 
In the event a trial valve is explanted in the late post-operative period, the Investigator/designee will 
provide information on the explant and determine the relationship to the trial valve. Every effort should 
be made to supply copies of available explant reports, to the Sponsor. As soon as possible, explanted trial 
valves should be returned to the Sponsor for analysis. Sponsor will provide “return kits” for explanted 
devices upon request by the clinical site manager. 
 
DATA MONITORING COMMITTEE 
The trial Sponsor will appoint a Data Monitoring Committee (DMC) composed of two or more independent 
physicians including a cardiothoracic surgeon and a cardiologist, and a statistician. Members of the DMC 
will not have scientific, financial, or other conflict of interest related to the Sponsor or the Investigators. 
DMC members must sign a non-conflict-of-interest statement in this regard. The primary purpose of the 
DMC is to ensure a consistent, independent review of aggregate safety data during the enrollment period 
to determine if the trial is being conducted safely and will decide if the clinical investigation should be 
modified, suspended, and/or stopped. The DMC will establish guideline criteria for recommending trial 

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termination. The DMC activities and meeting schedule is regulated by the DMC Charter.  The DMC will 
meet at least yearly or more often as determined by the Chairperson and possibly on an ad hoc basis to 
evaluate trial progress and results during the enrollment phase. 
 
CLINICAL EVENTS COMMITTEE (CEC) 
The Clinical Events Committee (CEC) is an independent institutional adjudicator which evaluates the 
adverse events that are endpoint related as well as those resulting in death. The CEC adjudicates early 
and late events for their relatedness to the investigational device and/or the valve implant procedure. 
The CEC activities and adjudication process is described in the CEC Adjudication Charter.  
The trial Sponsor will provide the CEC completed case report forms and any relevant source 
documentation/ subject information as provided by the clinical site investigators. The trial Sponsor will 
ensure that all information is de‐identified before presenting to the committee.  
12. TRIAL AND DATA MANAGEMENT 
 
ECHOCARDIOGRAPHY CORE LAB 
The Echocardiography Core Lab is responsible for independently evaluating echocardiograms submitted 
preoperatively and postoperatively by trial sites, and for reporting of hemodynamic and other valvular 
function results. The purpose of the Echocardiography Core Lab is to ensure unbiased, timely and 
consistent analysis of the diagnostic data, and for evaluating changes in subject status over the course of 
the trial based on serial echocardiographic studies conducted on the same subject. 
Personnel at the Echocardiography Core Lab must demonstrate appropriate training and experience for 
analyzing Doppler Echocardiography data.  Echocardiograms will be sent directly from the investigational 
sites to the Echocardiography Core Lab. The Echocardiography Core Lab reviews the Doppler 
echocardiograms upon receipt, and promptly notifies the site and the trial Sponsor if the quality of the 
echocardiograph is insufficient for analysis.  
 
 
 
DEVICE ACCOUNTABILITY 
An initial set of trial valves are shipped to the clinical site once the following conditions are met: FDA 
approval has been obtained, the site obtained regulatory approval (Institutional Review Board), and a 
signed Clinical Trial Agreement is in place. Additional devices are sent to the clinical site as devices are 
used or as needed. 

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 INVENTORY AND ACCOUNTABILITY RECORDS 
A Device Accountability Log is maintained by the Investigator noting all investigational devices received 
for use or returned during this clinical trial. The log is kept with the documents for the clinical trial and is 
available for review during trial Sponsor monitoring visits.  
All device shipments include inventory and shipment records (packing slip). The Principal Investigator or 
designee will take inventory of the product, complete the delivery documentation with receipt date, note 
the condition of the device(s), and complete the delivery documentation by signing the packing slip and 
dating with the receipt date.  Both the investigational site and the trial Sponsor retain copies of the packing 
slips and the Device Accountability Log. 
 DEVICE STORAGE 
The device inventory is to be stored in a locked, controlled, cool, dry and clean area as per the Instructions 
for Use for device storage. This storage area shall be accessible only to the Principal Investigator(s), Co-
Investigator(s) or approved designee(s). Only cardiac surgeons identified in the Clinical Trial Agreement 
and/or on the Delegation of Authority form on file may implant the investigational device. 
 DEVICE RETURN 
The Principal Investigator(s) is notified in writing upon termination of the clinical trial. All unused devices 
in original package and/or those in opened packages will be returned upon receipt of this notice as 
described in the IFU. The Investigator’s copy of the Device Accountability Log must document any unused 
devices that are returned. The trial Sponsor will provide shipping instructions. 
 
