A Multi-center, Non-randomized Trial to Determine the Safety and Effectiveness of the 17mm MDT-2215 Aortic Valve Bioprosthesis in Patients With Aortic Valve Disease
Phase: NA
Conditions: Aortic Stenosis
Sponsor: Medtronic Cardiac Surgery

 
 
 
 
 
 
 
 
 
Medtronic 
Clinical Investigation Plan 
Clinical Investigation Plan / Study Title 
PERIGON Japan Study 
Clinical Investigation Plan Identifier 
MDT2-15-14 
Study Product Name 
Avalus aortic bioprosthesis 17mm 
ClinicalTrials.gov Identifier 
NCT02686814  
Document Version / Date 
Version 1.0 / 21-NOV-2019 
 
 

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Clinical Investigation Plan 
Clinical Investigation Plan/Study Title  PERIGON Japan Study 
Clinical Investigation Plan Identifier  MDT2‐15‐14 
Study Product Name  Avalus aortic valve bioprosthesis 17mm 
Sponsor/Local Sponsor 
Medtronic Japan, Co., Ltd. 
1‐2‐70 Konan, Minato‐ku,  
Tokyo 108‐0075  
Japan 
Document Version / Date   Version 1.0 / 21‐NOV‐2019 
Coordinating Investigator 
Professor Yutaka Okita, MD 
Division of Cardiovascular Surgery, 
Takatsuki Hospital, Japan 
1‐3‐13 Kosobe‐cho, Takatsuki‐shi, Osaka 
659‐1192 Japan 
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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1. 
Table of Contents 
1. 
Table of Contents ............................................................................................................... 2 
2. 
Glossary .............................................................................................................................. 5 
3. 
Synopsis ............................................................................................................................. 7 
4. 
Introduction ....................................................................................................................... 8 
4.1. 
Background .................................................................................................................. 8 
4.2. 
Purpose ........................................................................................................................ 9 
5. 
Objectives and Endpoints ................................................................................................... 9 
5.1. 
Objectives .................................................................................................................... 9 
 
Primary Objective(s) ..................................................................................................... 9 
5.1.1.1 
Primary Endpoint ...................................................................................................... 9 
5.1.1.2 
Secondary Endpoint .................................................................................................. 9 
6. 
Study Design .................................................................................................................... 10 
6.1. 
Duration ..................................................................................................................... 10 
6.2. 
Rationale ................................................................................................................... 10 
7. 
Product Description .......................................................................................................... 11 
8. 
Selection of Subjects ........................................................................................................ 11 
8.1. 
Study Population ....................................................................................................... 11 
8.2. 
Subject Enrollment .................................................................................................... 12 
8.3. 
Inclusion Criteria ....................................................................................................... 12 
8.4. 
Exclusion Criteria ....................................................................................................... 12 
9. 
Study Procedures ............................................................................................................. 12 
9.1. 
Subject follow-up schedule ....................................................................................... 12 
 
Unscheduled Follow-up Visits ....................................................................................... 13 
 
Missed Follow-up Visits ............................................................................................... 13 
9.2. 
SUBJECT EXIT FROM STUDY ...................................................................................... 13 
9.3. 
TRIAL ASSESSSMENTS .............................................................................................. 14 
 
NYHA Functional Classification ..................................................................................... 14 
 
12-Lead ECG .............................................................................................................. 14 
 
Echocardiography ....................................................................................................... 15 
 
Hematology/Chemistry ................................................................................................ 15 
 
Hemostasis ................................................................................................................ 15 
9.4. 
Medications ............................................................................................................... 16 
9.5. 
Subject Consent ......................................................................................................... 16 
 
Informed Consent Form .............................................................................................. 16 
9.5.2. 
Informed Consent Process .......................................................................................... 16 
9.5.3. 
Special Cercumstances for Informed Consent Process and Signature ............................... 17 
9.6. 
Assessment of Safety ................................................................................................ 17 
9.7. 
Recording Data .......................................................................................................... 17 
9.7.1. 
Electronic Data Capture .............................................................................................. 17 
9.7.2. 
Data Collection ........................................................................................................... 17 
9.7.3. 
Data Validation .......................................................................................................... 18 
9.7.4. 
Source Documents ..................................................................................................... 18 
9.8. 
Deviation Handling .................................................................................................... 18 

