Medtronic PERIcardial SurGical AOrtic Valve ReplacemeNt Pivotal Trial A Multi-center, Non-randomized Trial to Determine the Safety and Effectiveness of the Model 400 Aortic Valve Bioprosthesis in Patients With Aortic Valve Disease
Phase: NA
Conditions: Aortic Stenosis
Sponsor: Medtronic Cardiac Surgery

PERIGON Pivotal Trial Clinical Investigation Plan  
 
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Medtronic PERIcardial SurGical AOrtic Valve ReplacemeNt  
Pivotal Trial (PERIGON) 
A multi-center, non-randomized trial to determine the safety and 
effectiveness of the Model 400 aortic valve bioprosthesis in patients 
with aortic valve disease. 
 
 
 
Clinical Investigational Plan (CIP) 
 
DOCUMENT #10099766DOC 
IDE# G140056 
VERSION 1F 
13 MARCH 2019 
 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of Medtronic. 
Any distribution, copying, or disclosure without the prior written authorization of Medtronic is strictly 
prohibited. Persons to whom the information is disclosed must know that it is confidential and that it 
may not be further disclosed by them. 
 
 

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Investigator Statement  
 
Clinical Investigational Plan: 
Medtronic PERIcardial SurGical AOrtic Valve ReplacemeNt 
Pivotal Trial (PERIGON) 
 
Title Clinical Investigational Plan: 
A multi-center, non-randomized trial to determine the 
safety and effectiveness of the Model 400 aortic valve 
bioprosthesis in patients with aortic valve disease. 
 
Current Version: 
 
 
Version 1F 13March 2019 
I have read the above named Clinical Investigational Plan and agree to conduct the trial as 
outlined and in compliance with country, local and internal institutional requirements. 
 
Name of Institution:  _______________________________________________ 
 
Name of Investigator: _________________________________ 
 
________________________________________ 
 
_________________ 
Investigator Signature 
 
 
 
 
Date: dd mmm yyyy 

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Version History  
Version 
Version date 
Summary of Changes  
 
Author(s)/Title 
1A 
16 July 2013 
Version 1A: for internal use only and not 
distributed to clinical sites or regulatory 
agencies 
Aimee 
Weber, 
Principal 
Clinical 
Research Specialist 
1B 
20 Nov 2013 
• 
Change study title and valve name 
from Perigon™ to Model 400 
• 
Increase number of centers 
• 
Separate out regulatory requirements 
for each geography  
• 
Update safety requirements 
• 
Add pathology core lab 
Minor administrative changes 
Aimee 
Weber, 
Principal 
Clinical 
Research Specialist 
1C 
21 May 2014 
• 
Updated Inclusion/Exclusion criteria 
based 
on 
requests 
from 
global 
regulatory agencies 
• 
Update to US Informed Consent 
template upon request from the U.S. 
FDA 
Aimee 
Weber, 
Principal 
Clinical 
Research Specialist 
1D 
15 July 2014 
• 
Updated study design elements based 
on recommendations from the U.S. 
FDA 
• 
Updated definitions based on requests 
from the U.S. FDA 
• 
Removed Appendix H: Device Return 
Instructions, 
due to 
an 
internal 
Medtronic  process change 
• 
Updated CE mark status on accessories 
and added reporting requirements 
• 
Clarified regulatory requirements 
Aimee 
Weber, 
Principal 
Clinical 
Research Specialist 

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1E 
22 April 2015 
• 
Increase study sample size to 1300 
• 
Clarified requirement for 8 sites to 
enroll at least 30 subjects 
• 
Clarify unavoidable medical conditions 
resulting from the index procedure 
• 
Updated STS risk calculator 
information, based on STS Version 
2.81, released Jan. 2015 
• 
Changed discharge visit window to 
discharge, up to 30 days post-index 
procedure to accommodate 
geography differences in standard 
follow up 
• 
Clarified that subjects who are found 
intraoperatively to require 
concomitant procedures not allowed 
in Inclusion/Exclusion criteria should 
be exited and treated with a 
commercial valve to avoid 
confounding adverse event data 
• 
Updated Appendix E definitions to 
reflect revised STS definitions and 
clarify bleeding and PVL AE reporting 
requirements. 
• 
Update IFU’s to current version 
Aimee 
Weber, 
Principal 
Clinical 
Research Specialist 
1F 
13 Mar 2019 
• 
Updated to clarify the valve sizes 
commercially 
available 
across 
geographies 
• 
Updated 
to 
allow 
the 
use 
of 
commercially available accessories 
• 
Administrative changes including small 
grammatical updates throughout 
• 
Administrative changes 
to match 
updated CIP template in SSMP 
• 
Updated Appendix G to allow upload of 
echoes into imaging portal (Medidata) 
Stephanie 
Yong, 
Clinical 
Research 
Specialist 
 

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Medtronic approvals are maintained in an electronic document control system. 
 
 

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Table of Contents 
1 
Introduction ........................................................................................................................................ 17 
1.1 
Background ................................................................................................................................ 17 
1.2 
Purpose ...................................................................................................................................... 18 
1.3 
Objectives .................................................................................................................................. 18 
1.3.1 
Primary Objectives ............................................................................................................ 18 
1.4 
Intended Use ............................................................................................................................. 18 
2 
Study Design ...................................................................................................................................... 19 
2.1 
Rationale .................................................................................................................................... 19 
2.2 
Duration ..................................................................................................................................... 19 
3 
Selection of Subjects ......................................................................................................................... 20 
3.1 
Study Population ....................................................................................................................... 20 
3.2 
Subject Enrollment ................................................................................................................... 20 
3.3 
Inclusion Criteria ....................................................................................................................... 20 
3.4 
Exclusion Criteria ...................................................................................................................... 20 
4 
Study Procedures .............................................................................................................................. 21 
4.1 
Subject Screening ..................................................................................................................... 22 
4.2 
Schedule of Events ................................................................................................................... 22 
4.3 
Baseline Procedures ................................................................................................................. 24 
4.4 
Implant Procedures .................................................................................................................. 24 
4.4.1 
Verification of Patient Status ........................................................................................... 24 
4.4.2 
Index Procedure ................................................................................................................ 25 
4.4.3 
Attempted Procedure ....................................................................................................... 25 
4.4.4 
Valve Reintervention ........................................................................................................ 26 
4.5 
Discharge up to 30 Day Assessment ..................................................................................... 26 
4.6 
3-6 Month Post-procedure Follow-up Assessment .............................................................. 26 
4.7 
1 Year Post-Procedure Follow-up Assessment ..................................................................... 27 
4.8 
18 Month and 30 Month Post- Procedure Follow-up Phone Call ....................................... 27 

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4.9 
Annual Years 2-5 Post-Procedure Follow-up Assessment .................................................. 27 
5 
Subject Accountability....................................................................................................................... 28 
5.1 
Missed Follow-up Visits ............................................................................................................ 28 
5.2 
Unscheduled Follow-up Visits ................................................................................................. 28 
5.3 
Subject Withdrawal or Discontinuation ................................................................................. 28 
6 
Trial Assessments .............................................................................................................................. 30 
6.1 
Baseline ...................................................................................................................................... 30 
6.1.1 
STS Risk Scores ................................................................................................................. 31 
6.2 
NYHA Functional Classification ............................................................................................... 31 
6.3 
12-Lead ECG .............................................................................................................................. 32 
6.4 
Echocardiography ..................................................................................................................... 32 
6.5 
Hematology/Chemistry ............................................................................................................ 32 
6.5.1 
Hematology/Clinical Chemistry ....................................................................................... 32 
6.5.2 
Hemostasis ......................................................................................................................... 33 
6.6 
Medications ................................................................................................................................ 33 
6.7 
Vital Status ................................................................................................................................. 33 
6.8 
Emergency Use ......................................................................................................................... 34 
6.9 
Deviation Handling ................................................................................................................... 34 
6.10 
Assessment of Safety ............................................................................................................... 35 
6.10.1 
Definitions .......................................................................................................................... 35 
6.10.2 
Evaluation and Documentation of Adverse Events and Device Deficiencies ........... 37 
6.10.3 
Classification of Causal Relationships ............................................................................ 40 
6.10.4 
Adverse Event and Device Deficiency Reporting Requirement .................................. 41 
6.10.5 
Documentation and Reporting of Device Deficiencies ................................................ 42 
6.10.6 
Vigilance Reporting ........................................................................................................... 42 
6.10.7 
Emergency Contact Details for Reporting Events and Device Deficiencies ............. 43 
7 
Statistical Design and Methods ....................................................................................................... 43 
7.1 
Primary Analysis ........................................................................................................................ 43 

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7.1.1 
Safety Objective ................................................................................................................ 43 
7.1.2 
Effectiveness Objective .................................................................................................... 46 
7.2 
Interim Analysis for Market Approval Outside of US ........................................................... 48 
7.2.1 
Safety Objective ................................................................................................................ 48 
7.2.2 
Effectiveness Objective .................................................................................................... 51 
7.3 
Additional Analysis Information .............................................................................................. 52 
7.3.1 
General Summaries .......................................................................................................... 52 
7.3.2 
Missing Data ...................................................................................................................... 52 
7.3.3 
Poolability of Data ............................................................................................................. 52 
7.3.4 
Controls .............................................................................................................................. 52 
7.3.5 
Minimizing Bias .................................................................................................................. 52 
8 
Risk Analysis ....................................................................................................................................... 54 
8.1 
Description of Risk Analysis .................................................................................................... 54 
8.2 
Risks and Benefits .................................................................................................................... 54 
8.2.1 
Potential Benefits .............................................................................................................. 54 
8.2.2 
Potential Risks ................................................................................................................... 55 
8.2.3 
Risk-Benefit Rationale ...................................................................................................... 57 
8.3 
Analysis of Adverse Device Effects ......................................................................................... 57 
9 
Product Description ........................................................................................................................... 57 
10 
Ethics .............................................................................................................................................. 60 
10.1 
Statements of Compliance....................................................................................................... 60 
11 
Study Administration .................................................................................................................... 61 
11.1 
Regulatory Submissions ........................................................................................................... 61 
11.2 
Investigational Site Initiation and Management .................................................................. 61 
11.2.1 
Investigator Selection ...................................................................................................... 61 
11.2.2 
Research Agreement and Financial Disclosure ............................................................. 62 
11.2.3 
Training of Investigative Staff ........................................................................................ 62 
11.2.4 
Site Activation/Supply of Trial Materials ........................................................................ 63 

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11.3 
Trial Site Investigative Team Members- Roles and Responsibilities ................................. 63 
11.3.1 
Principal Investigator........................................................................................................ 63 
11.3.2 
Cardiologist/Echocardiographer ...................................................................................... 64 
11.3.3 
Other Trial Support Staff ................................................................................................. 64 
11.4 
Medtronic Representative Involvement at the Site ............................................................. 64 
11.5 
Device Accountability / Disposition and Return Instructions ............................................. 65 
11.5.1 
Device Accountability and Disposition ........................................................................... 65 
11.5.2 
Device Explant and Return Procedures ......................................................................... 65 
11.6 
Data Management .................................................................................................................... 66 
11.6.1 
Electronic Data Capture ................................................................................................... 66 
11.6.2 
Data Collection .................................................................................................................. 66 
11.6.3 
Data Validation .................................................................................................................. 67 
11.6.4 
Recording Data.................................................................................................................. 67 
11.6.5 
Confidentiality .................................................................................................................... 68 
11.6.6 
Record Retention .............................................................................................................. 68 
11.7 
Suspension or Early Termination ............................................................................................ 69 
11.7.1 
Criteria for Study-wide Termination or Suspension ..................................................... 69 
11.7.2 
Criteria for Investigator/Center Termination or Suspension ...................................... 69 
11.7.3 
Procedures for Planned Study Closure, Termination, or Suspension ........................ 70 
11.8 
CIP Amendments ...................................................................................................................... 71 
11.9 
Publication and Use of Information ....................................................................................... 71 
11.10 Liability ....................................................................................................................................... 72 
12 
Monitoring ...................................................................................................................................... 72 
12.1 
Site Initiation Visit..................................................................................................................... 72 
12.2 
Periodic Monitoring Visit .......................................................................................................... 73 
12.2.1 
Trial Closure ....................................................................................................................... 74 
12.3 
Audits and Inspections ............................................................................................................. 74 
13 
Labeling .......................................................................................................................................... 74 

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13.1 
Device Labeling ......................................................................................................................... 74 
13.2 
Investigator Brochure .............................................................................................................. 74 
14 
Subject Consent ............................................................................................................................ 75 
14.1 
Consent Materials ..................................................................................................................... 75 
14.2 
Informed Consent Process ...................................................................................................... 75 
14.2.1 
Special Circumstances for Informed Consent Process and Signature ...................... 76 
15 
Ethics Board Information ............................................................................................................. 76 
16 
Other Institutions .......................................................................................................................... 77 
16.1 
Echocardiography Core Lab .................................................................................................... 77 
16.2 
Pathology Lab ............................................................................................................................ 77 
16.3 
Steering Committee .................................................................................................................. 77 
16.4 
Data Review Committees ........................................................................................................ 79 
16.4.1 
Clinical Events Committee (CEC) .................................................................................... 79 
16.4.2 
Data Safety Monitoring Board (DSMB) .......................................................................... 79 
17 
Records and Reports .................................................................................................................... 80 
17.1 
Responsibilities of the Investigator ........................................................................................ 80 
17.2 
Responsibilities of the Sponsor ............................................................................................... 84 
17.3 
Final Report ............................................................................................................................... 90 
18 
Report of Prior Investigations of the Device and Justification for the Trial ......................... 91 
19 
Glossary .......................................................................................................................................... 92 
20 
References ..................................................................................................................................... 95 
 
 
 
 

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Appendices 
 
APPENDIX A: SAMPLE PATIENT INFORMATION AND CONSENT FORMS 
APPENDIX B:  INSTRUCTIONS FOR USE 
APPENDIX C:  DEVICE LABELING 
APPENDIX D:  SAMPLE CASE REPORT FORMS 
APPENDIX E:  DEFINITIONS  
APPENDIX F:  SAMPLE INVESTIGATOR AGREEMENT 
APPENDIX G:  ECHOCARDIOGRAPHIC PROCEDURES 
 
 

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Synopsis    
Name of Trial 
PERIGON Pivotal Trial 
Title of Trial 
A multi-center, non-randomized trial to determine the safety and 
effectiveness of the Model 400 aortic valve bioprosthesis in patients with 
aortic valve disease. 
Name of Product 
Model 400 aortic valve bioprosthesis 
Purpose 
To evaluate the safety and effectiveness of the Model 400 bovine pericardial 
stented aortic bioprosthesis in a patient population undergoing surgical aortic 
valve replacement.  The collected data will be used to support regulatory 
applications in seeking market approval for the valve in Europe (CE Mark), the 
United States, Canada and other geographies.  
Design 
This is a prospective, interventional, non-randomized, worldwide, multi-site 
trial, with each center following a common protocol. 
Objectives 
To evaluate the safety and effectiveness of the Model 400 aortic valve 
bioprosthesis.  
Endpoints 
1. Safety:  
a. Thromboembolism 
b. Valve Thrombosis 
c. Hemorrhage  
d. Paravalvular leak  
e. Endocarditis 
f. Hemolysis 
g. Structural valve deterioration 
h. Non-structural dysfunction 
i. 
Reintervention 
j. 
Explant 
k. Death  
2. Effectiveness:  
a. Hemodynamic performance metrics 
b. NYHA functional classification 
Trial Sites 
The trial will be conducted at up to 40 sites worldwide with approximately 14 
in Europe, 4 in Canada and up to 22 in the United States. 
Sample Size 
A maximum of 1300 subjects will be implanted in the trial.  
Patient Population 
Patients requiring aortic valve replacement of the native or prosthetic valve. 
 
 

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Inclusion Criteria 
1. Patient has moderate or greater aortic stenosis or regurgitation, and 
there is clinical indication for replacement of their native or prosthetic 
aortic valve with a bioprosthesis, with or without concomitant 
procedures, which are limited to any of the following: 
i. LAA ligation 
ii. CABG 
iii. PFO closure  
iv. Ascending aortic aneurysm or dissection repair not 
requiring circulatory arrest 
v. Resection of a sub-aortic membrane not requiring 
myectomy 
2. Patient is geographically stable and willing to return to the implanting site 
for all follow-up visits 
3. Patient is of legal age to provide informed consent in the country where 
they enroll in the trial 
4. Patient has been adequately informed of risks and requirements of the 
trial and is willing and able to provide informed consent for participation 
in the clinical trial 
Exclusion Criteria: 
1. Patient has a pre-existing prosthetic valve or annuloplasty device in 
another position or requires replacement or repair of the mitral, 
pulmonary or tricuspid valve 
2. Patient has had previous implant and then explant of the Model 400 aortic 
valve bioprosthesis  
3. Patient presents with active endocarditis, active myocarditis or other 
systemic infection 
4. Patient has an anatomical abnormality which would increase surgical risk 
of morbidity or mortality, including: 
• 
Ascending aortic aneurysm or dissection repair requiring circulatory 
arrest 
• 
Acute Type A aortic dissection 
• 
Ventricular aneurysm 
• 
Porcelain aorta 
• 
Hostile mediastinum 
• 
Hypertrophic obstructive cardiomyopathy (HOCM) 
• 
Documented pulmonary hypertension (systolic >60mmHg) 

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5. Patient has a non-cardiac major or progressive disease, with a life 
expectancy of less than 2 years.  These conditions include, but are not 
limited to: 
• 
Child-Pugh Class C liver disease  
• 
Terminal cancer 
• 
End-stage lung disease 
6. Patient has renal failure, defined as dialysis therapy or GFR<30 
mL/min/1.73 m2  
7. Patient has hyperparathyroidism 
8. Patient is participating in another investigational device or drug trial or 
observational competitive study 
9. Patient is pregnant, lactating or planning to become pregnant during the 
trial period 
10. Patient has a documented history of substance (drug or alcohol) abuse 
11. Patient has greater than mild mitral valve regurgitation or greater than 
mild tricuspid valve regurgitation as assessed by echocardiography 
12. Patient has systolic EF<20% as assessed by echocardiography 
13. Patient has Grade IV Diastolic Dysfunction 
14. Patient has documented bleeding diatheses 
15. Patient has had an acute preoperative neurological deficit or myocardial 
infarction and has not returned to baseline or stabilized ≥30 days prior to 
enrollment 
16. Patient requires emergency surgery 
Follow-up 
For each subject, data will be collected preoperatively, intra-operatively, at 
hospital discharge up to 30 days, between 3 and 6 months post-operative, 1 
year, 18 months, 2 years, 30 months, 3 years, and annually thereafter through 
5 years, or until trial closure.   
Estimated Time Course 
Activities 
Timeline 
Expected First Enrollment 
Q2, 2014 
Expected Enrollment Duration 
Approximately 3 years or until 
commercial approval, 
whichever occurs first 
Completion of Follow-Up 
5 years, or until trial closure 
   Expected Trial Duration 
8 years, or until trial closure 
Global Sponsor 
Medtronic, Inc. 