PROTOCOL DEVIATIONS 
A protocol deviation is defined as an event where the Investigator or trial personnel did not conduct the 
trial according to the clinical protocol or the Clinical Trial Agreement.  
Deviations shall be reported to the trial Sponsor regardless of whether medically justifiable or taken to 
protect the subject in an emergency. Subject specific deviations and non-subject specific deviations, (e.g. 
unauthorized use of a trial device outside the trial, unauthorized use of a trial device by a physician who 
is not listed in the Clinical Trial Agreement, etc.) will be reported to Sponsor. Investigators will adhere to 
procedures for reporting trial deviations to the IRB/EC/REB in accordance with their specific reporting 
policies and procedures. 

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For reporting purposes, deviations are classified as major or minor: 
Major deviations – Major deviations will be documented on the appropriate case report form provided 
and reported to the trial Sponsor within 3 business days of awareness.  Additionally, these deviations will 
be reported to the IRB/REB/EC per institutional guidelines.  A major deviation is one that impacts subject 
safety, may affect the quality/integrity of study data, or leads to failure of meeting regulatory 
commitments.  Examples include:  
• 
Subject enrolled not meeting enrollment criteria  
• 
Informed consent not obtained  
• 
Loss or theft of data or breach of data security 
• 
UADE not reported to IRB/Sponsor within the required timeframe  
• 
Unauthorized use/implant of an investigational device  
The following escalation process will be followed for major deviations:  
• 
Investigator/Sponsor will promptly investigate root cause and secure compliance 
• 
Formulate corrective actions 
• 
Verify effectiveness of the corrective actions 
Minor deviations – Minor deviations do not pose a risk to subject safety; data integrity; study endpoints; 
or regulatory commitments. Minor deviations will be reported to the trial Sponsor on the appropriate 
case report form provided; and to the IRB/REB/EC per their guidelines.  Examples include: 
– 
Deviation from a protocol requirement such as incomplete/inadequate testing procedures (if this 
type of deviation does not pose a risk to subject safety); 
– 
Follow-up performed outside specified time windows in the protocol  
 
TRAINING AND MONITORING 
 TRAINING 
12.4.1.1 SPONSOR TRAINING RESPONSIBILITIES 
Sponsor will provide training on device usage, the protocol, the Electronic Data Capture (EDC) system, and 
Investigator/Designee Responsibilities per applicable country regulation (i.e., FDA CFRs for US Sites; 
ISO14155 for EU Sites). Training methods include live or online training sessions, teleconference, WebEx, 

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and/or read and review. Site personnel training requirements will be dependent on study role/delegated 
tasks defined in the site’s Delegation of Authority Log (DOA).  
A Training Matrix will outline the training requirements based on study roles and delegated tasks and/or 
nature of document revision (i.e., protocol amendment). The Training Matrix will be filed in the study 
master file.   
 SITE TRAINING RESPONSIBILITIES 
A Delegation of Authority Form (DOA) is completed by Investigator designating which individuals are 
allowed to perform specific clinical trial related tasks. Investigator or designee will be responsible for 
communicating/documenting site personnel changes from the Delegation of Authority (DOA) to the 
Sponsor. 
Investigators (Principal Investigators, PI) who conduct clinical investigations of medical devices under 21 
CFR Part 812, commit themselves to conducting the investigation in accordance to the Clinical Study 
Agreement, protocol, and applicable FDA regulations for patient safety and control of the investigational 
devices. When tasks are delegated by an Investigator, the PI should ensure that any individual to whom a 
task is delegated is qualified by education, training, and experience to perform the delegated task.  
Site personnel training is documented on a “Training Log” provided by the trial Sponsor, which the trainee 
must sign and date.  
 MONITORING 
Written procedures have been established by the trial Sponsor for monitoring clinical investigations, to 
assure the quality of the trial and to assure that each person involved in the monitoring process carries 
out his or her duties. Standardized written procedures, sufficiently detailed to cover the general aspects 
of clinical investigations, will be used as a basic monitoring plan and will be supplemented by more specific 
/ additional procedures specific to this clinical investigation. 
A pre-trial monitoring visit or meeting will be conducted to ensure that the Investigator clearly 
understands and accepts the obligations incurred in undertaking the clinical investigation as listed in Table 
6 (Regulations and Guidelines), and that the facilities are acceptable.   Periodic monitoring visits will be 
conducted with adequate frequency to ensure that the Investigator’s obligations as set forth in 21 CFR 
Parts 50, 56 and Part 812 are being fulfilled and that the facilities continue to be acceptable.  

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The trial Sponsor will assign a monitor to oversee the progress of the clinical investigation at each 
investigational center. The monitor will remain in close contact with each investigational center 
throughout the duration of the investigation to provide any needed materials, (i.e., investigation forms) 
and answer any questions. The monitor will be responsible for verifying that the subject signed the 
consent, reviewing all data recorded on the eCRFs, and visiting each investigational center periodically to 
observe trial progress and compliance with clinical protocol and regulations applicable to this clinical 
investigation.  Additionally, the monitor will provide assurance that complete records are being 
maintained, appropriate timely reports are made to the trial Sponsor and IRB/REB/EC, device inventory is 
controlled, and that the Investigator is carrying out all agreed upon activities. Any personnel changes must 
be reported to the monitor immediately and a training program must be scheduled and documented.   A 
close out monitoring visit will be conducted at the completion of the clinical trial to ensure that all data 
are properly documented and reported. 
The Sponsor may perform Investigator audits to evaluate compliance with regulatory requirements, the 
protocol, study agreement, and IRB policy and procedures.  
 
DOCUMENTATION REQUIREMENTS 
 SOURCE DOCUMENTS 
Clinical regulations require that Investigators maintain information in the clinical trial subject’s medical 
records that corroborate data collected on the eCRF. Certain data elements (e.g., blood pressure, weight, 
temperature, resolution of a symptom or sign) in a clinical investigation can be obtained at a study visit 
and can be entered directly into the eCRF by an authorized data originator. This direct entry of data can 
eliminate errors by not using a paper transcription step before entry into the eCRF. For these data 
elements, the eCRF is the source. If a paper transcription step is used, then the paper documentation 
should be retained and made available for FDA inspection and Sponsor Monitoring.  Sites will identify data 
elements entered directly in the eCRF (e.g., blood pressure, weight, temperature, resolution of a symptom 
or sign). 
To protect subject confidentiality, the subject’s name must not appear anywhere on the imaging media 
sent to trial Sponsor e.g. for reporting serious adverse device effects (SADE), or prepared for evaluation 
by the core lab. Each page should be identified with the subject’s unique trial ID number. All other subject 
identifiers (i.e. medical record number, personal number) are to be obscured. Original copies of all data 
must be kept at the site. 

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Site monitoring will include 100% source verification of events contributing to the safety and effectiveness 
endpoints and unanticipated adverse device effects (UADE).  
 TRIAL DOCUMENTS 
The trial Sponsor will provide pre-printed forms to each trial site for documentation of: 
• 
Investigator and site training to the protocol (Training Log) 
• 
Authorized trial site personnel (Delegation of Authority) 
• 
Subject consent and screening (Screening and Enrollment Log) 
• 
Monitoring visit tracking (Site Visit Log) 
• 
Investigational Device Accountability (Investigational Device Accountability Log) 
The site visit is recorded on the appropriate site visit report. All tasks and action items noted during the 
visit should be documented with detailed findings and comments provided as appropriate. The monitor 
provides a visit follow-up letter to the investigator and other appropriate trial staff briefly summarizing 
the visit and specifically addressing any outstanding issues and/or action items from the visit, any incidents 
of noncompliance with the protocol or applicable regulations noted during the visit, and any necessary 
corrective actions.  
During the course of the clinical trial, all correspondence (letters, records of telephone calls, emails and 
faxes) regarding the trial must be maintained in the regulatory binder provided by the trial Sponsor. This 
binder must be made available for monitoring visits and audits. 
 