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Local Sponsor: Europe 
 
 
 
 
 
Local Sponsor: Canada 
Coronary and Structural Heart Disease Management Clinical 
8200 Coral Sea Street N.E. 
MVS66 
Mounds View, MN 55112 
USA 
 
Medtronic Bakken Research Centre BV 
CardioVascular Department, Coronary and Structural Heart Disease 
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
 
Medtronic of Canada Ltd. 
99 Hereford St. 
Brampton, ON  
L6Y 0R3 
Canada 
Trial Oversight 
Jessica Halverson – US & Canada 
Clinical Research Manager 
Medtronic Coronary and Structural Heart Disease Management/ 
Heart Valve Therapies 
Phone: (+1-763) 514 9756 
Email: jessica.halverson@medtronic.com 
 
Eefke van den Bosch – Europe 
Clinical Research Specialist 
Medtronic Bakken Research Center 
CardioVascular Department, Coronary and Structural Heart Disease 
Phone: (+31-43) 3566 755 
 
Email: eefke.bosch@medtronic.com 
Sponsor contact information is subject to change and will be maintained in a 
document separate from the protocol, and provided to sites periodically. 

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Coordinating Principal 
Investigators 
Joseph Sabik, MD 
Department Chair, Thoracic and Cardiovascular Surgery 
Cleveland Clinic Main Campus 
Mail Code J4-1  
9500 Euclid Avenue 
Cleveland, OH 44195 
United States 
Prof. R.J.M. Klautz, MD 
Department Head, Cardiothoracic Surgery 
Leids Universitair Medisch Centrum 
Albinusdreef 2 
2333 ZA Leiden 
The Netherlands 
 
 

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1 Introduction  
1.1 Background 
Calcific or degenerative aortic stenosis and chronic aortic regurgitation are considered the most common 
valvular lesions1-3 among elderly patients.  The classic symptoms include angina, syncope, and dyspnea.4 
Once these symptoms develop, the cumulative mortality in untreated patients is high; with angina or 
syncope, the average survival is two to four years, whereas with congestive heart failure it is even less.5-7 
For patients without increased risk for operative mortality or complications, conventional surgical aortic 
valve replacement (SAVR) with cardiopulmonary bypass is the established standard of care for patients 
with symptomatic severe aortic stenosis or chronic severe aortic regurgitation.8,9 SAVR provides excellent 
functional outcomes, relieves symptoms, and improves survival. 10-14 
SAVR with a tissue bioprosthesis has become the preferred valve treatment for patients over 65 years of 
age, or those patients under 65 years of age who are unable or unwilling to be on lifelong anticoagulation 
with a mechanical heart valve.8 
Bovine pericardial aortic heart valves have good left ventricular mass regression (remodeling), freedom 
from structural valve deterioration (SVD), and a high rate of survival, which may offer better early 
hemodynamics (low transvalvular pressure gradients and increased effective orifice area) and ease of use 
(low stent profiles).15-18 For these reasons, bovine pericardial heart valves hold the majority of the stented 
aortic heart valve market.   
The market leader in the bovine pericardial stented aortic heart valve market is the Carpentier-Edwards 
Perimount series of heart valves (Perimount, Perimount Magna, and Perimount Magna Ease).  The original 
Perimount aortic heart valve has long-term results out to 18 years demonstrating freedom from explant 
due to SVD of 68±12% and survival of 22±4%.19 The original Perimount valve has undergone minor 
modifications/upgrades in the last several years and the name has been modified to reflect these changes.  
The Perimount Magna uses the original Perimount valve, which was modified to be a true supra-annular 
design for optimal hemodynamics and increased flow characteristics.20 The Magna Ease uses the Magna 
design, with a lower profile and contoured sewing ring to enhance implantability.21   The Perimount valves 
utilize anti-calcification treatments to inhibit the binding of calcium to the prosthetic leaflets. 
 
 

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Medtronic has developed the Model 400 aortic valve bioprosthesis, a stented bovine pericardial tissue 
valve.  This valve has been designed to incorporate the proven attributes of the leading bovine pericardial 
heart valves along with the use of the anti-calcification agent, alpha amino oleic acid (AOA™), which has 
been shown to mitigate leaflet calcification in animal studies.22-23 In order to evaluate the safety and 
effectiveness of the Model 400 aortic valve bioprosthesis, Medtronic will be conducting a worldwide, 
multi-center trial, with all sites following a common clinical protocol.  The target population (those for 
whom the device is intended) includes all subjects who are candidates for a tissue prosthetic valve.  The 
PERIGON Pivotal Trial is designed to enroll a maximum of 1300 subjects implanted with the Model 400 
aortic valve bioprosthesis at a maximum of 40 sites worldwide. 
1.2 Purpose  
The purpose of this pivotal trial is to evaluate the safety and effectiveness of the Medtronic Model 400 
aortic valve bioprosthesis [herein referred to as Model 400 valve] in a patient population undergoing 
SAVR. The collected data will be used to support regulatory applications in seeking market approval for 
the valve in Europe (CE Mark), the United States, Canada and other geographies.  The Model 400 valve is 
commercially available (AvalusTM) in the valve sizes: 19mm, 21mm, 23mm, 25mm, and 27mm after 
receiving FDA approval on July 31, 2017, Health Canada Approval on September 8, 2017, and CE mark 
approval on July 3, 2017.  The size 17mm and 29mm valve sizes are still considered investigational in all 
geographies. 
1.3 Objectives 
1.3.1 
Primary Objectives 
The objectives of the trial are to evaluate the safety and effectiveness of the Model 400 valve in a patient 
population undergoing aortic valve replacement of his/her native aortic valve, or replacement of a failed 
prosthesis. 
Trial endpoints are discussed in more detail in Section 7, Statistical Design and Methods. 
1.4 Intended Use 
The Medtronic Model 400 aortic valve bioprosthesis is indicated for the replacement of diseased, 
damaged, or malfunctioning native or prosthetic aortic valves.  
 
 

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2 Study Design  
This is a prospective, interventional, non-randomized, worldwide, multi-center trial, with each site 
following a common protocol.  The design of the trial is based on the recommendations by the FDA Heart 
Valve guidance (2010) and EN ISO 5840:2009 standard for cardiac valve prostheses. 
A maximum of 1300 subjects will be implanted at up to 40 sites with approximately 14 sites in Europe, 4 
in Canada and up to 22 in the United States.    
2.1 Rationale  
Enrollment parameters are included in the study to avoid introduction of bias to the trial results due to 
disproportionate enrollment.  Subjects will be enrolled at a minimum of 8 sites, with an expected 
minimum enrollment at each of these 8 sites of 15 subjects per EN ISO 5840:2009 and enrollment of 30 
subjects per FDA Heart Valve guidance (2010). The maximum number of subjects enrolled per site will be 
no more than 260 (or 20% of the total trial population).  The maximum number of subjects implanted in 
United States will not exceed 650 subjects. 
Trial-wide, it is anticipated that a minimum of 15 valves of each size- 17, 19, 21, 23, 25, 27, 29 mm will be 
implanted.  Up to 1300 valves will be implanted during the trial; more valves may be opened but not used.  
This estimate assumes that each subject will have one trial valve implanted.  
At the moment of commercialization of each valve size in any of the geographies participating in the trial 
(EU, Canada or US, enrollment in that geography will cease. Enrollment may continue in the remaining 
geographies until commercialization for a geography is approved or the maximum of 1300 total trial 
subjects is reached, whichever occurs first.  The estimated enrollment period, based upon the anticipated 
commercialization dates of EU, Canada and US, is approximately 36 months. Additional information 
regarding sample size justification is located in section 7.1.1.3.  
2.2 Duration 
Each implanted subject will be consented to be followed for 5 years, or until trial closure. A minimum 
follow-up of both 150 patients followed to 1-year and 400 patient-years will be completed to satisfy the 
requirements stated in EN ISO 5840:2009.  A minimum follow-up of both 300 patients followed to 1-year 
and 800 patient-years will be completed to satisfy the requirements stated in the FDA Heart Valve 
Guidance.  Total expected duration of the trial is approximately 8 years. 
 
 

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3 Selection of Subjects  
3.1 Study Population  
Patients who require aortic valve replacement (AVR) for any reason may be considered for this trial if they 
meet all of the inclusion and none of the exclusion criteria.  
3.2 Subject Enrollment  
The point of enrollment for this trial is once the IRB/MEC/REC-approved patient informed consent form 
has been signed and dated by all required parties. 
3.3 Inclusion Criteria 
Patients must meet all of the following criteria to be included in the trial. 
1. Patient has moderate or greater aortic stenosis or regurgitation, and there is clinical indication 
for replacement of their native or prosthetic aortic valve with a bioprosthesis, with or without 
concomitant procedures, which are limited to any of the following: 
• 
LAA ligation 
• 
CABG 
• 
PFO closure  
• 
Ascending aortic aneurysm or dissection repair not requiring circulatory arrest 
• 
Resection of a sub-aortic membrane not requiring myectomy 
2. Patient is geographically stable and willing to return to the implanting site for all follow-up visits 
3. Patient is of legal age to provide informed consent in the country where they enroll in the trial 
4. Patient has been adequately informed of risks and requirements of the trial and is willing and able 
to provide informed consent for participation in the clinical trial 
3.4 Exclusion Criteria 
1. Patients who meet any of the following criteria will not qualify for participation in the trial.  Patient 
has a pre-existing prosthetic valve or annuloplasty device in another position or requires replacement 
or repair of the mitral, pulmonary or tricuspid valve 
2. Patient has had previous implant and then explant of the Model 400 aortic valve bioprosthesis 
3. Patient presents with active endocarditis, active myocarditis, or other systemic infection 
4. Patient has an anatomical abnormality which would increase surgical risk of morbidity or mortality, 
including: 
• 
Ascending aortic aneurysm or dissection repair requiring circulatory arrest 
• 
Acute Type A aortic dissection 
• 
Ventricular aneurysm 

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• 
Porcelain aorta 
• 
Hostile mediastinum 
• 
Hypertrophic obstructive cardiomyopathy (HOCM) 
• 
Documented pulmonary hypertension (systolic >60mmHg) 
5. Patient has a non-cardiac major or progressive disease, with a life expectancy of less than 2 years.  
These conditions include, but are not limited to: 
• 
Child-Pugh Class C liver disease  
• 
Terminal cancer 
• 
End-stage lung disease 
6. Patient has renal failure, defined as dialysis therapy or GFR<30 mL/min/1.73 m2. 
7. Patient has hyperparathyroidism 
8. Patient is participating in another investigational device or drug trial or observational competitive 
study 
9. Patient is pregnant, lactating, or planning to become pregnant during the trial period 
10. Patient has a documented history of substance (drug or alcohol) abuse 
11. Patient has greater than mild mitral valve regurgitation or greater than mild tricuspid valve 
regurgitation as assessed by echocardiography 
12. Patient has systolic EF<20% as assessed by echocardiography 
13. Patient has Grade IV Diastolic Dysfunction 
14. Patient has documented bleeding diatheses 
15. Patient has had an acute preoperative neurological deficit or myocardial infarction and has not 
returned to baseline or stabilized ≥30 days prior to enrollment 
16. Patient requires emergency surgery 
4 Study Procedures  
Subjects in whom the Model 400 aortic valve bioprosthesis is implanted will be evaluated at baseline, 
implant, hospital discharge (up to 30 days), between 3 and 6 months, 1 year, 18 months, 2 years, 30 
months, 3 years, 4 years and 5 years, or until trial closure.  Protocol-required evaluations should be 
performed at the investigative trial site. 
 
 

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4.1 Subject Screening  
Patients identified with malfunctioning aortic valves requiring replacement will be screened by the site’s 
investigative team for possible inclusion in the trial.  All sites will be required to maintain a record of 
patients screened for the trial, including reason for screen failure if applicable.  
Patients who meet all inclusion and no exclusion criteria will be asked to participate in the trial.   If the 
patient agrees to participate, prior to any trial-specific tests or procedures, a personally signed and 
dated informed consent will be obtained, as detailed in Section 14 of this document.  The point at which 
the informed consent is executed by all parties will be considered the point of enrollment, and the 
patient is from then on considered a trial subject.  The subject’s medical record must indicate that the 
subject is enrolled in the PERIGON Pivotal Trial.  Sites will maintain a subject enrollment and 
identification log. 
Failure to obtain a handwritten signed and hand-dated informed consent prior to any trial-specific 
procedures constitutes a protocol deviation, which is reportable to the IRB/MEC/REB (all henceforth 
referred to as an “Ethics Board”), the FDA/Health Canada, and other regulatory authorities as applicable.  
However, if any required baseline exams (e.g. Transthoracic Echocardiography (TTE), labs, 12-lead ECG) 
have been performed as standard of care for diagnostic purposes prior to consenting the patient, they 
can be used as the baseline/qualifying exams and will not be considered a protocol deviation, provided 
they meet the following criteria: 
• 
The Principal Investigator (PI) determines that the exams contain the protocol-required data and 
are adequate for evaluation 
• 
The exams were completed within 45 days (TTE within 90 days) prior to scheduled implant 
procedure 
4.2 Schedule of Events  
The following table indicates the parameters expected to be routinely evaluated by physicians 
participating in the trial. 
 
 

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Table 1:  Schedule of Events  
Data Collection 
Requirement 
 
 
Assessment Intervals 
Baseline 
Implant 
Discharge  
up to 30 
days  
3-6 
Months 
1 Year 
 
Annually 
years 2-5 
18 & 30 
month 
phone 
call 
Un-
scheduled 
Visits 
Exit 
Visit Window 
-45 
days/ 
-90 days 
for TTE 
from 
implant 
Date of 
Model 
400 
Valve 
Implant 
≤ 30 days 
+90-180 
days 
± 30 
days 
± 60    
days 
547± 30 
days & 
912± 30 
days 
As 
necessary 
Date 
of 
Exit  
Demographics 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
X* 
 
Pregnancy Test 
X** 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
STS risk score 
X 
 
 
 
 
 
 
 
 
NYHA Classification 
X 
 
X 
X 
X 
X 
 
X* 
 
12-Lead ECG 
X 
 
X 
X 
X 
X 
 
X* 
 
Blood Labs 
X 
 
X 
X 
X 
X 
 
X* 
 
Transthoracic Echo 
(TTE) 
X 
 
X 
X 
X 
X 
 
X* 
 
Transesophageal 
Echo (TEE) 
 
X 
 
 
 
 
 
 
 
Adverse Event/ 
Device Deficiency 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Relevant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X* 
 
Vital Status 
 
 
 
 
 
 
X 
 
X 
Operative 
Information 
 
X 
 
 
 
 
 
 
 
*Any assessments for unscheduled visits are done at the discretion of the Investigator.  
**Pregnancy test is required for female subjects who are not exempt; see Section 6.1. 
 

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4.3 Baseline Procedures 
The following baseline evaluations will be completed and recorded on the appropriate eCRF. 
1. Demographics   
2. Medical History (including diagnosis of valvular lesion and etiology of aortic valve disease) 
3. Pregnancy Test (as applicable; see Section 6.1) 
4. Physical examination 
5. NYHA classification 
6. Society of Thoracic Surgeons (STS) Score 
7. 12-lead ECG 
8. Hematology/chemistry data, including serum creatinine  
9. Echocardiography examination (TTE) 
10. Relevant medications 
11. Adverse Events 
Baseline evaluations are to be completed within 45 days of the scheduled implant procedure, with the 
exception of the TTE, which must be completed within 90 days of the scheduled implant procedure. 
4.4 Implant Procedures 
The implant technique for the Model 400 aortic bioprosthesis is expected to be similar to that for other 
stented aortic bioprosthetic valves.  Detailed information is provided in the “Instructions for Use” included 
in each valve package. 
4.4.1 
Verification of Patient Status 
The exclusion criterion, “Patient has had an acute preoperative neurological deficit or myocardial 
infarction and has not returned to baseline or stabilized ≥30 days prior to enrollment” must be 
reconfirmed prior to the planned SAVR procedure.  Every subject should be evaluated on the day of 
procedure prior to entering the operating room, to ensure that there has not been an acute status change. 
If there is an acute status change related to a neurological deficit or myocardial infarction between 
enrollment and the planned SAVR procedure: 
• 
The surgeon will wait ≥30 days from the time that the subject either returns to baseline or the 
subject has stabilized, to implant the Model 400 valve 
or 
• 
The surgeon will exit the subject from the trial, and continue with an alternative treatment plan 
(i.e., implant a commercially available device or other treatment). 

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Additionally, to avoid potentially confounding event data due to concomitant procedures, enrolled 
subjects who are intraoperatively found to require additional unplanned concomitant procedures that are 
not allowed per the inclusion and exclusion criteria, should be exited from the study prior to implant of 
the study valve. These patients should receive a commercially available valve per standard of care 
practices. 
4.4.2 
Index Procedure 
The Index procedure is defined as the procedure where the Model 400 valve is implanted in the trial 
subject.  
 The following implant data will be collected and recorded on the Implant eCRF. 
1. Procedure details including condition of explanted valve and any additional procedures or 
interventions (as applicable) 
2. Serial number, valve size and disposition of implanted valve or opened valve packages 
3. Documentation of device failure or malfunction (as applicable) 
4. Peri-operative Transesophageal Echocardiography (TEE) 
5. Adverse events/device deficiency 
6. Relevant medications 
4.4.3 
Attempted Procedure 
An attempted procedure is one where the trial subject has entered the Operating Room/Theater and the 
Investigator intends to implant the Model 400 valve, but the trial subject does not receive the Model 400 
valve.  The procedure could be aborted either before or during the attempted valve implant, or due to 
additional subject anatomic/medical considerations which would preclude the use of the Model 400 valve, 
or the Investigators’ decision to use a product other than the Model 400 valve. 
If the Model 400 valve (or accessories) passes the plane of the body, but the Model 400 valve is not 
implanted, the subject will be followed for safety reporting only for 30 days post-attempted implant, and 
then exited from the trial.  AE data should be collected on the AE eCRF, and trial exit data on the Trial Exit 
eCRF. 
 