DATA COLLECTION 
All required data for this trial are to be collected with standardized Case Report Forms (CRF) for individual 
subjects; 
. Electronic CRF (eCRF) 
will be utilized for this trial. Each eCRF must be signed electronically by the Principal Investigator listed in 
the Clinical Trial Agreement and Delegation of Authority Log. If for any reason an eCRF is unavailable 
and/or inaccessible, a paper CRF will be provided by the trial Sponsor to be completed, signed by the 
Principal Investigator or designee and submitted to the trial Sponsor. 
 
Case Report Form Instructions will be provided to assist the Investigator(s) and appropriate trial staff with 
the completion of each required eCRF. 

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The Sponsor’s data management group is responsible for database development and validation, database 
maintenance, control and management of data collected from CRFs, data validation, and statistical 
support.  The Data Management team will employ a full-featured relational database application (or 
equivalent) on a central server, and the system is fully compliant with 21 CFR Part 11 regulations. The 
application provides the capability of secured data collection remotely through the Internet so authorized 
personnel at participating sites may log on to the system and enter the data. Other data management 
programming and/or data analyses activities will be done within the trial Sponsor’s internal network.   
 
DATA AND DOCUMENT RETENTION 
Trial-related correspondence, subject records, consent forms, records of device implant, and source 
document worksheets are to be maintained on file by the trial site. The trial Sponsor requires that it be 
notified in writing if the Principal Investigator wishes to relinquish ownership of the data and information 
so that mutually agreed upon arrangements can be made for transfer of ownership to a qualified entity.  
Per FDA regulation 21 CFR 812.140, records of each subject’s participation in the trial must be maintained 
for a period of two (2) 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 or a notice of completion of a product development protocol. 
 
TRIAL PROTOCOL AMENDMENTS 
Changes in the protocol are made only by written amendment agreed upon by the trial Sponsor, the 
applicable regulatory agency, including the United States Food and Drug Administration, and if pertinent, 
the IRB/REB/EC. As appropriate, the trial Sponsor will submit changes in the protocol to the applicable 
regulatory agencies, including the United States Food and Drug Administration and investigators to obtain 
IRB/REB/EC re-approval. A report of withdrawal of IRB, REB or EC approval must be submitted to the trial 
Sponsor within five (5) business days. Any revisions to the protocol, including the Informed Consent Form 
other than very minor revisions must be approved by trial Sponsor, the IRB/EC/REB and the FDA and/or 
other regulatory agencies. 
 
TRIAL COMPLETION 
The principal investigator will be notified in writing upon termination/conclusion of the clinical trial. The 
trial Sponsor retains the right to suspend or terminate this clinical trial at any time.  
A final clinical report shall be compiled once data collection is complete. Such reports include all 

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information required and outlined in this protocol. The final report will be provided to regulatory agencies 
and/or institutional review boards/independent ethics committees and other regulatory agencies as per 
applicable laws. The final clinical report will be filed in the clinical trial master file. 
 
 FUTURE PLANS 
No changes are planned at this time. 
 
13. STATEMENTS OF COMPLIANCE, CONFIDENTIALITY AND RESPONSIBILITIES 
This trial will be conducted in compliance with all applicable US Federal regulations pertaining to 
investigational devices including but not limited to: 21 CFR Part 50, Part 54, Part 56, Part 812 and the 
Health and Insurance Portability and Accountability Act (HIPAA). The protocol and supporting documents 
for this trial will be reviewed and approved by an appropriately constituted IRB, REB or EC prior to trial 
initiation. All reviews and approvals will be in accordance with applicable standards, regulations (local and 
national) and institutional policies. 
 
PROTECTION OF SUBJECT CONFIDENTIALITY 
Subject confidentiality will be maintained in accordance with applicable governmental regulations, HIPAA, 
and institutional policies. 
 