 

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4.4.4 
Valve Reintervention 
Any intervention post-index procedure, which is required to repair, remove, alter, or replace a previously 
implanted Model 400 valve is considered a valve reintervention.  All Model 400 valve reinterventions are 
considered prosthesis-related.  The details of a reintervention should be collected on a Reintervention 
eCRF and the reason for the reintervention should be collected on an AE eCRF.  
If a subject’s study valve is explanted, the subject will be followed for safety reporting only for 30 days 
post-explant.  AE data should be collected on the AE eCRF, and trial exit data on the Trial Exit eCRF. 
4.5 Discharge up to 30 Day Assessment  
The discharge visit will occur at the time of subject’s discharge from the hospital or up to 30 days post-
procedure.  The following evaluations will be completed and data recorded on the Discharge or 30 Day 
eCRF: 
1. NYHA classification 
2. 12-lead ECG 
3. Hematology/ chemistry data  
4. Echocardiography examination (TTE) 
5. Relevant medications  
6. Adverse events/device deficiency 
All evaluations may be performed any time during the discharge visit window through 30 days post-index 
procedure.   Any data collected after 30 days will result in a protocol deviation. 
4.6 3-6 Month Post-procedure Follow-up Assessment 
Subjects will be seen in the office at 3-6 months (90-180 days) post procedure.  The following evaluations 
will be completed and data recorded on the Follow-up eCRF: 
1. NYHA classification 
2. 12-lead ECG 
3. Hematology/ chemistry data 
4. Echocardiography examination (TTE) 
5. Relevant medications  
6. Adverse events/device deficiency 
 
 

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4.7 1 Year Post-Procedure Follow-up Assessment 
Subjects will be seen in the office at 1 year (± 30 days) post-procedure.  The following evaluations will be 
completed and data recorded on the Follow-up eCRF: 
1. NYHA classification 
2. 12 lead ECG 
3. Hematology/chemistry data 
4. Echocardiography examination (TTE) 
5. Relevant medications  
6. Adverse events/device deficiency 
4.8 18 Month and 30 Month Post- Procedure Follow-up Phone 
Call 
Subjects will be contacted by phone at 18 and 30 months (± 30 days) post procedure to verify their health 
status.  The following data will be collected and recorded on the Telephone Follow-up eCRF: 
1. Vital Status (alive or deceased) 
2. Relevant medications  
3. Adverse events/device deficiency   
In the event that the subject reports a new Serious Adverse Event (SAE) or device-related adverse event, 
at the discretion of the investigator, the subject may be asked to return to the office for an unscheduled 
visit and further assessment.   
4.9 Annual Years 2-5 Post-Procedure Follow-up Assessment  
Subjects will be seen in the office at 2, 3, 4 and 5 years (± 60 days) post-procedure.  The following 
evaluations will be completed and data collected on the Follow-up eCRF:    
1. NYHA classification 
2. 12 lead ECG 
3. Hematology/chemistry data 
4. Echocardiography examination (TTE) 
5. Relevant medications  
6. Adverse events/device deficiency 
 
 

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5 Subject Accountability 
5.1 Missed Follow-up Visits 
Every effort should be made to ensure subjects return to the clinic for all protocol required follow-up visits 
(excluding 18 and 30 month phone visits).  If the subject is unable to return for an in-person clinic visit, 
the Investigator (or designee) must document the reason the subject was unable to complete the visit 
and, if applicable, follow the requirements for deviation reporting as outlined in Section 6.9.  The 
Investigator should also make every effort to contact the subject within the visit window, to collect the 
subject’s vital status (recorded on the Follow-up eCRF) as well as information related to potential adverse 
events (recorded on the AE eCRF).   
5.2 Unscheduled Follow-up Visits 
If a subject returns to the institution between the protocol-required follow-up visits, the visit will be 
treated as an unscheduled visit and the assessments completed at this visit will be done at the discretion 
of the investigator.  The reason for the unscheduled visit, as well as any assessment data will be recorded 
on the Follow-up eCRF and AE data on the AE eCRF. 
5.3 Subject Withdrawal or Discontinuation  
It is the subject’s right to withdraw at any time from the trial and for any reason without sanction, penalty 
or loss of benefits to which the subject is otherwise entitled, and without jeopardizing their future medical 
care.  The investigator may withdraw the subject at any time to protect the health, safety or welfare of 
the subject.  At the last point of contact (if outside a trial-required visit), the subject’s vital status should 
be recorded on a Trial Exit eCRF, and every effort should be made to collect the status of any ongoing 
adverse events.  Sites shall request permission from the subject to follow-up outside of the trial, if issues 
arise with the investigational device safety or performance. 
The subject may only be considered lost to follow-up after all efforts to obtain compliance are exhausted.  
At a minimum, four attempts must be made to contact the subject and documented in the subject’s trial 
records: 
• 
3 telephone attempts to the subject’s last known phone number, and if unsuccessful,  
• 
1 certified letter from the PI to the subject’s last known address  
If the site is unable to reach the subject after the documented attempts, the site should make every 
attempt to verify the subject’s vital status (alive or deceased).   
All subjects will be encouraged to remain in the trial through the last follow-up visit.  Subjects who 
discontinue participation prematurely will be included in the analysis of results, but will not be replaced 
in the enrollment of total trial subjects.  If the subject discontinues participating in the trial prior to 

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completing the trial requirements, the reason for withdrawal will be recorded in the subject’s trial records 
and on the Trial Exit eCRF. 
There are many scenarios in which a subject may exit the trial.   Table 2 below details how the data will 
be handled for each scenario.   
Table 2: Trial exit scenarios 
Scenario 
Follow-up Required 
CRFs Required 
Subject enrolled (informed 
consent signed), but the study 
device(s) (sizer, handle, valve) 
never contacts subject, and no 
Model 400 valve is implanted 
None 
-Inclusion/Exclusion eCRF 
-Baseline eCRF (as applicable)  
-AE eCRF (as applicable) 
-Unscheduled eCRF (as applicable)  
-Trial Exit eCRF 
Subject enrolled, the study 
devices(s) (sizer, handle, valve) 
comes into contact with the 
subject (i.e., passes the body 
plane) but no Model 400 valve is 
implanted 
30 days post-
attempted implant 
for safety only 
-Inclusion/Exclusion eCRF 
-Baseline eCRF (including labs/echo) 
-Implant eCRF 
-Discharge or 30 Day eCRF (including 
labs/echo) 
-AE eCRF (as applicable) 
-Other unscheduled eCRFs (as applicable) 
-Trial Exit eCRF 
Subject enrolled, implanted with 
Model 400 valve, and exits the 
trial early due to explant 
30 days post-
explant for safety 
only 
-All required/ unscheduled eCRFs through last 
visit completed 
-Valve Reintervention eCRF 
-AE eCRF (as applicable) 
-Trial Exit eCRF 
Subject enrolled, implanted with 
Model 400 valve, and exits the 
trial early due to any of the 
following: 
- 
Lost to Follow-up 
- 
Death 
- 
Withdrawal 
 
Through point of 
death, withdrawal, 
or last visit 
completed 
 
 
-All required/ unscheduled eCRFs through last 
visit completed 
-AE eCRF (as applicable) 
-Trial Exit eCRF 
Subject enrolled, implanted and 
completes the trial requirements 
Through 5 year 
follow-up 
-All required/ unscheduled eCRFs 
-AE eCRF (as appropriate) 
-Trial Exit eCRF 
 
 
 

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6 Trial Assessments 
6.1 Baseline 
A careful medical history and physical examination should be taken prior to the implant procedure.  
Attention should be taken to document any chronic illnesses and pre-existing cardiac arrhythmias.    
For any cardiac interventions, the date of the most recent intervention should be captured. 
Use of the following medications will be collected at baseline; see Section 6.6 for additional information 
about specific data collection for medications: 
• 
Anticoagulants 
• 
Antiplatelets 
• 
Aspirin (including Carbasalate Calcium) 
Data to be collected at baseline: 
• 
Gender 
• 
Age at time of enrollment (in years and months) 
• 
Race/Ethnicity- to be collected per the FDA Guidance for Collection of Race and Ethnicity Data in 
Clinical Trials (2005), in support of regulatory submissions in the United States (FDA) and Japan 
(PMDA).  This requirement will be waived for subjects participating in countries where it is 
unlawful to collect race and ethnicity data. 
• 
Co-existing cardiovascular conditions (including, but not limited to congestive heart failure, 
cardiomyopathy, peripheral vascular disease, coronary artery disease, previous myocardial 
infarction (MI), atrial enlargement, cardiac arrhythmias) 
• 
Previous cardiovascular operations (including, but not limited to implanted cardiac device 
(pacemaker, defibrillator, CRT device), coronary artery bypass, coronary artery angioplasty, 
percutaneous valvuloplasty, operative valvuloplasty, previous aortic heart valve replacement, 
annuloplasty) 
• 
Co-existing chronic and transient medical conditions (including, but not limited to liver, kidney, 
lung disease, substance abuse (alcohol/drug), diabetes (Type I or Type II), hypertension, 
endocarditis) 
• 
12-Lead ECG to collect cardiac rhythm (sinus rhythm, atrial fibrillation, atrial flutter, heart block, 
etc.) 
• 
NYHA Classification 
• 
STS risk score 
• 
Hematology/chemistry, including serum creatinine to allow for the calculation of a EuroSCORE. 

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For female subjects of child-bearing potential, a pregnancy test will be done at baseline to confirm that 
the subject is not pregnant.  Subjects exempt from this requirement are those who have been surgically 
sterilized, who are infertile, or who have been post-menopausal for at least 12 months (no menses). 
6.1.1 
STS Risk Scores 
The Society of Thoracic Surgeons’ risk models predict the risk of operative mortality and morbidity after 
adult cardiac surgery on the basis of patient demographic and clinical variables.   
http://riskcalc.sts.org/stswebriskcalc/#/ 
The online calculator provides additional guidance for each of the parameters used to calculate the scores. 
Risk of Mortality and Risk of Morbidity or Mortality scores should be recorded on the Baseline eCRF.  The 
STS Risk Scores should be printed from the online calculator and filed as source documentation for trial 
subjects. 
6.2 NYHA Functional Classification 
The New York Heart Association (NYHA) Functional Classification is a system for defining cardiac disease 
and related functional limitations into four broad categorizations as defined in Table 3. 
Table 3: New York Heart Association (NYHA) Classification 
Class I 
Subject with cardiac disease but without resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain. 
Class II 
Subjects with cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain. 
Class III 
Subjects with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary physical activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
Class IV 
Subjects with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of cardiac insufficiency or of the 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
NYHA classification will be assessed at baseline, discharge (up to 30 days), and all in-office follow-up visits, 
and the results recorded on the appropriate eCRF.  The NYHA classification should be assessed by a 
medical doctor, physician assistant or nurse practitioner.  

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6.3 12-Lead ECG 
A standard 12-Lead ECG should be taken at baseline, discharge (up to 30 days), and all in-office follow-up 
visits to assess cardiac rhythm, noting any cardiac arrhythmias and indications for pacing.  The site will 
record ECG data on the appropriate eCRF. 
The Investigator or Sub-Investigator should review and sign/date each 12-lead ECG recording conducted 
as part of the trial requirements, verify or correct any automated diagnosis generated by the ECG machine, 
and note the clinical significance of any diagnosis/finding of the ECG.  Any new abnormalities should be 
recorded on an Adverse Event eCRF. 
6.4 Echocardiography 
Transthoracic echocardiography (TTE) is required at baseline, discharge (up to 30 days), and all in-office 
scheduled follow up visits.  The site will record echocardiography data on the Site Echo eCRF.  
A peri-procedural Transesophageal Echocardiogram (TEE) is required before the subject leaves the 
operating room/theater to assess the valve implant and evaluate/characterize any paravalvular leak and 
peak /mean gradient.  The site will record the TEE data on the Implant eCRF. 
All TTE exams will be sent to the Echo Core Lab for central assessment; the Echo Core Lab will record the 
central assessment on the Echo Core Lab Assessment eCRF. 
Details of the Echocardiography methods are provided in Appendix G:  Echocardiographic Procedures.  
Additional information regarding the Echo Core Lab can be found in Section 16.1. 
6.5 Hematology/Chemistry 
This section describes the laboratory parameters required at baseline and at each postoperative in-office 
interval.   
6.5.1 
Hematology/Clinical Chemistry 
• 
Complete Blood Count: 
o White Blood Cell (WBC) Count 
o Red Blood Cell (RBC) Count 
o Hemoglobin 
o Hematocrit 
o Plasma Free Hemoglobin* 
o Platelet Count 
 
 

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• 
Reticulocytes Count  
• 
Haptoglobin 
• 
Serum lactate dehydrogenase (LDH) 
• 
Serum Creatinine (at baseline only, to allow for EuroSCORE to be calculated) 
*Plasma free hemoglobin (PFH) will be the primary lab result used to diagnose hemolysis; however, if PFH 
results are inconclusive or not available, serum lactate dehydrogenase, haptoglobin and reticulocyte 
count may be used together to diagnose hemolysis, and may do so without reporting a protocol 
deviation.  If neither PFH nor the combination of serum lactate dehydrogenase, haptoglobin and 
reticulocyte count are completed, the site must report a protocol deviation. 
6.5.2 
Hemostasis 
The following blood labs are required for subjects on anticoagulation therapy (as appropriate for the type 
of anticoagulant): 
• 
International Normalized Ratio (INR) 
• 
Activated Partial Thromboplastin Time (aPTT) 
• 
Prothrombin Time (PT) 
For subjects continuing on anticoagulation therapy, coagulation panels should be performed as part of 
the follow-up assessments.   
6.6 Medications 
Use of the following medications will be collected at baseline and at each postoperative interval and 
recorded on the appropriate eCRF: 
• 
Anticoagulants 
• 
Antiplatelets 
• 
Aspirin (including Carbasalate calcium) 
The physician will determine the appropriate anticoagulation therapy for each subject.  Except where 
contraindicated, Medtronic recommends anticoagulation therapy during the initial healing stages after 
implantation in accordance with normal practices for bioprosthetic valves.  Long-term anticoagulant 
and/or antiplatelet therapy should be considered for subjects with a dilated left atrium, a history of 
thromboembolic events, or a cardiac rhythm of atrial fibrillation or atrial flutter. 
Subjects should be weaned off of anticoagulants per the Investigator’s standard clinical practice.   
6.7 Vital Status 

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A vital status (alive or deceased) should be confirmed for trial subjects at the 18 and 30 month phone calls 
and at trial exit and recorded on the appropriate eCRF.   
6.8 Emergency Use 
Given the investigational status of the Model 400 valve, and the availability of approved surgical valves, 
emergency cases are not allowed under this protocol. 
6.9 Deviation Handling  
A trial deviation is any event in which the trial is not conducted according to the CIP and/or agreement.  
Deviations may include, but are not limited to the following: 
• 
Failure to obtain informed consent prior to participation 
• 
Incorrect version of the informed consent form used 
• 
Failure to obtain Ethics Board approval before the start of enrolling subjects in the trial 
• 
Implanted subject did not meet inclusion/exclusion criteria 
• 
Required testing and/or measurements not done or incorrectly done 
• 
Subject did not attend follow-up visit  
• 
Follow-up visit was completed outside window 
• 
Unauthorized use of investigational devices 
• 
Adverse events/UADE or device deficiencies not reported in the required timeframe by country 
regulation or as specified in the CIP 
• 
Control of trial devices not maintained 
• 
Source data permanently lost 
• 
Enrollment of subjects during lapse of Ethics Board approval 
• 
Enrollment limits exceeded 
The investigator is not allowed to deviate from the CIP, except when necessary to protect the life or 
physical well-being of a subject in an emergency situation.  Trial deviations must be reported to Medtronic 
on the Protocol Deviation eCRF. 
In the event the deviation involves a failure to obtain a subject’s consent, or is made to protect the life or 
physical well-being of a subject in an emergency, the deviation must be reported to the Ethics Board as 
well as Medtronic as soon as possible but no later than five (5) working days from the date of the deviation 
occurrence.  
Reporting of all other study deviations should comply with Ethics Board policies and/or local laws and 
must be reported to Medtronic as soon as possible upon the center becoming aware of the deviation.  
Reporting of deviations must comply with Ethics Board policies, local laws, and/or regulatory agency 

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requirements.  Refer to Tables 13-18 for geography-specific deviation reporting requirements and 
timeframes for reporting to Medtronic and/or regulatory bodies.  
Medtronic is responsible for analyzing deviations, assessing their significance, and identifying any 
additional corrective and/or preventive actions which may include amending the CIP, conducting 
additional training, terminating the investigation, etc.  Repetitive or serious investigator compliance issues 
may represent a need to initiate a corrective action plan with the investigator and site, and in some cases, 
necessitate suspending enrollment at that site until the problem is resolved or ultimately terminating the 
investigator's participation in the study.  Medtronic may provide center-specific reports to investigators 
summarizing information on deviations that occurred at the investigational site on a periodic basis. 
6.10 Assessment of Safety  
6.10.1 
Definitions  
The definitions to be applied for the purposes of safety reporting are provided in Table 4. 
Table 4: Definitions of Adverse Events for the PERIGON Pivotal Trial 
Event Type 
Definition 
Adverse Event 
(AE) 
(EN 
ISO14155:2011 
3.2) 
Any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the investigational medical device. 
NOTE 1: This definition includes events related to the investigational medical device 
or the comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
NOTE 3: For users or other persons, this definition is restricted to events related to 
investigational medical devices. 
Serious Adverse 
Event (SAE) 
(EN 
ISO14155:2011 
3.37) 
Adverse event that  
a) 
led to death, 
b) 
led to a serious deterioration in the health of the subject, resulting in  
1) 
a life-threatening illness or injury, or  
2) 
a permanent impairment of a body structure or a body function, or 
3) 
in-patient or prolonged hospitalization, or  
4) 
medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body 
function, 
c) 
led to foetal distress, foetal death or a congenital abnormality or birth 
defect.  

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Event Type 
Definition 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required 
by the CIP, without serious deterioration in health, is not considered a serious 
adverse event. 
Adverse Device 
Effect (ADE) 
or Device- 
Related Adverse 
Event  
(EN 
ISO14155:2011 
3.1) 
Adverse event related to the use of an investigational medical device. 
NOTE 1: This definition includes adverse events resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, or 
operation, or any malfunction of the investigational medical device.  
NOTE 2: This definition includes any event resulting from an error use or from 
intentional misuse of the investigational medical device. 
Serious Adverse 
Device Effect 
(SADE)  
(EN 
ISO14155:2011 
3.36) 
Adverse device effect that has resulted in any of the consequences characteristic of 
a Serious Adverse Event. 
Unanticipated 
Adverse Device 
Effect (UADE) 
(21 CFR 812.3) 
Any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, a device, if that effect, problem, or death was 
not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application, or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects. 
Unanticipated 
Serious Adverse 
Device Effect 
(USADE) 
(EN 
ISO14155:2011 
3.42) 
Serious adverse device effect which by its nature, incidence, severity or outcome 
has not been identified in the current version of the risk analysis report, or any 
other unanticipated serious problem associated with a device that relates to the 
rights, safety, or welfare of subjects. 
NOTE: Anticipated serious adverse device effect (ASADE) is an effect which by its 
nature, incidence, severity or outcome has been identified in the risk analysis report. 
Device 
Deficiency 
(EN ISO14155 
:2011 3.15) 
Inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety or performance.  
NOTE: Device deficiencies include malfunctions, use errors, and inadequate labeling. 