REGULATIONS AND GUIDELINES 
The regulations listed in Table 6 must be observed to comply with the trial Sponsor’s policy for conduct 
of clinical studies; they represent good clinical practice. It is the responsibility of the investigator(s) to 
comply with the requirements. 
Table  6. FDA Regulations  
FDA Regulations 
- Investigational Device Exemption (IDE), 21 CFR Part 812 
- Protection of Human Subjects, 21 CFR Part 50 
- Financial Disclosure, 21 CFR part 54 
- Institutional Review Board (IRB), 21 CFR Part 56 
 
 
 

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INVESTIGATOR RESPONSIBILITIES 
Trial Investigators (Principal Investigators, PI) who conduct clinical investigations of medical devices 
commit themselves to conducting the investigation in accordance to the Clinical Study Agreement, trial 
protocol, and in compliance with applicable governmental and institutional regulations. The trial 
Investigator(s) is responsible for obtaining proper institutional approvals, and reporting to regulatory 
authorities per all applicable regulations. An investigator shall report to the sponsor, within 5 working 
days, a withdrawal of approval by the reviewing IRB of the investigator's part of an investigation. The PI 
must ensure that any individual to whom a task is delegated is qualified by education, training, and 
experience to perform the delegated task. Upon completion or termination of the trial, the Principal 
Investigator must submit a final written report to Edwards Lifesciences and the IRB as required by the 
regulations. The report must be submitted within 3 months (90 days) of completion or termination of the 
trial. 
 
 
 
SPONSOR RESPONSIBILITIES 
The trial Sponsor will adhere to the trial protocol and compliance with applicable government and 
institutional regulations. The trial Sponsor is responsible for obtaining proper regulatory approvals, and 
reporting to regulatory authorities per applicable country regulations. A sponsor shall notify FDA and all 
reviewing IRB's and participating investigators of any withdrawal of approval of an investigation or a part 
of an investigation by FDA or a reviewing IRB within 5 working days after receipt of the withdrawal of 
approval.  
 
 
14. PUBLICATIONS 
Edwards Lifesciences, as the trial Sponsor of record, has a proprietary interest in this trial. Authorship and 
manuscript composition will reflect cooperation between multiple investigators and sites, core 
laboratories, and Edwards Lifesciences. Authorship will be established prior to writing of the manuscript. 
No individual publications will be allowed prior to the completion of the final report for this trial and as 
agreed in writing by Edwards Lifesciences.  
 
 

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15. REFERENCES 
 
[1]  Shinkawa T, Anagnostopoulos PV, Johnson NC, Watanabe N, Sapru A, Azakie A, "Performance of 
bovine pericardial valves in the pulmonary position," Ann Thorac Surg, pp. Oct;90(4):1295-300, 
2010.  
[2]  Lee C, Park CS, Lee CH, Kwak JG, Kim SJ, Shim WS, Song JY, Choi EY, Lee SY., "Durability of 
bioprosthetic valves in the pulmonary position: long-term follow-up of 181 implants in patients 
with congenital heart disease.," J Thorac Cardiovasc Surg., pp. 142(2):351-8., 2011 Aug.  
[3]  Chen PC, Sager MS, Zurakowski D, Pigula FA, Baird CW, Mayer JE Jr, Del Nido PJ, Emani SM, 
"Younger age and valve oversizing are predictors of structural valve deterioration after pulmonary 
valve replacement in patients with tetralogy of Fallot," J Thorac Cardiovasc Surg, pp. 
Feb;143(2):352-60, 2012.  
[4]  Chen XJ, Smith PB, Jaggers J, Lodge AJ, "Bioprosthetic pulmonary valve replacement: 
contemporary analysis of a large, single-center series of 170 cases," J Thorac Cardiovasc Surg, pp. 
Dec;146(6):1461-6., 2013.  
[5]  Morales DL, Braud BE, DiBardino DJ, Carberry KE, McKenzie ED, Heinle JS, Fraser CD Jr., 
"Perimount bovine pericardial valve to restore pulmonary valve competence late after right 
ventricular outflow tract repair," Congenit Heart Dis, pp. Mar-Apr;2(2):115, 2007.  
[6]  Fiore AC, Rodefeld M, Turrentine M, et al, "Pulmonary valve replacement: a comparison of three 
biological valves," Ann Thorac Surg, p. 85:1712– 8, 2008.  
[7]  Fukada J, Morishita K, Komatsu K, Abe T, "Influence of pulmonic position on durability of 
bioprosthetic heart valves," Ann Thorac Surg, pp. Dec;64(6):1678-80, 1997.  
[8]  Jang W, Kim YJ, Choi K, Lim HG, Kim WH, Lee JR, "Mid-term results of bioprosthetic pulmonary 
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