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Event Type 
Definition 
Mandatory 
Problem 
Reporting 
Incident  
(SOR/98-282  59-
61.1(2)) 
An incident that (a) is related to a failure of the device or a deterioration in its 
effectiveness, or any inadequacy in its labeling or in the directions for use, and (b) 
has led to the death or a serious deterioration in the state of health of a patient, 
user or other person, or could do so were it to recur.  
NOTE: this definition and reporting requirement pertains to events that occur within 
Canada only. 
6.10.2 
Evaluation and Documentation of Adverse Events and Device Deficiencies 
Investigators are required to assess and document in the medical record all AEs and Device Deficiencies 
(per the definitions in Table 4) observed in trial subjects from the time they are consented until they are 
no longer participating in the trial.   
All AEs that occur during the trial need to be reported to Medtronic via the AE eCRF. Documented pre-
existing conditions are not considered to be reportable unless there is a change in the nature or severity 
of the condition. Pre-existing events should be reported as Adverse Events in the situation where a new 
treatment has to be started or an existing treatment has to be changed to treat the adverse event and 
the event is accompanied with signs and symptoms. 
Unavoidable events are conditions which do not fulfill the definition of an Adverse Event, meaning those 
medical occurrences, clinical signs (including toward abnormal laboratory findings), diseases or injuries 
that are not untoward in nature, specifically those resulting from the intended injury such as the index 
surgical aortic valve replacement procedure.   
The events in Table 5 below are expected and appropriate to occur with any open heart surgery and 
therefore do not fulfill the definition of Adverse Event, and do not need to be reported as Adverse Events, 
unless they occur outside of the stated timeframe, are otherwise considered to be an Adverse Event 
according to the treating investigator, or are suspected or confirmed to be device-related. 
 
 

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Table 5: Non-Reportable Medical Occurrences associated with Index Procedure 
Body category 
Occurrence 
Timeframe (hours) from 
the Index Procedure 
Hematologic 
Blood transfusion and anemia occurring during 
the index procedure within expected ranges (part 
of the regular hospital protocol) 
0  
Hematologic 
Any bleeding during the index procedure 
0 
Hematologic 
Any bleeding after index procedure with < 3 units 
blood transfusion, or < 1 liter blood loss  
24 
Cardiac 
Short transient episode of arrhythmia (including 
ventricular fibrillation) during index procedure 
0 
Central nervous 
system 
Confusion, anxiety and/or disorientation (other 
than TIA/stroke) starting within 48 hours with or 
without medical intervention  
120 (5 days) 
Central nervous 
system 
Temporary change in mental status (other than 
TIA/stroke) not requiring additional medical 
interventions or new medical assessments (e.g. 
CT) 
72 
Central nervous 
system 
Dizziness and/or lightheadedness with or without 
treatment  
24 
Central nervous 
system 
Headache with or without treatment 
72 
Central nervous 
system 
Sleep problems or insomnia with or without 
treatment 
120 (5 days) 
Respiratory/pulmonary Mild dyspnea or cough with or without treatment 72 
Respiratory 
Oxygen supply after extubation / “forced 
breathing therapy” 
48  
Gastrointestinal 
Diarrhea with or without treatment 
48 

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Gastrointestinal 
Obstipation / Constipation with or without 
treatment 
72 
Gastrointestinal 
Anesthesia-related nausea and/or vomiting with 
or without treatment  
24 
Body Temperature 
Low-grade fever (<101.3°F or <38.5°C) without 
confirmed infection 
48 
Body Temperature 
Low body temperature 
6 
Pain 
Pain (e.g. back, shoulder) related to laying on the 
procedure table with or without treatment 
72 
Pain 
Incisional pain (pain at access site) with or without 
standard treatment and patient not returning to 
clinic to have additional treatment 
No time limit 
Pain 
Pain in throat and/or trachea due to intubation 
72 
Skin and subcutaneous 
System 
Mild to moderate bruising or ecchymosis 
168 (7 days) 
Respiratory 
Atelectasis / Pleural Effusion not requiring 
punctuation 
168 (7 days) 
General  
Edema resulting in weight increase up to 4 kg / 
9lbs from baseline 
168 (7 days) 
• 
The general process for reporting Adverse Events is as follows: Report the event to Medtronic as 
soon as possible but no later than the timeframes outlined in Table 7.  Sites will be provided with 
the contact information of the appropriate Medtronic designee.  
• 
Complete all sections of the Adverse Event eCRF.  
• 
Each unique event/diagnosis must be documented separately.  
• 
Documented pre-existing conditions are not considered to be reportable AEs unless there is a 
change in the nature or severity of the condition.  
• 
The Adverse Event eCRF must be reviewed and approved by the Investigator. 
 
 

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The following information should be collected on the Adverse Event eCRF: 
• 
Date of onset or first observation 
• 
Date of first awareness by investigator 
• 
Description of the event 
• 
AE code number (provided by Medtronic) 
• 
Seriousness of the event 
• 
Causal relationship of the event to the Model 400 valve 
• 
Causal relationship of the event to the TruSize™ Sizer or Valve Handle 
• 
Causal relationship of the event to the implant procedure 
• 
Action taken, including any medical or surgical intervention and date of intervention 
• 
Outcome or status of the event; any reported event should be followed until it has resolved, has 
a stable level of sequelae, or is no longer clinically significant in the investigator’s opinion 
In addition, for all endpoint-related adverse events and deaths, sites should submit relevant, de-identified 
source documents to Medtronic for the Clinical Events Committee (CEC) members to use in their 
adjudication of the event.  The CEC may request source documentation on additional events, at their 
discretion and according to the CEC Charter.  Additional information regarding the CEC is detailed in 
Section 16.4.1. 
6.10.3 
Classification of Causal Relationships 
For each reported AE, the causal relationship between the AE and the trial devices and implant procedure 
will be classified as related, not related or unknown.  The causal relationships are defined in Table 6. 
Table 6: Adverse Event Causal Relationship Definitions 
Related to  
Definition 
Model 400 valve,  
TruSize™ Sizer or Valve  
Handle 
Any AE involving the function of the device, or the presence of the device in 
the body.  Included in this category are events that are directly attributed to 
the device. 
Model 400 valve  
implant procedure 
Any AE that results from the implant procedure through 30 days post-
implant.  Events in this category are directly related to the general procedural 
sequelae. 

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6.10.4 
Adverse Event and Device Deficiency Reporting Requirement 
Adverse events and device deficiencies that occur during this trial are required to be reported to 
Medtronic via the AE or device deficiency eCRF, as soon as possible after the event occurs, but no later 
than the timeframes listed in Table 7 or local requirements, whichever is more stringent. 
Table 7: Required Timeframes for Adverse Event reporting to Medtronic 
Event Type 
Timeframe for Reporting 
Adverse Event (AE) 
No later than 10 working days of the investigator’s / site’s 
first knowledge of the event 
Serious Adverse Event (SAE) 
Immediately, but no later than 72 hours of the 
investigator’s / site’s first knowledge of the event 
Adverse Device Effect (ADE) or Device 
Related Adverse Event 
Immediately, but no later than 72 hours of the 
investigator’s / site’s first knowledge of the event 
Serious Adverse Device Effect (SADE) 
Immediately, but no later than 72 hours of the 
investigator’s / site’s first knowledge of the event 
Unanticipated Adverse Device Effect 
(UADE) 
Immediately, but no later than 72 hours of the 
investigator’s / site’s first knowledge of the event 
Unanticipated Serious Adverse Device 
Effect (USADE) 
Immediately, but no later than 72 hours of the 
investigator’s / site’s first knowledge of the event 
Device Deficiency 
No later than 72 hours of the investigator’s / site’s first 
knowledge of the event 
Device Deficiency that might have led to 
an SADE 
Immediately, but no later than 72 hours of the 
investigator’s / site’s first knowledge of the event 
Mandatory Problem Reporting Incident  
(Canada ONLY) 
No later than 72 hours of the investigator’s / site’s first 
knowledge of the event, to Health Canada 
In addition, Investigators are obligated to report adverse events in accordance with the requirements of 
their reviewing Ethics Board and local regulations. 
The Sponsor is obligated to report adverse events and device deficiencies that occur during this trial to 
the Regulatory Authorities and Ethics Board as per local requirements. The applicable timeframes are 
described in the PERIGON Safety Plan. 

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6.10.5 
Documentation and Reporting of Device Deficiencies 
Device deficiency information will be collected throughout the trial and reported to Medtronic.  Device 
deficiencies that led to an AE are reported on the AE eCRF.   
Device deficiencies that did not lead to an AE should be reported on a Device Deficiency eCRF (one for 
each device deficiency). 
Device deficiencies that did not lead to an adverse event but might have led to an SADE if a) a suitable 
action had not been taken, or b) an intervention had not been made, or c) circumstances had been less 
fortunate, should be reported to Medtronic immediately of the site’s first learning of the event on a Device 
Deficiency eCRF.  
Any device or accessory involved with a device deficiency should be returned to Medtronic (unless 
implanted) for analysis. 
6.10.6 
Vigilance Reporting  
The Model 400 and accessories are commercially available in the United States, Canada, Europe, and 
Japan.  The Model 400 valve is commercially available (AvalusTM) in the valve sizes: 19mm, 21mm, 23mm, 
25mm, and 27mm.  The sizers are commercially available under both TruSizeTM and Avalus sizer names.  
The reporting of product complaints is not part of the clinical study and should be done in addition to the 
Adverse Event reporting requirements. 
• 
Product Complaint: Any written, electronic or oral communication that alleges deficiencies 
related to the identity, quality, durability, reliability, safety, effectiveness or performance of a 
medical device that has been placed on the market. 
• 
Vigilance Reporting: A system used to notify the Competent Authority (CA) about incidents with 
regard to medical devices that carry the CE mark. This system requires a manufacturer to notify 
the competent authority of incidents immediately on learning of them. 
• 
Incident: Any malfunction or deterioration in the characteristics and/or performance of a device, 
as well as any inadequacy in the labeling or the instructions for use which, directly or indirectly, 
might lead to or might have led to the death of a patient, or user or of other persons or to a 
serious deterioration in their state of health. Any technical or medical reason resulting in 
withdrawal of a device from the market by the manufacturer. 
It is the responsibility of the investigator to report all product complaint(s) associated with a medical 
device distributed by Medtronic (i.e. the TruSize™ sizers and Valve Handles) regardless whether they are 
related to intended use, misuse or abuse of the product. Reporting must be done immediately (within 48 
hours) and via the regular channels for market released products. 

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6.10.7 
Emergency Contact Details for Reporting Events and Device Deficiencies 
Investigators should contact the Medtronic Trial Manager (listed in the synopsis of this document) if they 
have any questions regarding reportable events.  Sponsor contact information is subject to change and 
will be maintained in a document separate from the protocol and provided to sites periodically. 
7 Statistical Design and Methods  
Statistical analysis will be performed by Medtronic employed statisticians or their designated 
representatives. A separate Statistical Analysis Plan (SAP) will be developed to further describe pre-
specified statistical methods, data handling rules, and analyses that will be employed. Any deviation from 
the original statistical analysis plan will be reported in the final trial report, along with justification for the 
deviation(s). 
The safety and effectiveness analyses will be performed on those subjects implanted with the Model 400 
valve (As Treated population).   
The data from the subjects with attempted procedures, but who were not implanted with the Model 400 
valve will be summarized separately, and reported as descriptive statistics.  A sub-analysis of the operative 
mortality of this group will be included in the overall safety analysis.  The subjects with attempted 
procedures will not be counted towards the total number of implants. 
Additional exploratory analyses of the data may be conducted as deemed appropriate.   
7.1 Primary Analysis 
The statistical design for the primary analysis of the trial data is based on the recommendations of the 
FDA Heart Valve guidance document (2010) and EN ISO 5840:2009 standard for cardiac valve prostheses.  
This primary analysis will be used in a Pre-Market Approval (PMA) submission to the U.S. Food and Drug 
Administration (FDA), application for CE Mark in Europe, application for Medical Device License (MDL) to 
Health Canada, and may be used for other regulatory submissions. 
7.1.1 
   Safety Objective 
The objective is to evaluate the safety of the Model 400 valve with regard to valve-related adverse events 
and death.  
 
 

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7.1.1.1 Endpoints  
Safety of the valve will be evaluated by the time-related incidence of valve-related adverse events and 
death. The following valve-related adverse events will be evaluated in this study: Thromboembolism, 
Thrombosis, Hemorrhage (all and major), Paravalvular leak (PVL, all and major), Endocarditis, Hemolysis, 
Structural valve deterioration, Non-structural dysfunction, Reintervention, Explant, and Death. 
Definitions for the above valve-related adverse events are located in Appendix E. 
7.1.1.2  Hypothesis 
The safety objective will be assessed by comparing linearized valve-related adverse event rates from 
subjects implanted with the Model 400 valve to acceptable linearized valve-related adverse event rates 
following valve replacement as defined by FDA in the Heart Valve Guidance 2010 and EN ISO 5840:2009 
as Objective Performance Criteria (OPC).  The OPC for tissue valves (based on the linearized rate) are 
presented in Table 8. 
Table 8: OPC for Tissue Prosthetic Heart Valves 
Adverse Event 
Linearized Rate 
(% per Patient-year) 
Thromboembolism 
2.5 
Valve Thrombosis 
0.2 
All Hemorrhage 
1.4 
Major Hemorrhage 
0.9 
All Paravalvular Leak 
1.2 
Major Paravalvular Leak 
0.6 
Endocarditis 
1.2 
 
The trial is designed to test the hypothesis that the true linearized adverse event rate for the Model 400 
valve (R_Model 400) is equal to or greater than twice the acceptable rate of commercially available tissue 
prosthetic valves (R_OPC). The null (H0) and alternative (HA) hypotheses are written as follows.  
H0: R_Model 400 ≥ 2 X R_OPC 
HA: R_Model 400 < 2 X R_OPC 
Where R_Model 400 is the linearized adverse event rate for the Model 400 valve and R_OPC is the acceptable 
rate of commercially available tissue prosthetic valves. To reject the null hypothesis demonstrates 
statistically that the rate for the Model 400 valve is less than two times the acceptable rate. 

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7.1.1.3 Sample Size 
Sample size estimation is based on the methods of Grunkemeier24. The amount of data required to test 
the null hypothesis using the smallest acceptable adverse event rate of 1.2% per patient-year (excluding 
Valve Thrombosis, Major Hemorrhage and Major PVL) is 800 patient-years. This estimation assumes a 95% 
confidence level, a power of 0.80, and an annual attrition rate of 5%. If all subjects are enrolled within a 
one year time frame, and followed for one year postoperatively, then a total of 556 implants are required. 
Accounting for potential variability in attrition and enrollment rate, a sample size of 650 was originally 
approved in protocol revisions 1B through 1D. With version 1E of the investigational protocol, the sample 
size has been increased to 1300.  While the increased sample size adds exposure of the investigational 
device to a larger cohort of patients, the sample size is within acceptable limits based on the following 
justification: 
• 
The current risk and benefit analysis suggests that the benefits of surgical aortic valve 
replacement far outweigh the risks associated with implant of an aortic bioprosthesis. Given the 
relatively low expected incidence of late valve-related adverse events and the assumed linearized 
occurrence of such events as detailed in the published OPC data from the FDA Heart Valve 
Guidance 2010 and ISO5840:2009, the increased risk to the overall population of subjects 
requiring SAVR is minimal.   
• 
Due to the linearized OPC model utilized in the evaluation of the primary safety endpoints, an 
increased sample size will allow for a more rapid evaluation of the primary safety endpoints 
through faster accumulation of valve-years.  
• 
A similar sample size has been used by both Medtronic and other industry sponsors in the 
evaluation of other tissue aortic valves that have a similar design, the same intended use, and the 
same primary safety endpoints as the PERIGON trial. Notably, the pivotal trial for the Medtronic 
MosaicTM valve utilized a cohort of 1252 subjects for evaluation of the primary safety endpoints 
which were compared to the same published OPC. Likewise, the most recently approved tissue 
aortic valve, TrifectaTM, which is manufactured by St. Jude Medical, utilized a cohort of 1014 
subjects for evaluation of the primary safety endpoints compared to the same published OPC.  
Therefore, there is historical precedent that a cohort similar to that of the PERIGON trial is 
justified. 
 
 

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Additional rationale for increasing the sample size:  
• 
An increased sample size provides a larger cohort from which to establish future long term safety, 
effectiveness and valve durability (e.g. follow-up beyond the current 5-year period).  
• 
An increase of the trial cohort to up to 1300 subjects will allow for enrollment to continue until 
the point of anticipated commercialization, to avoid a significant interruption in access to 
surgeons of the latest surgical valve technology. 
• 
All subjects will continue to be followed under the current rigorous clinical evaluation plan and 
follow-up schedule, including safety committee (CEC and DSMB) oversight.  
7.1.1.4 Analysis Methods 
Primary endpoint analyses for regulatory approval will be done on consecutive subjects, and according to 
the requirements of the guidance documents: 
• 
ISO5840:2009:  for regulatory submissions in geographies adhering to the ISO5840:2009 
standards (minimum of 150 subjects with 1 year follow up and 400 patient years) 
• 
FDA Heart Valve Guidance 2010 for US FDA PMA (minimum of 300 subjects with 1 year follow up 
and 800 patient years).   
Early rates of adverse events will be calculated as the number of early adverse events divided by the total 
number of subjects, expressed as a percentage.  Early events are events occurring on or before 30 days 
post-operative.  
Linearized rates will be calculated as the number of late events divided by the cumulative late post-
operative patient-years, expressed as a percentage.  Late events are events occurring after 30 days post-
operative.  For those adverse events with OPC available, the linearized rates and their associated one-
sided upper 95% confidence bounds will be compared to 2 x the OPC rate to show that they are within 
acceptable limits.  
Kaplan-Meier survival analyses will also be performed to summarize the adverse event data.     
In addition, control articles based on current literature of previously approved heart valves will be 
selected.  Adverse event data from the control articles will be provided so as to inform the reader of the 
current state of heart valve technology, as expressed by articles in quality peer-reviewed journals, and 
allow additional evaluation of the Model 400 adverse event data. 
7.1.2 
   Effectiveness Objective 
The effectiveness objective is to confirm the effectiveness of the Model 400 valve, with regard to NYHA 
Functional Classification and hemodynamic performance.  

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7.1.2.1 Endpoints 
The effectiveness endpoints are 
• 
NYHA Functional Classification (at discharge (up to 30 days), 3-6 months, 1 year and annually 
thereafter through 5 years) 
• 
Hemodynamic Performance (at discharge (up to 30 days), 3-6 months, 1 year and annually 
thereafter through 5 years) including 
o effective orifice area (EOA) 
o effective orifice area index (EOAI) 
o peak pressure gradient 
o mean pressure gradient 
o valvular regurgitation 
o performance index 
o cardiac output 
o cardiac index 
7.1.2.2 Analysis Methods 
NYHA functional classification and echocardiographic hemodynamic data will be summarized using 
descriptive statistics for continuous variables and frequency tables for discrete variables.  NYHA functional 
class will be evaluated based on the percentage of subjects in each specific NYHA class at each 
postoperative time-point and the percentage of subjects at each postoperative time-point who have 
improved, worsened, or not changed in NYHA class compared to preoperative baseline. 
Hemodynamic data will be summarized by valve size and visit.  Control articles based on current literature 
of previously approved heart valves will be selected.  Effectiveness data from the control articles will be 
provided so as to inform the reader of the current state of heart valve technology, as expressed by articles 
in quality peer-reviewed journals, to allow for evaluation of the Model 400 valve effectiveness data. 
 
 

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7.2    Interim Analysis for Market Approval Outside of US 
An interim analysis of the trial data is planned to evaluate the early safety profile of the Model 400 valve.   
The interim analysis will be included as supplementary information in a submission for CE Mark, and may 
be used for regulatory submissions in other geographies.  There is no intention to evaluate or stop the 
study prematurely unless there is a safety concern regarding the Model 400 aortic bioprosthesis. The 
interim analysis results will not be distributed to US study sites, and will not be available on Medtronic’s 
website for U.S. physicians to access. If material is published in peer reviewed journals, these results will 
not be distributed by Medtronic within the U.S. prior to FDA approval. Therefore, it is highly unlikely 
results from this interim analysis would present bias for the overall IDE study results. 
7.2.1 
Safety Objective 
The safety objective is to evaluate the safety of the Model 400 valve with regard to valve-related adverse 
events and death.  
7.2.1.1 Endpoints 
Safety of the valve will be evaluated by the time-related incidence of valve-related adverse events and 
death. The following valve-related adverse events will be evaluated in this study: Thromboembolism, 
Thrombosis, Hemorrhage, Paravalvular leak, Endocarditis, Hemolysis, Structural valve deterioration, Non-
structural dysfunction, Reintervention, Explant, and Death. 
7.2.1.2 Hypothesis 
The safety objective will be assessed by comparing a composite linearized adverse event rate from 
subjects implanted with the Model 400 valve to a composite linearized adverse event rate of valve-related 
Thromboembolism, Endocarditis, Major PVL and Thrombosis.  The composite rate was developed using 
individual valve-related event rates from the Objective Performance Criteria (OPC) as defined by FDA in 
the Heart Valve Guidance 2010 and EN ISO 5840:2009.  From Table 8, twice the composite linearized 
adverse event rate of Thromboembolism, Endocarditis, Major PVL and Thrombosis is 2 X (2.5 + 0.2 + 0.6 
+ 1.2) = 9%. 
The trial hypothesis is to test that the true composite linearized adverse event rate of Thromboembolism, 
Endocarditis, Major PVL and Thrombosis for the Model 400 valve (P_Model 400) is equal to or greater than 
twice the composite linearized adverse event rate of commercially available tissue prosthesis valves.  
The null (H0) and alternative (HA) hypotheses are written as follows.  
H0: P_ Model 400  ≥ 9% 
HA: P_ Model 400  < 9% 

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Where P_ Model 400 is the composite linearized adverse event rate for the Model 400 valve. 
7.2.1.3 Rationale for the Composite Endpoint  
The composite rate was chosen because it provides an overall evaluation of safety of the device by 
incorporating significant device-related events that are clinically relevant to evaluating a new 
bioprosthetic heart valve. 
7.2.1.4 Sample Size 
A fixed sample size group sequential design with O’Brien-Fleming boundaries for one interim analysis will 
be utilized. A fixed sample size design of 400 patient-years with one interim analysis at 200 patient-years 
achieves at least 90% power. 
The assumptions for sample size / power calculation: 
• 
P_Baseline (the baseline rate: observed in the literature) = 3.5% 
• 
P_ Model 400  (the assumed rate for the Model 400 valve) = 3.5%  
• 
Type I error (α) =0.05 
• 
One interim analysis at 200 patient-years  
The objective will be evaluated with a fixed sample size group sequential design with one interim analysis 
at 200 patient-years and one possible second analysis at 400 patient-years.  
7.2.1.5 Analysis Method 
This trial will have up to two analyses of this objective.  The first analysis will occur when 200 patient-years 
of data are collected and the second analysis may occur when 400 patient-years of data are collected.  
Spending function with boundaries similar to that for O’Brien-Fleming will be used to control the Type I 
and Type II error probabilities. The table below illustrates the O’Brien-Fleming boundaries and the 
associated z-statistic and p-value for each analysis under an assumption that 200 patient-years of data are 
observed at the interim analysis. However, if the observed patient-years of data are different at the time 
of the interim analysis, the boundaries and p-values will be recalculated to reflect the appropriate 
percentage of the total sample size observed at the time of the interim analysis.  
  Table 9: O’Brien-Fleming boundary at the interim and 400 patient-year analysis 
Analysis 
Z-statistic 
P-value 
Interim 
-2.3585, 0.0000 
0.0092, 0.5000 
400 patient-years 
-1.6677 
0.0477 
 

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*S-Plus 8.2/S+ SeqTrial used with the O’Brien-Fleming Type I error spending function. 
The above sample rate boundaries are also shown in Figure 1: 
Figure 1:  Event Rate boundaries using O'Brien-Fleming Method 
 
Since there may be up to two analyses, there are two thresholds for which the observed test statistic 
will be evaluated.  Call this set of thresholds Zt =(Z1 ,Z2 ).  Each of these thresholds will be a standard 
normal Z statistic evaluated at the nominal alpha level for the analysis.  For example, in the table 
above, the nominal alpha level for the interim analysis is 0.0092 with an associated Z statistic of -
2.3585.  Thus, if the Z statistic is smaller than -2.3585, the null hypothesis may be rejected at the 
interim analysis.  Similarly, if the null hypothesis cannot be rejected at the interim analysis, the null 
hypothesis may be rejected at the 400 patient-years analysis provided the Z statistic is smaller than -
1.6677.  To reject the null hypothesis demonstrates statistically that the Model 400 valve composite 
adverse event rate is less than 9%.  This method preserves the Type I error rate at 5% since the 
conservative O’Brien-Fleming rules are utilized in setting the rejection thresholds Zt.   
• 
At the interim analysis (200 patient-years), if the data support the alternative hypothesis that the 
Model 400 valve composite rate is <9%, the results will be summarized and submitted for CE Mark 
approval.  The 400 patient-year analysis will not be performed under this scenario. 
• 
If the criteria are not met at the 200 patient-year interim analysis, the trial will continue to gather 
data to at least 400 patient-years and then summarize the data and submit for CE Mark approval.  
Each component of the composite adverse event rate will also be summarized and described. 
Kaplan-Meier survival analyses will also be performed to summarize the adverse event data. 

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In both scenarios, the trial conduct will not be altered, and the trial will not stop, but continue until at 
least 800 patient-years of data are collected.  
7.2.2 
Effectiveness Objective 
The effectiveness objective is to confirm the effectiveness of the Model 400 valve with regard to the NYHA 
Functional Classification and hemodynamic performance.  
7.2.2.1 Endpoints 
The effectiveness endpoints are: 
• 
NYHA Functional Classification (at discharge or within 30 days, 3-6 months, 1 year and annually 
thereafter through 5 years) 
• 
Hemodynamic Performance (at discharge or within 30 days, 3-6 months, 1 year and annually 
thereafter through 5 years) including 
o effective orifice area (EOA) 
o effective orifice area index (EOAI) 
o peak pressure gradient 
o mean pressure gradient 
o valvular regurgitation 
o performance index 
o cardiac output 
o cardiac index 
 
 

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7.2.2.2 Analysis Methods 
NYHA functional classification and echocardiographic hemodynamic data will be summarized using 
descriptive statistics for continuous variables and frequency tables for discrete variables.  These data will 
also be summarized by valve size and visit.  Contemporary control articles based on current literature of 
previously approved heart valves will be selected.   Effectiveness data from the control articles will be 
provided so as to inform the reader of the current state of heart valve technology, as expressed by articles 
in quality peer-reviewed journals; and allow evaluation of the Model 400 valve effectiveness data. 
7.3 Additional Analysis Information 
7.3.1 
General Summaries 
Baseline demographic and clinical variables will be summarized. Continuous variables will be summarized 
as means, medians, standard deviations and ranges.  Categorical variables will be summarized as 
frequencies and percentages.  
7.3.2 
Missing Data 
Every effort will be undertaken to minimize missing data.  Missing (accidentally, due to withdrawal, 
missing follow-up or loss-to-follow up etc.), unused and spurious data will remain identifiable in the 
database. The number of subjects included in the analysis will be reported, so the impact of missing data 
can be assessed.  Unless otherwise specified in each objective, no statistical techniques will be used to 
impute missing data. 
7.3.3 
Poolability of Data 
A poolability analysis among geographies, investigational sites and baseline data will be performed for the 
safety endpoint and will be described in detail in the SAP.  In addition, the endpoints will be evaluated for 
possible differences between genders. 
7.3.4 
Controls 
The clinical trial will include appropriate controls including literature-based objective performance criteria 
(OPCs) for safety data and contemporary literature articles and reports for both safety and effectiveness 
data.  
7.3.5 
Minimizing Bias 
Sponsor shall avoid improper influence on, or inducement of, the subject, monitor, any investigator(s) or 
other parties participating in, or contributing to, the clinical trial.  

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Selection of subjects, treatment of subjects and evaluation of trial data are potential sources of bias.  
Methods incorporated in the trial design to minimize potential bias include (but are not limited to): 
• 
For sites that are participating in other SAVR studies which may have similar enrollment criteria 
as the PERIGON Pivotal Trial, a written process for avoiding selection bias is required 
• 
Subjects will be screened to confirm trial eligibility with defined inclusion/exclusion criteria prior 
to enrollment.  Sites are required to maintain a log of all subjects screened and enrolled for the 
trial. 
• 
Demographics and medical history will be collected at baseline in order to later assess possible 
characteristics that may influence endpoints 
• 
Data collection requirements and trial procedures will be standardized across all geographies 
• 
All geographies will follow the same version of the CIP and eCRFs 
• 
No more than 20% of expected enrollments may come from a single site 
• 
All trial investigators will be required to meet the requirements of 21CFR Part 54, Financial 
Disclosure by Clinical Investigators 
• 
All trial site and Medtronic personnel will be trained using standardized training materials 
• 
Regular monitoring visits will be conducted to verify adherence to the CIP and source data 
• 
An independent Clinical Events Committee (CEC) will be utilized to regularly review and adjudicate 
reported adverse events 
• 
An independent Data Safety Monitoring Board (DSMB) will be utilized to review data, help 
safeguard the interests of trial subjects and monitor the overall conduct of the trial 
 
 

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8 Risk Analysis 
8.1 Description of Risk Analysis 
Medtronic has determined the Model 400 valve to be a significant risk medical device.  Therefore, in 
accordance with the FDA Heart Valve Guidance (2010) and EN ISO5840:2009 requirements, Medtronic is 
required to conduct a human trial and obtain appropriate regulatory approvals to do so. 
In the United States, Medtronic will obtain an Investigational Device Exemption from the United States 
Food and Drug Administration.  Medtronic will obtain approval from country-specific Competent 
Authorities in the EU, and approval from Health Canada to conduct the human trial. 
Risk Analysis procedures were completed in accordance with EN ISO 14971:2012, and the results are 
detailed in the Investigator Brochure/Report of Prior Investigations. 
8.2 Risks and Benefits 
8.2.1 
Potential Benefits  
Potential benefits from use of the device are similar to those associated with commercially available 
bioprosthetic valves. The primary benefit is restoration of heart blood flow control by replacement of the 
diseased heart valve. The chosen tissue (bovine pericardial) has proven durable performance, as 
demonstrated in currently approved valves. 19 
This valve is designed to incorporate the proven attributes of the leading bovine pericardial heart valves: 
a flexible, radiopaque, low-profile stent, a contoured sewing cuff, and anti-calcification agent (AOA™).   
The Model 400 valve may offer the following benefits: 
• 
The valve tissue is treated with an alpha amino oleic acid (AOA™) anti-mineralization process that 
has been shown to mitigate calcification of bioprosthetic valves. 
• 
The base frame PEEK material is impregnated with barium sulphate to allow for radiographic 
visualization to use it for potential TAVI procedures in the future.  
• 
The valve has a low profile, so that the chance of obstructing the coronary ostia is minimized.  
• 
Wide range of available sizes 
• 
Pliable sewing ring with enhanced needle penetration, facilitating implant suturing and seating. 
There is no direct benefit associated to participation in this trial, but the information obtained during this 
trial will be used scientifically. The results of this trial can help physicians understand the safety and 
effectiveness of the heart valve.   

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8.2.2 
Potential Risks 
There are risks associated with any surgical procedure. Risks associated with the Model 400 aortic valve 
bioprosthesis are expected to be similar to commercially available tissue heart valves.  These risks include: 
• 
angina 
• 
cardiac dysrhythmias 
• 
endocarditis or other infection 
• 
heart failure 
• 
hemolysis 
• 
hemolytic anemia 
• 
hemorrhage, anticoagulant/antiplatelet-related 
• 
leak, transvalvular or paravalvular 
• 
myocardial infarction 
• 
nonstructural dysfunction (leaflet entrapment/impingement, obstructive pannus ingrowth, 
suture dehiscence, inappropriate sizing, other) 
• 
prosthesis regurgitation 
• 
stroke 
• 
structural deterioration (calcification, leaflet tear, stenosis, other)  
• 
thromboembolism 
• 
valve thrombosis 
These complications could lead to: 
• 
reintervention  
• 
explant of the bioprosthesis  
• 
permanent disability 
• 
death 
The Model 400 valve has not been studied in humans; however, the expected rates of adverse device 
effects are well characterized in the ANSI/AAMI/EN ISO 5840:2009 “Cardiovascular implants- Cardiac valve 
prostheses”, Table R1, objective performance criteria (OPC).  Table 10 lists the highest anticipated rates 
(2 x the OPC rates) for these OPC events.  It is expected that the rates of risks of the Model 400 valve will 
be similar to currently-market approved bioprosthetic aortic valves. 

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Table 10: Upper bound (2 x OPC) of expected rates of ADEs in the PERIGON Pivotal Trial 
Adverse Event 
Rate (2x OPC) (% per patient-year) 
Endocarditis 
2.4% 
Hemorrhage 
2.8% 
Paravalvular leak 
2.4% 
Thromboembolism 
5.0% 
Valve thrombosis 
0.4% 
Preoperative evaluation and close postoperative monitoring will minimize foreseeable risk and 
discomfort.   
There are no expected additional risks due to subject participation in the trial. 
The following measures will be implemented to minimize risks to trial subjects: 
• 
Investigators will have expertise in aortic heart valve replacement procedures. 
• 
Investigative sites will have comprehensive cardiology and surgery programs. 
• 
Investigators will be trained on the use of the Model 400 valve and accessories. 
• 
Subjects receiving the Model 400 valve will be rigorously followed over the course of the trial.  
The protocol includes regular follow-up visits to assess device safety and effectiveness. These 
visits will enable detection of deterioration in Model 400 valve function should it occur, and allow 
appropriate intervention.  The safety events will be closely monitored by a panel of expert 
physicians. 
Potential treatments for the foreseeable risks may include medication, surgery, medical monitoring or 
other applicable treatments, and will be provided at the discretion of the Investigator. 
Any unanticipated or unforeseen complications will be reported by the principal investigator (or 
authorized designee) to the Ethics Board and to Medtronic.  Medtronic will in turn report any necessary 
findings to the appropriate regulatory agencies/bodies in each of the respective geographies. 
 
 

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8.2.3 
Risk-Benefit Rationale  
It has been demonstrated that implantation of aortic tissue valves can be performed safely, and that these 
devices provide competent valve function. 
Given the poor prognosis of patients with aortic valve deficiencies, and the expectation that risks of the 
Model 400 valve are similar to current market-released aortic tissue valves, the potential benefits 
outweigh the risks and the investigation of this valve is justified. 
8.3 Analysis of Adverse Device Effects 
The Model 400 valve has undergone extensive pre-clinical testing and has demonstrated comparable 
results to other commercially available tissue heart valves.  A summary of pre-clinical testing is included 
in the Investigator Brochure/Report of Prior Investigations. 
9 Product Description  
The Medtronic Model 400 aortic valve bioprosthesis (manufactured by Medtronic, Inc.) is indicated for 
the replacement of a diseased, damaged, or malfunctioning native or prosthetic aortic valve. 
The Model 400 valve (Figure 2) consists of a polyester covered base frame and tri-leaflet support frame, 
which are injection molded using Polyetheretherketone (PEEK) material.  The base frame PEEK material is 
impregnated with barium sulphate to allow for radiographic visualization. 
Figure 2: Model 400 bioprosthetic aortic valve 
 
 
The valve leaflets are laser cut from bovine tissue that has been cross-linked in buffered glutaraldehyde. 
The leaflets are inserted between the cloth covered tri-leaflet support frame and base frame, and then all 
components are securely sutured together. The Model 400 valve is treated with an alpha amino oleic acid 
(AOA™) anti-mineralization process that has been shown to mitigate calcification of bioprosthetic valves 
in animal studies. 

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A sewing ring, fabricated from polyester cloth, is integrated into the inflow base frame cover to allow for 
suturing and seating of the valve in the supra-annular position. Sewing markers are located on the sewing 
ring in the mid sinus area of each cusp to provide guidance for even spacing of implant sutures.  
A disposable valve holder (Figure 3)  is attached to the outflow of the valve to facilitate implantation. The 
disposable holder is designed to fit the reusable Medtronic Valve Handle (Medtronic Valve Handle, 
manufactured by Medtronic, Inc.) (Figure 4), and features a single cut point to remove the holder from 
the valve. 
Figure 3: Valve Holder 
 
Figure 4: Medtronic Valve Handle 
 
Double-ended, reusable TruSize™ sizers (Figure 5) (manufactured by Medtronic, Inc.) are used to select 
the appropriate valve size; the barrel end represents the valve orifice, and the replica end imitates the 
prosthesis geometry.  
Figure 5: TruSize™ Sizer 
 
 
 

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The Valve Handle and TruSize™ sizers are housed in an optional accessory tray (Figure 6) 
Figure 6:   Model 400 Accessory Tray 
         (a)  Tray Lid 
 
 
 
 
       (b) Tray bottom 
 
 
 
 
 
 
 
 
Device model numbers are listed in Table 11: 
Table 11: Model 400 aortic valve bioprosthesis /Implant Accessory Model Numbers 
Valves 
Model Number 
17mm 
40017 
19mm 
40019 
21mm 
40021 
23mm 
40023 
25mm 
40025 
27mm 
40027 
29mm 
40029  
Accessory Parts 
 
TruSize™ Sizer 
7400S 
Avalus™ Sizer (commercial) 
7400S 
Medtronic Valve Handle 
7420 
Model 400 Accessory Tray 
T7400 
Complete Accessory Kit  
(sizer, handle and tray) 
7400K 
 

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The Model 400 valve and accessories (sizer/handle) are commercially available (AvalusTM) in the valve 
sizes: 19mm, 21mm, 23mm, 25mm, and 27mm after receiving FDA approval on July 31, 2017, Health 
Canada Approval on September 8, 2017, and CE mark approval on July 3, 2017.  The size 17mm and 29mm 
valve sizes are still considered investigational in all geographies and will be labeled as such (see Section 
13.1 for specific language on the device label).  Use of the valve is limited to the clinical investigation and 
according the Clinical Investigational Plan (CIP) for the 17mm and 29mm valve sizes.  Commercially 
available accessories may also be used during implant of the Model 400 valve according to the CIP.  
Complete Instructions for Use are included in Appendix B.  The device classification of the Model 400 valve 
and its accessories are listed in Table 12. 
Table 12: Device Classification 
Device 
Classification by Geography 
USA  
(FDA) 
Europe  
(MDD) 
Canada 
(Health Canada) 
Model 400 aortic bioprosthetic valve 
Class III 
Class III 
Class IV 
TruSize™ Sizer1 
Class I 
Class IIa 
Class II 
Valve Handle 
Class I 
Class IIa 
Class II 
Model 400 Accessory Tray 
Not a medical 
device 
Not a medical 
device 
Class I 
1Sizers are commercially named Avalus sizers in Europe 
10 Ethics  
10.1 Statements of Compliance  
The PERIGON Pivotal Trial was designed to reflect the good clinical practice (GCP) principles outlined in 
ISO 14155:2011. These include the protection of the rights, safety and well-being of human subjects, 
controls to ensure the scientific conduct and credibility of the clinical investigation and the definition of 
responsibilities of the sponsor and investigators. 
The study will be conducted according to federal, national and local laws, regulations, standards, and 
requirements of the countries/geographies where the study is being conducted. The study will also be 
conducted in accordance with the Declaration of Helsinki. The principles of the Declaration of Helsinki are 
implemented in this study by means of the Patient Informed Consent (IC) process, Ethics Board approval, 
study training, clinical trial registration, pre-clinical testing, risk benefit assessment, and publication policy. 
 
 

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In the United States, the study will be conducted under an FDA Investigational Device Exemption (IDE) in 
compliance with 21 CFR Parts 11, 50, 54, 56 and 812. In addition, the study will be conducted in 
compliance with 21 CFR Part 11 and 54 in all participating geographies. 
In Europe and Canada, the study will be conducted in compliance with ISO 14155:2011. 
In Canada, SOR/98-282, Section 79-88 will also be followed.  
In Europe, MDD 93/42/EEC and MEDDEV 2.7/3 will also be followed. 
Regulatory authority notification/approval to conduct the trial is required in all participating geographies.  
Investigational sites will be not be activated, nor begin enrolling subjects until the required 
approval/favorable opinion from the respective regulatory agency has been obtained (as appropriate).  
Additionally, any requirements imposed by a local regulatory agency or ethics board shall be followed, as 
appropriate. 
This study will be publicly registered prior to first enrollment in accordance with the 2007 Food and Drug 
Administration Amendments Act (FDAAA) and Declaration of Helsinki on http://clinicaltrials.gov (PL 110-
85, Section 810(a)).  
11 Study Administration 
11.1 Regulatory Submissions 
The PERIGON Pivotal Trial will be used to support application for market release in several targeted 
geographies, particularly the United States, Canada and Europe. 
For commercialization in the United States, the trial will be conducted to meet the requirements detailed 
in the FDA Draft Heart Valve Guidance, 2010.  
Likewise, for commercialization in other markets including Canada and Europe, the study will be 
conducted in accordance with ISO 5840:2009 Cardiovascular implants- Cardiac valve prostheses. 
11.2 Investigational Site Initiation and Management 
11.2.1 
Investigator Selection 
The following criteria will be used to select investigators and sites for participation: 
• 
Experience in cardiothoracic surgery and surgical aortic valve replacement 
• 
The presence or capacity of establishing an investigative team capable of managing the duties of 
the clinical trial 

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• 
Access to the necessary cardiovascular facilities and services to complete protocol required study 
procedures and follow-up. 
• 
A sufficient patient population to meet enrollment expectations (minimum enrollment of 15 
subjects expected at each site, with a maximum of 130 subjects (or 20% of the total trial 
population)) 
• 
Willingness to comply with the requirements described in this CIP 
11.2.2 
Research Agreement and Financial Disclosure 
A Clinical Investigation Agreement shall be signed by the participating investigational site and/or the 
principal investigator at each investigational site per the local legal requirements, and returned to 
Medtronic prior to trial activation.  The investigator is required to indicate their approval of the CIP (and 
any subsequent amendments), by signing and dating the agreement. 
All investigators will be asked to complete financial disclosure statements provided by Medtronic prior to 
their participation in the trial. 
11.2.3 
Training of Investigative Staff 
Medtronic will provide training to the investigative team, according to the Training Plan, on the trial 
requirements and EN ISO 14155:2011/FDA/Health Canada requirements as applicable.  Training required 
per local law will occur prior to site activation at each site, and will include the following topics: 
• 
Technical overview of device(s)  
• 
CIP overview and trial procedures  
• 
Investigational device disposition and accountability procedures  
• 
Procedures for returning unused/explanted devices  
• 
Case report form (CRF) completion and management, including electronic data entry  
• 
Investigator and sponsor responsibilities  
• 
Procedures for obtaining informed consent  
• 
Ethics Board requirements  
• 
Adverse event/device deficiency reporting procedures  
• 
Deviation reporting procedures  
• 
Monitoring requirements and expectations  
• 
Potential regulatory inspections and audits by the sponsor or sponsor representative  
• 
Site record maintenance and retention  
• 
Device/product reimbursement information (based on geographic regulations)  
• 
Investigational site and subject compensation  
• 
Any additional regulatory requirements  

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Site personnel (including new personnel) must be trained and activated by Medtronic prior to performing 
any protocol related duties. 
11.2.4 
Site Activation/Supply of Trial Materials 
Investigational sites will receive a formal letter of site activation, upon receipt of or completion of the 
following: 
• 
Curriculum vitae of the principal and sub-investigators and all key site staff 
• 
A signed research agreement 
• 
Financial disclosure from the investigators 
• 
Competent Authority/FDA/Health Canada approval (as applicable to the geography) 
• 
A copy of the Ethics Board approval letter, along with the voting roster 
• 
The Ethics Board approved patient informed consent form 
• 
Documented training of the investigative team 
• 
Delegated Task List 
• 
Lab certificate and lab normal values/ranges 
• 
Confirmation of adequacy of equipment/facilities 
Medtronic will control the supply of devices and trial materials, and will only ship investigational devices 
once the above activation criteria are met, and the site receives a formal activation letter from Medtronic. 
11.3 Trial Site Investigative Team Members- Roles and 
Responsibilities 
The following is a description of the key personnel who will form the investigative team at each trial site.   
11.3.1 
Principal Investigator  
Each site will have a Principal Investigator (PI), who is a cardiothoracic surgeon.  The PI has overall 
responsibility for the conduct of the trial at the site and for the integrity of the trial data generated by 
their site.  Specifically, the PI is responsible for the following: 
• 
Protecting the rights, safety, and welfare of the subjects in their care 
• 
Obtaining written informed consent of all subjects prior to any trial-related procedures, and only 
after Ethics Board and regulatory approval of the trial 
• 
Obtaining and maintaining Ethics Board approval 
• 
Conducting the investigation in accordance with the signed agreement, investigational plan, 
applicable laws and regulations, and any conditions of approval imposed by an Ethics Board or 
regulatory body  

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o For Canadian sites:  Investigators must comply with Subsection 81(k) of Canadian Medical 
Devices Regulations (SOR /98-282) 
• 
Providing accurate financial disclosure to the sponsor, including any relevant changes during the 
course of the trial and for 1 year after the completion of the trial. 
• 
Ensuring control and accountability of the investigational devices, and return or disposal of the 
devices at the close of the trial per Sponsor instructions. 
• 
Reporting adverse events and device deficiencies in accordance with the CIP and according to 
country regulations 
• 
Approving all case report forms (or authorizing a sub-investigator to do so); approval of the case 
report form indicates the data represented are accurate and have been reviewed. 
• 
Maintaining accurate, complete, and current records, including:  
o All correspondence with another investigator, the sponsor, the monitor, the Ethics Board 
(including required reports), or regulatory agency 
o Records of receipt, use, or disposition of investigational devices 
o Records of each consented subject’s case history, signed and dated informed consent(s), 
exposure to the device, eCRFs, and source documents 
o The CIP, and documentation of dates of and reasons for each protocol deviation 
o Any records required by a regulatory agency 
• 
Allowing time with the trial monitor and Sponsor trial staff members during Sponsor site visits 
11.3.2 
Cardiologist/Echocardiographer 
Each site will have a designated cardiologist/echocardiographer whose primary responsibilities are to 
assure echocardiography exams are performed in compliance with the CIP. 
11.3.3 
Other Trial Support Staff 
The PI will ensure that the investigative site has the appropriate support staff to maintain the trial.   
Additional staff may include sub-investigators, trial coordinators, and other specialized health care 
professionals.  The PI will document authorization of delegated tasks using the Delegation of Tasks Log 
provided by Medtronic. 
11.4 Medtronic Representative Involvement at the Site 
Medtronic representatives will provide administrative support for the sites, as is standard when 
conducting a clinical research trial.  Medtronic representatives may also attend the implant procedures, 
in order to assure that all study requirements are met.  

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11.5 Device Accountability / Disposition and Return Instructions 
11.5.1 
Device Accountability and Disposition 
The Model 400 aortic valve bioprosthesis 17mm and 29mm valve sizes are considered investigational and 
must be stored as labeled and placed in a secure/locked location which meets the labeling requirements 
for device storage.  The Model 400 aortic valve bioprothesis accessories (sizers/handle) are commercially 
available for use and will not be required to be maintained on the device records.  Sites are required to 
maintain investigational device records on only the investigational valves that contain the following 
information on all components shipped to the site for the trial:  
• 
Investigational device name 
• 
Device serial/model number 
• 
Date of receipt of device 
• 
Name of person receiving the device 
• 
Name of person using/opening the device (if applicable) 
• 
Date of implant or use (if applicable) 
• 
Subject Identification Number (SID) of subject receiving or using the device(if applicable) 
• 
Disposition (implanted, disposed of, or returned to Medtronic) 
For devices that are returned to Medtronic or disposed of, sites are required to document the following 
additional information: 
• 
The reason for the device being returned to Medtronic or disposed of 
• 
Name of the person who returned or disposed of each device 
• 
Date shipped to Medtronic, if returned  
• 
If device is disposed of, the method of disposal 
At the end of the trial enrollment period, all remaining investigational devices must be returned to 
Medtronic.  
11.5.2 
Device Explant and Return Procedures 
In the event of a device malfunction of the Model 400 valve prior to, during or after implant (due to 
reintervention or autopsy), the device should be returned to Medtronic.  Sites should contact their 
Medtronic clinical trial representative to obtain further instruction on device return procedures.   All 
explanted devices will be analyzed by an independent lab. 

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11.6 Data Management 
Trial sites will designate a unique subject ID number (SID) at the point of subject enrollment, which is 
assigned by Medtronic in the Electronic Data Capture system.   Records of the subject/SID relationship 
will be maintained by the trial site. 
11.6.1 
Electronic Data Capture 
Medtronic will use the Oracle Clinical Remote Data Capture database system for data collection.   The 
database is located on a secure server at a Medtronic facility located in the United States.  All users will 
be trained on the use of the database prior to obtaining access.  Once access is granted, users will have a 
unique User ID and will create their own password.  Data stored electronically shall be maintained in 
compliance with 21CFR Part 11.   The database for this trial will be maintained for the life of Medtronic, 
according to corporate policy and record retention schedule. 
11.6.2 
Data Collection 
It is the responsibility of the participating Investigator to ensure the quality of the data being collected.  
Required data will be recorded on electronic case report forms (eCRFs) by authorized site personnel as 
indicated on the Delegation of Tasks List. The eCRFs must be completed and/or updated to reflect the 
latest observations on the subjects participating in the trial.   
The investigator (or authorized sub-investigator) will electronically sign each eCRF. 
The EDC system maintains an audit trail on entries, changes or corrections in eCRFs, once the eCRF is 
saved as complete. If changes are made to an already signed eCRF, the investigator shall re-sign this eCRF. 
 
 

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11.6.3 
Data Validation 
The sponsor and/or assigned designee will be responsible for the processing and quality control of the 
data (data management) per the Data Management Plan, which describes the procedures for data review, 
database cleaning and issue/resolution of data queries.  Data will be collected and stored in a validated, 
password protected database.  Data analysis will be conducted utilizing validated software and analysis 
programs by qualified biostatisticians.  
Trial data collected will be monitored and verified against source documents in accordance with 
ISO14155:2011 guidelines and international standards.  Any data discrepancies will be addressed through 
queries posted within the EDC system.   
11.6.4 
Recording Data  
Data entered must be traceable to source documents.  Source documentation is defined as the first time 
data appear, and may include original documents, data and records (e.g., hospital records, clinical and 
office charts, procedure reports, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-
technical departments involved in the clinical trial). 
The eCRFs (or paper copies) may not serve as source documents.  Source documentation for data 
elements not routinely captured in medical records (e.g. echocardiography variables) may vary from site 
to site; the site may use source document worksheets if identified as source documents. 
The Investigator must ensure the availability of source documents from which the information on the 
eCRFs was derived.  Where printouts of electronic medical records, are provided as source documents, or 
where copies of source documents are retained as source documents, they should be signed and dated 
by a member of the investigational site team indicating they are a true reproduction of the original source 
document. 
The source documents must be made available for monitoring or auditing by the sponsor’s representative 
or representatives of the competent authorities and other applicable regulatory agencies.   
 
 

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11.6.5 
Confidentiality 
All information and data sent to parties involved in trial conduct concerning subjects or their participation 
in this trial will be considered confidential.  Trial sites will assign a unique subject ID number (SID) to each 
subject.  Records of the subject/SID relationship will be maintained by the trial site.  The SID number is to 
be recorded on all trial documents to link them to the subject’s medical records at the site.   
Confidentiality of data will be observed by all parties involved at all times throughout the clinical 
investigation.  All data shall be secured against unauthorized access.  The privacy of each subject and 
confidentiality of his/her information shall be preserved in reports and when publishing any data. 
In the United States, “Protected Health Information” (PHI) will be maintained in compliance with the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  To maintain confidentiality, the 
subject’s name or any other PHI should not be recorded on any trial document other than the informed 
consent form, as required by EN ISO5840: 2009.  This scenario will be covered in the Patient Information-
Informed Consent Form.  In the event a subject’s name/PHI is included for any reason, it will be blinded 
as applicable.  In the event of inability to blind the identification (e.g., digital media), it will be handled in 
a confidential manner by the authorized personnel. 
Data relating to the trial might be made available to third parties (for example in case of an audit 
performed by regulatory authorities), provided the data are treated as confidential and that the subject’s 
privacy is guaranteed.   No identifiable subject information will be published. 
11.6.6 
Record Retention 
All trial-related documents must be retained for a period of at least 2 years after the last approval of a 
marketing application (or longer if required by local law) and until there are no pending or contemplated 
marketing applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation 
of clinical development of the investigational device.  Medtronic will inform the investigator/site when 
these documents are no longer required to be retained. 
No trial document or image will be destroyed without prior written agreement between the Sponsor and 
the investigator.  Measures shall be taken to prevent accidental or premature destruction of documents.  
Should the investigator wish to assign the trial records to another party or move them to another location, 
advance written notice must be given to the Sponsor. 
The sponsor will retain the trial records for the life of Medtronic, according to Medtronic corporate policy 
and record retention schedule. 

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11.7 Suspension or Early Termination  
Study closure is defined as closure of a clinical study that occurs when Medtronic and/or regulatory 
requirements have been satisfied per the Clinical Investigational Plan and/or by a decision by Medtronic 
or regulatory authority, whichever occurs first. Study Closure is a process initiated by distribution of an 
initial study closure letter. In all geographies, the study closure process is complete upon distribution of 
the Final Report or after final payments, whichever occurs last. Each lead cohort may have independent 
study closure timelines. 
For each center, Ethics Board approval renewals are required per local/country regulation until the study 
closure process is complete at that center. 
Termination of the Study is discontinuance, by sponsor or by withdrawal of Ethics Board or FDA approval, 
or local regulatory body of an investigation before completion. This is possible for the whole study, for all 
centers in a country, or for a single center. Study suspension is a temporary postponement of study 
activities related to enrollment and distribution of the investigational product(s). This is possible for the 
whole study, for all centers in a country or a single center. 
11.7.1 
Criteria for Study-wide Termination or Suspension 
Possible reasons for considering study suspension or termination of the study for all centers include but 
are not limited to: 
• 
AEs and device deficiencies associated with the system or product under investigation 
which might endanger the safety or welfare of subjects 
• 
Observed/suspected performance different from the product’s design intent 
• 
Decision by Medtronic or regulatory body (medically/ethically justifiable) where the study 
is operating under regulatory body authority 
11.7.2 
Criteria for Investigator/Center Termination or Suspension 
Possible reasons for clinical investigator or center termination or suspension include but are not limited 
to: 
• 
Failure to obtain initial Ethics Board approval or annual renewal of the study 
• 
Consistent non-compliance to the CIP (e.g. failure to adhere to inclusion/exclusion 
criteria, failure to follow subjects per scheduled follow-ups, etc.) 
• 
Lack of enrollment 

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• 
Noncompliance to regulations and the terms of the Clinical Trial Agreement (e.g. failure 
to submit data in a timely manner, failure to follow-up on data queries and monitoring 
findings in a timely manner, etc.) 
• 
Ethics Board suspension of the center 
• 
Fraud or fraudulent misconduct (as defined by local law and regulations) 
• 
Investigator request (e.g. no longer able to support the study) 
11.7.3 
Procedures for Planned Study Closure, Termination, or Suspension 
Medtronic will promptly inform the clinical investigators of the reasons for a study termination or 
suspension and inform the regulatory authority (ies) (where required per regulatory requirements). 
11.7.3.1 Medtronic-initiated 
In the case of study termination or suspension for reasons other than a temporary Ethics Board approval 
lapse, the investigator will promptly inform the Ethics Board. 
In the case of study termination, the investigator must inform the subjects and may inform the personal 
physician of the subjects to ensure appropriate care and follow-up is provided. 
In the case of a study suspension, subject enrollment must stop until the suspension is lifted by Medtronic. 
Subjects already enrolled should continue to be followed out of consideration of their safety, rights, and 
welfare. 
11.7.3.2 Investigator-initiated 
• 
The investigator will promptly inform: 
o Medtronic and provide a detailed written explanation of the termination or 
suspension 
o The institution (where required per regulatory requirements) 
o The Ethics Board 
o The subjects and may inform the personal physicians of the subjects to ensure 
appropriate care and follow-up is provided 
• 
In the case of a study suspension: 
o Subject enrollment must stop until the suspension is lifted 
o Subjects already enrolled should continue to be followed out of consideration of 
their safety, rights, and welfare 

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11.7.3.3 Ethics Board -initiated 
• 
The investigator will promptly inform: 
o Medtronic and provide a detailed written explanation of the termination or 
suspension within 5 business days 
o The institution (where required per regulatory requirements) 
o The subjects and may inform the personal physicians of the subjects, with the 
rationale for the study termination or suspension 
• 
In the case of a study suspension: 
o Subject enrollment must stop until the Ethics Board suspension is lifted 
o Subjects already enrolled should continue to be followed in accordance with 
Ethics Board policy or its determination that an overriding safety concern or 
ethical issue is involved 
11.8 CIP Amendments  
Any revisions or amendments to the CIP, Investigator Brochure/Report of Prior Investigations, or Informed 
Consent document, along with a statement of justification for the changes, will be submitted to all 
affected Regulatory Authorities (FDA, CA, and Health Canada) and governing Ethics Boards, according to 
applicable regulations.  If the CIP is amended, a review of the CRFs will be completed to determine if 
amendment to the forms is necessary.  All amendments to the CIP shall be agreed between the sponsor 
and the Principal Investigator(s).  Approval by regulatory agencies and Ethics Board must be obtained prior 
to implementing a CIP revision at the site. 
11.9 Publication and Use of Information  
The trial will be registered at http://clinicaltrials.gov before first enrollment in the trial. Trial data and 
results will be made available as required per regulations. 
Medtronic, as the Sponsor of this trial, recognizing the seminal importance of this investigation, is 
committed to the widespread dissemination of all endpoint results.  At the conclusion of the trial, a 
multisite abstract reporting the primary results will be prepared by the Coordinating Principal 
Investigators (in collaboration with others including, but not limited to, the Steering Committee and CEC) 
and presented at an annual scientific meeting (e.g. STS, AATS or EACTS).  A multisite publication will 
similarly be prepared for publication in a reputable scientific journal.  The publication of the principal 
results from any single site experience within the trial is not allowed until both the preparation and 
publication of the multisite results, and then only with written permission from Medtronic.  
Following analysis and presentation of the endpoint results, active participation of all Investigators will be 
solicited for data analysis and abstract and manuscript preparation.  Submission of all abstracts and 

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publications regarding the endpoints from the trial requires approval by the Coordinating Principal 
Investigators after review by the Steering Committee. 
A separate publication plan will provide detailed information about the Steering Committee, authorship, 
publication proposals, and requests for data.  
11.10 
Liability 
Medtronic, Inc. (including all wholly owned subsidiaries) maintains appropriate clinical trial liability 
insurance coverage as required under applicable laws and regulations and will comply with applicable law 
and custom concerning specific insurance coverage. If required, a Clinical Trial Insurance 
statement/certificate will be provided to the Ethics Board.  
Medtronic will provide subject indemnification according to local laws where this trial will be conducted. 
12 Monitoring  
Monitoring and monitoring oversight will be provided by Medtronic (Mounds View, MN, USA, and 
Maastricht, the Netherlands) and detailed in a Monitoring Plan separate from this CIP.  Representatives 
of Medtronic (i.e. contractors and designees) may also act as the trial monitors to the site.  A list of the 
trial monitors will be kept separate from this document, and the Sponsor will provide updated lists to the 
investigative sites. 
According to the Monitoring Plan, the trial data will be 100% source document verified through market 
approval.  A risk-based monitoring strategy may be implemented once market approval has been obtained 
in the target geographies (EU, US and Canada); Medtronic will update the Monitoring Plan and notify the 
Investigators, Ethics Boards and regulatory agencies under separate cover from this CIP. 
12.1 Site Initiation Visit 
Medtronic will conduct a site initiation visit prior to first implant, to prepare the site to conduct the trial.  
Medtronic may conduct Investigator Meetings in place of, or in addition to on-site initiation visits.  
Monitors (and/or other Medtronic representatives) will ensure that the PI and study staff (depending on 
their role in the trial): 
• 
Have received and understand the requirements and contents of 
o CIP 
o Investigator Brochure (IB) 
o Patient Information/Informed Consent Form (PI/ICF) 
o Electronic CRFs 
o IFU 
o Any written clinical investigation agreements (as appropriate) 

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• 
Have access to an adequate number of investigational devices 
• 
Have been trained in the use of the investigational device 
• 
Are familiar with the responsibilities of the Principal Investigator 
12.2 Periodic Monitoring Visit 
Periodic monitoring visits will be made at all active investigational sites throughout the clinical trial to 
ensure the safety and wellbeing of the subjects, verify that the Investigator obligations are fulfilled, and 
all applicable regulations and guidelines are being followed.   Monitors will review at a minimum: 
• 
Data submitted on eCRFs are complete and accurate with respect to the subject source 
documentation 
• 
Facilities remain acceptable 
• 
Subject informed consent is being obtained and properly documented 
• 
The CIP is being followed 
• 
Complete records are being maintained 
• 
Appropriate and timely reports have been made to Medtronic and/or its designees and the Ethics 
Board 
• 
Device and Device inventory are controlled 
• 
The Investigator is carrying out all agreed activities 
• 
Any equipment to be used for assessing the clinical investigation variables are 
maintained/calibrated according to the site’s standard protocol 
The progress of the trial will be monitored by: 
• 
On-site review, as deemed appropriate by the sponsor 
• 
Telephone communications between the site personnel (e.g., Investigator, Trial Coordinator) and 
trial monitors 
• 
Review of eCRFs and the associated clinical records 
• 
Review of regulatory documents 
 
 

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12.2.1 
Trial Closure 
Upon trial completion Site Closeout Visits will be conducted, as outlined in the Monitoring Plan. 
After the trial has been completed, medical care will be provided to the subjects upon the discretion of 
the treating physician.  
12.3 Audits and Inspections 
Medtronic may conduct audits at participating clinical sites.  The purpose of an audit is to verify the 
performance of the monitoring process and the trial conduct, independently of the personnel directly 
involved in the trial.  Regulatory bodies, such as the Food and Drug Administration, may also perform 
inspections at participating sites.  The investigator and/or institution shall permit Medtronic and 
regulatory bodies direct access to source data and documents. 
13 Labeling 
13.1 Device Labeling 
The labeling of the Model 400 valve will be provided in English and the local language, if needed according 
to local requirements.  The labeling will indicate that the device is for investigational use only, and only to 
be used by qualified investigators.  The following are the required statements on the labeling for the 
geographies where this study is being conducted: 
• 
Europe:  “Exclusively for clinical investigations” 
• 
United States:  “CAUTION: Investigational Device. Limited by Federal Law (USA) to 
Investigational Use”  
• 
Canada:  “Investigational Device. To Be Used by Qualified Investigators Only”  
A copy of the current device labeling can be found in Appendix C.  If changes are made to the labeling, 
they will be provided under separate cover to the appropriate authorities per local requirements. 
13.2 Investigator Brochure 
The Investigator Brochure for the Model 400 valve will be provided under separate cover.  Medtronic will 
update the Investigator Brochure in accordance with EN ISO14155:2011, and provide those updates to 
sites and regulatory agencies.  For geographies under EN ISO14155:2011, documentation of receipt of the 
Investigator Brochure by each site’s Ethics Board is required for all versions of the Investigator Brochure. 
 
 

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14 Subject Consent  
14.1 Consent Materials 
Geography-specific templates of the Patient Information and Informed Consent Form (PI/ICF) can be 
found in Appendix A. These template may be modified to suit the requirements of the individual site.  For 
US sites, this must include Health Insurance Portability and Accountability Act (HIPAA) Authorization 
language.  This language may be incorporated into the consent form or if required by the IRB, included as 
a separate document.   
Medtronic, the Competent Authorities (CA), and site Ethics Board shall approve all informed consent 
documents prior to implementation in the trial.  Medtronic, Ethics Board, and CAs, where applicable must 
pre-approve all language changes to the PI/ICF throughout the course of the trial prior to implementation; 
this includes initial submission, annual reviews (if applicable) and protocol amendment reviews.  The 
original Ethics Board-approved PI/ICF must be retained at the investigational site, and a copy sent to 
Medtronic prior to device shipment.  Any updated PI/ICF must be sent to Medtronic upon approval of the 
materials by the Ethics Board. 
Medtronic will provide any important new information that impacts the health, safety or welfare of trial 
subjects, for inclusion in PI/ICF updates as it becomes available.   Sites should following any Medtronic, 
CA or Ethics Board requirements for disseminating new information and re-consenting subjects during the 
course of the trial. 
14.2 Informed Consent Process 
The Investigator or authorized designee must administer the approved PI/ICF to each prospective trial 
patient without coercion or undue improper influence on, or inducement of, the patient to participate.  
During the consent discussion the Investigator (or designee) must fully inform the patient of all pertinent 
aspects of the trial, using native non-technical language that is understandable to the patient.   The patient 
must be informed about their right to withdraw from the trial at any time and for any reason without 
sanction, penalty, or loss of benefits to which the patient is otherwise entitled, and also informed that 
withdrawal from the trial will not jeopardize their future medical care.  The patient must also be informed 
that by participating in the trial, they are not waiving their legal rights.  The patient must have ample time 
and opportunity to inquire about details of the trial, and to decide whether or not to participate in the 
clinical trial. All questions about the trial should be answered to the satisfaction of the patient.  All items 
discussed in the PI/ICF must be explained. 
Informed consent will be obtained in writing from the patient. The date of consent and process by which 
the consent was obtained (including documentation of special circumstances, if applicable; see 
Section14.2.1) will be documented in the patient’s medical record prior to any trial-specific procedures.  
Patient informed consent must be obtained in accordance with the national and local laws, regulations 

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and guidelines of each site.   The institutional standard procedure consent form does not replace the trial 
PI/ICF. 
The patient’s signature and date of consent serve to document that they understand the written and 
verbal information that the Investigator (or designee) provides, and their agreement to participate.  The 
Investigator or authorized delegate who conducted the informed consent process must provide their 
handwritten signature and date the consent was completed on the PI/ICF.  The original signed consent 
form will be retained in the patient’s trial records.  A copy of the signed informed consent will be provided 
to the patient and a copy of the signed consent will be placed in the patient’s medical record. 
14.2.1 
Special Circumstances for Informed Consent Process and Signature 
If a patient cannot read or write, an impartial witness must be present during the entire informed consent 
discussion.  The written informed consent form and any other information shall be read aloud and 
explained to the patient and witness. The witness signs and personally dates the informed consent form 
attesting that the information was accurately explained and that informed consent was freely given.  The 
patient will sign and date if possible.   
15 Ethics Board Information 
All necessary documents (CIP, PI/ICF, and Investigator Brochure/Report of Prior Investigations) will be 
provided by Medtronic to the site for submission to their Ethics Board. Documented approval of the Ethics 
Board affiliated with the site is required before enrollment can begin.  The documented approval must 
include: 
• 
The Ethics Board approval date 
• 
Version and/or date of the documents approved (including CIP, PI/ICF and other written trial 
materials) 
• 
Any specific Ethics Board requirements relative to the trial (if applicable) 
The investigator and trial staff must comply with any additional requirements imposed by the Ethics 
Board.  Investigators must inform Medtronic of any change in status of Ethics Board approval once the 
investigation site has started enrollment. 
 
 

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The approval letter needs to be accompanied by an Ethics Board roster to allow verification that the 
investigator or other site trial staff members are not members of the Ethics Board.  If they are members 
of the Ethics Board, written documentation is required stating that he/she did not participate in the 
approval process.  
Medtronic will provide a complete listing of participating sites and Ethics Board chairpersons to 
participating investigational sites and regulatory agencies (if required), within 6 months of the first 
enrollment in the trial.  
16 Other Institutions 
16.1 Echocardiography Core Lab 
The Echocardiography Core Laboratory (Echo Core Lab) is responsible for developing protocol 
requirements, reviewing echo exams, interpreting subject echo data, and providing feedback on the 
quality of the echo exams to participating sites. The Echo Core Lab will review, analyze, and record data 
on the Echo Core Lab Assessment eCRF. The Echo Core Lab Cardiologist’s interpretation of all 
echocardiograms (up to FDA approval) will be used for the data analyses.  All transthoracic 
echocardiography recordings will be evaluated by the team of Dr. Neil J. Weissman at:   
Cardiovascular Core Labs 
MedStar Health Research Institute 
100 Irving Street, NW 
East Building, Room 5123 
Washington, DC 20010 USA 
Phone: +1-202-877-0223 
Fax: +1-202-877-0206 
16.2 Pathology Lab 
All explanted study valves will be independently analyzed by CVPath Institute, Inc., 19 Firstfield Road, 
Gaithersburg, MD 20878.  A pathology protocol will be provided under separate cover. 
16.3 Steering Committee 
The Steering Committee will be an advisory body to Medtronic. Their roles and responsibilities may 
include, but are not limited to the following: 
• 
Overall conduct of the trial with regard to  
o CIP development and implementation 
o Trial progress 
o Subject safety 

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o Data quality and integrity 
• 
Quality performance at individual sites 
o The Steering Committee will support site investigators in resolving any clinical or 
procedural issues that may impact subject well-being or integrity of the trial 
o Any site placed on probation for any reason may be terminated from the trial after an 
appropriate review by the Steering Committee 
• 
Review of all Data Safety Monitoring Board (DSMB) recommendations 
• 
Review and provide input on the publication strategy: 
o Defining and refining the Publication Plan 
o Overseeing the development of manuscripts, abstracts, and presentations 
o Identifying and appointing the manuscript/abstract first 
author(s)/writer(s)/presenters(s) 
o Reviewing the publication 
• 
Assess requests for sub-studies 
• 
Assist with Publication efforts by disseminating trial information through appropriate scientific 
sessions and publications 
o All requests for abstract and manuscript preparation and submission require Steering 
Committee review and approval. All final decisions will be made by Medtronic; however, 
the recommendations made by the Steering Committee will be highly considered 
• 
Participate in Investigator Meetings (and other trial related meetings) 
• 
Serve as a contact for other trial investigators (providing peer consultation) 
The Steering Committee will establish a charter and a Publication Plan.  The Steering Committee charter 
and Publication Plan will be approved by Medtronic and the Steering Committee members.   
 
 

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16.4 Data Review Committees 
16.4.1 
Clinical Events Committee (CEC) 
An independent Clinical Events Committee (CEC) will be established prior to the first enrollment of the 
trial.  The purpose of the CEC is to conduct a medical review and classify/adjudicate, at a minimum, all 
deaths and endpoint related adverse events for seriousness and relatedness to the trial device/procedure 
according to definitions and processes outlined in the protocol and the CEC charter.  The CEC will consist 
of qualified cardiologists, and cardiothoracic surgeons (including a chairperson), who are not participants 
in the trial.  Additional specialists, such as echocardiologists, may also be selected as part of the CEC.  
Prior to the onset of the trial, the CEC will draft a charter to establish explicit rules outlining the minimum 
amount of data required and the algorithm followed in order to classify/adjudicate a trial endpoint related 
clinical event.  The charter will be approved by Medtronic and the CEC members. 
All deaths and potential endpoint events will be reviewed and adjudicated by a minimum of two CEC 
members. All other events will be reviewed and classified by the Sponsor, by qualified internal Medtronic 
safety individual(s) to ensure they should not be adjudicated by the full CEC and that the events are 
appropriately classified by the investigator. 
CEC decisions will be documented in meeting minutes, which will be maintained in the trial master file.   
Additional details about the CEC will be outlined in the CEC charter. 
16.4.2 
Data Safety Monitoring Board (DSMB) 
A DSMB will be established to review accumulating data from the trial, and advise Medtronic on the 
continuing safety of current and future trial participants, and the continuing validity and scientific merit 
of the trial.  The board will be independent of Medtronic and the trial investigators and will be comprised 
of at least 3 experts (including a chairperson) and at a minimum, one cardiothoracic surgeon, one 
cardiologist and one statistician. 
A DSMB charter will be developed and approved by Medtronic and the DSMB members prior to the first 
subject enrollment, and include: 
• 
Criteria for trial termination recommendations if safety concerns warrant. These DSMB 
recommendations may include recommendations on trial status such as continuing the trial 
without modifications, continuing the trial with modifications, stopping the enrollment in the 
trial, or recommendations about trial conduct including recommendations around enrollment or 
protocol deviations.  
• 
Frequency of meetings 

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• 
Handling of emergency situations 
• 
Documentation procedures of the DSMB meetings 
The DSMB will meet at least 2 times during the trial to monitor adverse events.  Meetings will consist of 
both open and closed sessions.  Following each full DSMB meeting, the board will report to Medtronic in 
writing and may recommend changes in the conduct of the trial.  The DSMB may call additional meetings 
if, at any time, there is concern about any aspect of the trial.  All data presented at the meetings will be 
considered confidential and returned to the trial statistician at the closure of the DSMB meeting. 
Additional details about the DSMB will be outlined in the DSMB charter. 
17 Records and Reports 
17.1 Responsibilities of the Investigator 
The Investigator is responsible for the preparation, review, and signature (as applicable), and retention of 
the records listed as follows: 
• 
All essential correspondence that pertains to the investigation 
• 
Device use/disposition records 
• 
Records of each subject’s case history and exposure to the device.  Case histories include the 
eCRFs and supporting data (source documentation), including, for example: 
o Signed and dated consent forms 
o Medical records, including, for example, progress notes of the physicians, the subject’s 
hospital chart(s) and the nurses’ notes 
o All adverse event/device deficiency information  
o A record of the exposure of each subject to the investigational device (e.g., date of 
implant procedure and follow-up assessment dates) 
• 
Documentation of any deviation from the CIP, including the date and the rationale for such 
deviation 
• 
Signed Investigator Agreement, signed and dated curriculum vitae of the PI, sub-investigator(s) 
and key members, signed Delegated Task List 
• 
The approved CIP, PI/ICF, IB and any amendments 
• 
Insurance certificate, where applicable 
• 
Ethics Board approval documentation and voting list 
• 
Sample eCRFs 
• 
Regulatory authority notification and approval documentation 
• 
List of sponsor contacts and monitoring contact list 
• 
List of investigation sites 
• 
Training records 

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• 
Disclosure of conflict of interest 
• 
Certification of adequacy of equipment 
• 
Lab certificate/lab normal ranges 
• 
Subject ID and enrollment log 
• 
Sponsor’s statistical analyses and clinical investigation report 
The Investigator may withdraw from responsibility to maintain records by transferring custody to another 
person, who will accept responsibility for record and report maintenance.  The Investigator is responsible 
for the preparation, review, signature, and submission of the reports listed in Table 13, Table 14, and 
Table 15.  These are also subject to inspection by government agencies and must be retained. 
Reports will be submitted to regulatory authorities per local reporting requirements/regulations.  For 
Adverse Event reporting requirements, see Table 7. 
Table 13: Investigator records and reporting responsibilities applicable to the United States 
Investigator Reports Applicable to the United States 
Report 
Submit To 
Description/Constraints 
Withdrawal of IRB 
approval (either 
suspension or termination) 
Sponsor 
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.  (21 CFR 812.150(a)(2)). 
Progress report  
Sponsor and IRB 
The investigator must submit this report to the sponsor and 
IRB at regular intervals, but in no event less than yearly. (21 
CFR 812.150 (3)).   
Study deviations  
Sponsor and IRB 
Notice of deviations from the CIP to protect the life or physical 
well-being of a subject in an emergency shall be given as soon 
as possible, but no later than 5 working days after the 
emergency occurred. (21 CFR 812.150(a)(4)) 
Failure to obtain IC prior to 
investigational device use 
Sponsor and IRBs 
If an investigator uses a device without obtaining informed 
consent, the investigator shall report such use within 5 
working days after device use. (21 CFR 812.150(a)(5)) 
Final investigator report 
Sponsor, IRB s and 
Relevant Authorities 
This report must be submitted within 3 months of study 
completion or termination of the investigation or the 
investigator’s part of the investigation. (21 CFR 812.150(a)(6)) 

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Investigator Reports Applicable to the United States 
Report 
Submit To 
Description/Constraints 
Other 
IRB and FDA 
An investigator shall, upon request by a reviewing IRB, FDA or 
any other regulatory agency, provide accurate, complete, and 
current information about any aspect of the investigation. (21 
CFR 812.150(a)(7)) 
 
Table 14:  Investigator Reports Applicable to Europe 
Investigator Reports Applicable to Europe 
Report 
Submit To 
Description/Constraints 
Withdrawal of MEC 
approval 
Sponsor 
The investigator must report a withdrawal of approval by the 
reviewing MEC of the investigator’s part of the investigation 
within 5 working days of the date of withdrawal. (Medtronic 
Requirement) 
Progress Report  
Sponsor and Ethics 
Board 
Provide if required by local law or MEC.  
(ISO 14155:2011) 
Study Deviations  
Sponsor and Ethics 
Board and 
Regulatory 
Authority 
Any deviation from the CIP shall be recorded together with an 
explanation for the deviation.  Deviations shall be reported to 
the sponsor who is responsible for analyzing them and 
assessing their significance.   
Note: When relevant, MECs, competent authorities or the 
appropriate regulatory bodies should be informed. (ISO 
14155:2011) 
Notice of deviations from the CIP to protect the life or physical 
well-being of a subject in an emergency shall be given as soon 
as possible, but no later than 5 working days after the 
emergency occurred. (Medtronic Requirement) 
Final investigator report 
Ethics Boards and 
Relevant Authorities 
This report must be submitted within 3 months of study 
completion or termination of the investigation or the 
investigator’s part of the investigation. (Medtronic 
Requirement) 

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Table 15:  Investigator Reports Applicable to Canada 
Investigator Reports Applicable to Canada 
Report 
Submit To 
Description/Constraints 
Withdrawal of REB approval 
Sponsor 
The investigator must report a withdrawal of approval by 
the reviewing REB of the investigator’s part of the 
investigation within 5 working days of the date of 
withdrawal. (Medtronic Requirement) 
Study Deviations  
Sponsor and REB 
Any deviation from the clinical investigational plan shall be 
recorded together with the explanation of the deviation. 
Notice of deviations from the CIP to protect the life or 
physical well-being of a subject in an emergency shall be 
given as soon as possible, but no later than 5 working days 
after the emergency occurred.  (Medtronic Requirement) 
Final Report 
REB, Relevant 
Authorities 
This report must be submitted within 3 months of study 
completion or termination of the investigation or the 
investigator’s part of the investigation. (Medtronic 
Requirement) 
 
 
 

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17.2 Responsibilities of the Sponsor 
The Sponsor will maintain the following records, including but not limited to: 
• 
All essential correspondence related to the clinical trial 
• 
Signed Investigator Agreement 
• 
Signed and dated current curriculum vitae for each Investigator 
• 
Records of device shipment and disposition (shipping receipts, material destruct records, etc.) 
• 
Adverse event and device deficiency information  
• 
Device complaint documentation 
• 
All data forms, prepared and signed by the Investigators, and received source documentation and 
core lab reports 
• 
CIP, investigator brochure or report of prior investigations and subsequent amendments 
• 
Site monitoring reports 
• 
Financial disclosure information 
• 
Trial training records for site participants and internal trial staff members 
• 
Contact lists of all participating investigators/investigative sites, Ethics Board information, trial 
monitors and Sponsor staff members; Sponsor will maintain these lists and provide updates to 
the necessary parties.  
• 
Sample of device labeling attached to investigational device 
• 
Insurance certificates 
• 
Ethics Board approval documentation and voting list 
• 
Regulatory authority notification and approval documentation 
• 
Lab certificates /Lab normal ranges 
• 
Statistical analyses 
• 
Clinical investigation report 
The Sponsor is responsible for the preparation of, the accuracy of the data contained in, the review of and 
the submission of the reports listed in Table 16, , and Table 18. 
 
 

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Table 16: Sponsor records and reporting responsibilities applicable to the United States 
Sponsor Reports for United States 
Report 
Submit To 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical investigation 
Investigators, IRB, 
and Relevant 
authorities 
Provide prompt notification of termination or suspension and 
reason(s). (ISO 14155:2011), (MHLW Ordinance 36, Article 32)  
Unanticipated 
Adverse Device Effect 
Investigators, IRB, 
FDA, and relevant 
authorities 
Notification within ten working days after the sponsor first receives 
notice of the effect.  (21 CFR 812.150(b)(1)) 
Withdrawal of IRB 
approval 
Investigators, IRB, 
FDA, and relevant 
authorities 
Notification within five working days after receipt of the 
withdrawal of approval.  (21 CFR 812.150(b)(2))   
Withdrawal of FDA 
approval 
Investigators, IRB, 
and relevant 
authorities 
Notification within five working days after receipt of notice of the 
withdrawal of approval.  (21 CFR 812.150(b)(3)) 
Investigator List 
FDA 
Submit at 6-month intervals, a current list of the names and 
addresses of all investigators participating in the investigation.  (21 
CFR 812.150(b)(4)) 
Progress Reports 
IRB and FDA 
Progress reports will be submitted at least annually.  (21 CFR 
812.150(b)(4)(5), 812.36(f)   
Recall and device 
disposition 
Investigators, IRB, 
relevant authorities, 
and FDA 
Notification within 30 working days after the request is made and 
will include the reasons for any request that an investigator return, 
repair, or otherwise dispose of any devices.  (21 CFR 812.150(b)(6)) 
Failure to obtain IC  
FDA 
Investigator’s report will be submitted to FDA within five working 
days of notification.  (21 CFR 812.150(b)(8)) 
Final Report 
Investigators, IRB, 
Regulatory 
authorities upon 
request, and FDA 
Medtronic will notify FDA within 30 working days of the completion 
or termination of the investigation.  A final report will be submitted 
to the FDA, investigators, and IRBs within six months after 
completion or termination of this study.  (21 CFR 812.150(b)(7)) 

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Sponsor Reports for United States 
Report 
Submit To 
Description/Constraints 
Study deviation  
Investigators 
Ensure that all deviations from the CIP are reviewed with the 
appropriate clinical investigator(s), are reported on the case report 
forms and the final report of the clinical investigation.   
Site specific study deviations will be submitted to investigators 
quarterly.  (ISO 14155:2011) 
 
Table 17:  Sponsor records and reporting responsibilities applicable to Europe 
Sponsor Reports for Europe 
Report 
Submit To 
Description/Constraints 
Unanticipated Serious 
Adverse Device Effects 
(USADE) 
MEC, Investigators, 
Competent 
Authorities 
Medtronic will notify investigators and MEC in all geographies as 
soon as possible, but not later than 10 working days after the 
sponsor first learns of the effect.  
For reporting to Regulatory authorities, all UADEs are classified as 
SADEs and should follow the applicable reporting requirements. 
(ISO 14155:2011) and Note for Guidance on Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting 
(CPMP/ICH/377/95 3.A.1).  Reporting timeframe as per local 
competent authority.( ISO 14155:2011 3.42) 
Serious Adverse Event 
(SAE) 
MEC, Competent 
Authorities 
Submit to MEC per local reporting requirement.  Submit to 
Competent Authority per local reporting requirement.  Reports 
will be in compliance with MDD 93/42/EEC and MEDDEV 2.7/3 
requirements. 
Serious Adverse Device 
Effects (SADE) 
MEC, Competent 
Authorities 
Submit to MEC per local requirement (ISO 14155:2011).  Submit to 
regulatory authority as per local competent authority reporting 
timelines. 
Device Deficiency that 
might have led to an 
SADE 
MEC, Competent 
Authorities 
Submit to MEC per local requirement. Submit to regulatory 
authority as per local competent authority requirement. 
Premature termination 
or suspension of the 
clinical investigation 
Investigators, MEC, 
Relevant Authority 
Provide prompt notification of termination or suspension and 
reason(s). (ISO 14155:2011)  

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Sponsor Reports for Europe 
Report 
Submit To 
Description/Constraints 
Withdrawal of MEC 
approval 
Investigators, MEC, 
Relevant Authority 
All applicable investigators will be notified only if required by local 
laws or by the MEC. 
Withdrawal of 
Competent Authority 
approval 
Investigators, MEC, 
and Regulatory 
Authority 
Investigators and MECs will be notified only if required by local 
laws or by the MEC. 
Progress Reports 
MEC, Regulatory 
Authority (upon 
request) 
This will be submitted to the MEC and/or Regulatory Authority 
only if required.  
Final Report 
CA, Investigators, 
MEC, and 
Regulatory 
Authority (upon 
request) 
The investigator shall have the opportunity to review and 
comment on the final report.  If a clinical investigator does not 
agree with the final report, his/her comments shall be 
communicated to the other investigator(s).  The principal clinical 
investigator in each center shall sign the report. (ISO 14155:2011) 
Study deviation  
Investigators 
Ensure that all deviations from the CIP are reviewed with the 
appropriate clinical investigator(s), are reported on the case report 
forms and the final report of the clinical investigation.   
Site specific study deviations will be submitted to investigators 
quarterly. (ISO 14155:2011) 
Significant new 
information 
MEC and Regulatory 
Authority 
Ensure that the MECs and Regulatory Authorities are informed of 
significant new information about the clinical investigation (ISO 
14155:2011) 
 
 
 

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Table 18:  Sponsor records and reporting responsibilities applicable to Canada 
Sponsor Reports for Canada 
Report 
Submit To 
Description/Constraints 
Unanticipated Serious 
Adverse Device Effects 
(USADE) 
REB, Investigators, 
Health Canada 
Medtronic will notify investigators and Ethics Boards in all 
geographies as soon as possible, but not later than 10 working 
days after the sponsor first learns of the effect.  
Preliminary and final reporting to the Canadian Ministry of Health 
of events occurring inside (always) or outside Canada (in case of 
corrective actions) that is related to a failure of the device or a 
deterioration in its effectiveness, or any inadequacy in its labeling 
or its directions for use and has led to the death or a serious 
deterioration in the state of health of a patient, user or other person 
or could do so were it to recur. Report a) within 10 days after 
awareness, if incident has led to death or a serious deterioration in 
the state of health of a patient, user or other person b) within 30 
days, if incident has not led to death or a serious deterioration in 
the state of health of a patient, user or other person, but could do 
so were it to recur c) as soon as possible, if incident occurred outside 
of Canada and is related to a corrective action. (Canada Medical 
Device Regulations, SOR/98-282; Mandatory Problem Reporting 
59(1), 59(2), 60 (1)) 

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Sponsor Reports for Canada 
Report 
Submit To 
Description/Constraints 
Serious Adverse Device 
Effects (SADE) 
REB, Health Canada 
Submit to Ethics Boards per local requirement (ISO 14155) 
Preliminary and final reporting to the Canadian Ministry of Health 
of events occurring inside (always) or outside Canada (in case of 
corrective actions) that is related to a failure of the device or a 
deterioration in its effectiveness, or any inadequacy in its labeling 
or its directions for use and has led to the death or a serious 
deterioration in the state of health of a patient, user or other person 
or could do so were it to recur. Report a) within 10 days after 
awareness, if incident has led to death or a serious deterioration in 
the state of health of a patient, user or other person b) within 30 
days, if incident has not led to death or a serious deterioration in 
the state of health of a patient, user or other person, but could do 
so were it to recur c) as soon as possible, if incident occurred outside 
of Canada and is related to a corrective action. (Canada Medical 
Device Regulations, SOR/98-282; Mandatory Problem Reporting 
59(1), 59(2), 60 (1)) 
Device Deficiency that 
might have led to an 
SADE 
REB, Investigators, 
Health Canada 
Submit to Ethics Board per local requirement.  Submit to 
regulatory authority as per local requirement.  
Premature termination 
or suspension of the 
clinical investigation 
Investigators, REB, 
Health Canada 
Provide prompt notification of termination or suspension and 
reason(s). (ISO 14155:2011) 
Recall and device 
disposition 
Investigators, Head 
of Institution, REB, 
Health Canada 
Notification within 30 working days of the request and will 
include the reasons for any request that an investigator return, 
repair, or otherwise dispose of any devices. (Medical Devices 
Regulation Mandatory Problem Reporting 63 – 65.1) 
 
Final Report 
Investigators, REB, 
and Health Canada 
The investigator shall have the opportunity to review and 
comment on the final report.  If a clinical investigator does not 
agree with the final report, his/her comments shall be 
communicated to the other investigator(s).  The principal clinical 
investigator in each center shall sign the report. (ISO 14155:2011) 

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Description/Constraints 
Study deviation  
Investigators 
Ensure that all deviations from the CIP are reviewed with the 
appropriate clinical investigator(s), are reported on the case 
report forms and the final report of the clinical investigation.   
Site specific study deviations will be submitted to investigators 
quarterly. (ISO 14155:2011) 
Significant new 
information 
Ethics Board and 
Health Canada 
Ensure that the Ethics Boards and Regulatory Authorities are 
informed of significant new information about the clinical 
investigation (ISO 14155:2011) 
17.3 Final Report 
Medtronic will provide a final written report of the trial results according to applicable regulations, and 
will include: 
• 
Identification of the device(s) 
• 
Description of the methodology and design of the clinical investigation 
• 
Summary of the deviations from the CIP 
• 
Statistical analysis of the trial data 
• 
Critical appraisal of the aims of the trial 
Medtronic will submit this final report to the PIs for review and comment, and shall document and 
disseminate discrepant comments to all trial PIs.  The coordinating investigators will provide their 
signatures, indicating their agreement with the content of the final report. 
All required trial reports will be submitted to regulatory authorities per local reporting 
requirements/regulations. 
 
 
 

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18 Report of Prior Investigations of the Device and Justification 
for the Trial 
The complete Report of Prior Investigations is available under separate cover. 
The use of human subjects is required as part of an EN ISO 5840:2009 clinical trial to evaluate the safety 
and effectiveness of the use of device in humans which includes evaluations that cannot be made using 
bench testing.  Therefore, the conduct of the PERIGON Pivotal Trial is justified. 
 
 

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19  Glossary  
Acronym  
Term 
AE 
Adverse Event 
ADE 
Adverse Device Effect 
AOA 
Alpha-amino Oleic Acid 
aPTT  
Activated Partial Thromboplastin Time 
AR 
Aortic Regurgitation 
AS 
Aortic Stenosis 
CA 
Competent Authority 
CE – Mark 
Conformité Européenne (European Conformity) 
CEC 
Clinical Events Committee 
CFR 
U.S. Code of Federal Regulations 
CIP 
Clinical Investigational Plan 
CRF 
Case Report Form 
DSMB 
Data Safety Monitoring Board 
DTL 
Delegated Task List 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOA 
Effective Orifice Area 
EOAI 
Effective Orifice Area Index 
EU 
European Union 
FDA 
U.S. Food and Drug Administration 

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Acronym  
Term 
HIPAA 
Health Insurance Portability and Accountability 
Act 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDE 
Investigational Device Exemption 
IFU 
Instructions for use 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
LDH 
Lactate Dehydrogenase 
MEC 
Medical Ethics Committee 
MI 
Myocardial Infarction 
mL 
Milliliters 
mm 
Millimeters 
NYHA 
New York Heart Association 
OPC 
Objective Performance Criteria 
PE 
Product Experience 
PEEK 
Polyetheretherketone 
PERIGON 
Medtronic PERIcardial SurGical AOritc Valve 
ReplacemeNt Pivotal Trial 
PI 
Principal Investigator 

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Acronym  
Term 
PI/ICF 
Patient Information/ Informed Consent Form 
PPM 
Patient Prosthesis Mismatch 
PT 
Prothrombin time 
PVL  
Paravalvular leak 
REB 
Regulatory Ethics Board 
SAE 
Serious Adverse Event 
SADE 
Serious Adverse Device Effect 
SAP 
Statistical Analysis Plan 
SAVR 
Surgical Aortic Valve Replacement 
SID 
Subject Identification 
SOP 
Standard Operating Procedures 
STS 
Society of Thoracic Surgeons 
SVD 
Structural Valve Deterioration 
TAVI 
Transcatheter Aortic Valve Implantation 
TEE 
 
Transesophageal Echocardiography 
TTE 
Transthoracic Echocardiography 
UADE 
Unanticipated Adverse Device Effect 
US 
United States 
USADE 
Unanticipated Serious Adverse Device Effect 
 
 
 

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20 References 
1. Lindroos M, Kupari M, Heikkila J, Tilvis R. Prevalence of aortic valve abnormalities in the elderly: 
an echocardiographic study of a random population sample. Journal of the American College of 
Cardiology 1993;21:1220-5. 
2. Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of 
valvular heart diseases: a population-based study. Lancet 2006;368:1005-11. 
3. Iung B, Vahanian A. Degenerative calcific aortic stenosis: a natural history. Heart (British Cardiac 
Society) 2012;98 Suppl 4:iv7-13. 
4. Bonow RO, Carabello BA, Kanu C, et al. ACC/AHA 2006 guidelines for the management of 
patients with valvular heart disease: a report of the American College of Cardiology/American 
Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 
Guidelines for the Management of Patients With Valvular Heart Disease): developed in 
collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for 
Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation 
2006;114:e84-231. 
5. Ross J, Jr., Braunwald E. Aortic stenosis. Circulation 1968;38:61-7. 
6. Rapaport E. Natural history of aortic and mitral valve disease. The American journal of 
cardiology 1975;35:221-7. 
7. Frank S, Johnson A, Ross J, Jr. Natural history of valvular aortic stenosis. British heart journal 
1973;35:41-6. 
8. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 focused update incorporated into the 
ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report 
of the American College of Cardiology/American Heart Association Task Force on Practice 
Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients 
with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, 
Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. 
Journal of the American College of Cardiology 2008;52:e1-142. 
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