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9.9. 
Subject Withdrawal or Discontinuation .................................................................... 19 
10.  Risks and Benefits ............................................................................................................ 19 
10.1.  Potential Risks ........................................................................................................... 19 
10.1.1. 
Description of Risk Analysis ...................................................................................... 19 
10.1.1.1 
Risk ....................................................................................................................... 19 
10.1.1.2 
Potential Benefits .................................................................................................... 20 
11.  Adverse Event and Device Deficiencies ............................................................................ 20 
11.1.  Definitions/Classifications ........................................................................................ 20 
11.2.  Potential Adverse Events ........................................................................................... 21 
11.3.  Reporting of Adverse Events ..................................................................................... 22 
11.3.1. 
Evaluation and Documentation of Adverse Events and Device Deficiencies ................... 22 
11.3.2. 
Classification of Causal Relationships ........................................................................ 23 
11.3.3. 
Adverse Events and Device Deficiency Reporting Requirement .................................... 23 
11.3.4. 
Regular Reporting of Adverse Event and Device Deficiencies (Annual Report) ............... 24 
11.3.5. 
Documentation and Reporting of Device Deficiencies.................................................. 24 
11.3.6. 
Emergency Contact Details for Reporting Events and Device Deficiencies ..................... 25 
12.  Data Review Committees ................................................................................................. 25 
12.1.  Echocardiography Core Lab ....................................................................................... 25 
12.2.  Pathology Lab ............................................................................................................ 25 
12.3.  Clinical Event Committee (CEC) ................................................................................ 26 
12.4.  Data Safety and Monitoring Board (DSMB) ............................................................... 26 
13.  Statistical Design and Methods ........................................................................................ 27 
13.1.  Missing Data .............................................................................................................. 27 
14.  Ethics ................................................................................................................................ 27 
14.1.  Statement(s) of Compliance ...................................................................................... 27 
14.1.1. 
Applicable Laws and Regulations .............................................................................. 27 
14.1.2. 
Investigational Site Initiation and Management .......................................................... 28 
14.1.2.1 
Investigator Selection .............................................................................................. 28 
14.1.2.2 
Research Agreement and Conflict of Interest ............................................................. 28 
14.1.2.3 
Training of Investigative Staff .................................................................................. 28 
14.1.2.4 
Site Activation ......................................................................................................... 29 
14.1.2.5 
Study Site Investigative Team Members – Roles and Responsibilities ........................... 29 
14.1.2.5.1 
Principal Investigator ........................................................................................... 29 
14.1.2.5.2 
Cardiologist/Echocardiographer ............................................................................. 30 
14.1.2.5.3 
Other Study Support Staff .................................................................................... 30 
14.2.  Ethics Board Information .......................................................................................... 30 
15.  Study Administration ........................................................................................................ 30 
15.1.  Management of Study Contact Information .............................................................. 30 
15.2.  Monitoring ................................................................................................................. 31 
15.2.1. 
Site Initiation Visit ................................................................................................... 31 
15.2.2. 
Periodic Monitoring Visit........................................................................................... 31 
15.2.3. 
Study Closure ......................................................................................................... 31 
15.3.  Data Management ..................................................................................................... 32 
15.4.  Direct Access to Source Data/Documents ................................................................. 32 
15.5.  Confidentiality ........................................................................................................... 32 
15.6.  Liability ...................................................................................................................... 32 

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15.7.  Subject Compensation ............................................................................................... 32 
15.8.  Report to the Head of Research Site ......................................................................... 32 
15.9.  Clinical Investigation Plan Amendments .................................................................. 33 
15.10. Records and Report ................................................................................................... 33 
15.11. Publication and Use of Information .......................................................................... 35 
15.12. Use of Subject Data in the Future ............................................................................. 35 
15.13. Suspension or Early Termination ............................................................................... 36 
15.13.1. 
Planned Study Closure ............................................................................................. 36 
15.13.2. 
Early Termination or Suspension .............................................................................. 36 
15.13.3. 
Criteria for Study-wide Termination or Suspension ..................................................... 36 
15.13.4. 
Criteria for Investigator/Center Termination or Suspension ......................................... 36 
15.13.5. 
Procedure for Planned Study Closure, Termination, or Suspension ............................... 36 
15.13.5.1  Medtronic-initiated .................................................................................................. 37 
15.13.5.2  Investigator-initiated ............................................................................................... 37 
15.13.5.3  Ethics Board-initiated ............................................................................................... 37 
16.  References ........................................................................................................................ 37 
17.  Appendices ....................................................................................................................... 38 
18.  Version History ................................................................................................................. 38 
 
 
 

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2. 
Glossary 
Term 
Definition 
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  
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 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDE 
Investigational Device Exemption 
IFU 
Instructions for use 

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Term 
Definition 
INR 
International Normalized Ratio 
EC 
Institutional Review Board 
ISO 
International Organization for Standardization 
LDH 
Lactate Dehydrogenase 
mm 
Millimeters 
MHLW 
Ministry of Health, Labour and Welfare 
NYHA 
New York Heart Association 
OPC 
Objective Performance Criteria 
PEEK 
Polyetheretherketone 
PERIGON 
Medtronic PERIcardial SurGical AOritc Valve 
ReplacemeNt  Study 
PI 
Principal Investigator 
PI/ICF 
Patient Information/ Informed Consent Form 
PT 
Prothrombin time 
EC 
Ethics Committee 
SAE 
Serious Adverse Event 
SADE 
Serious Adverse Device Effect 
SAP 
Statistical Analysis Plan 
SAVR 
Surgical Aortic Valve Replacement 
SOP 
Standard Operating Procedures 
SVD 
Structural Valve Deterioration 
TTE 
Transthoracic Echocardiography 
US 
United States 
USADE 
Unanticipated Serious Adverse Device Effect 
 
 

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3. 
Synopsis 
Title 
PERIGON Japan Study 
Clinical Study Type 
Prospective, nonrandomized, multicenter and observational study 
Product Name 
Avalus aortic valve bioprosthesis 17mm, 17 mm 
Sponsor  
Medtronic Japan, Co., Ltd. 
Local Sponsor 
Medtronic Japan, Co., Ltd. 
1-2-70 Konan, Minato-ku,  
Tokyo 108-0075  
Japan 
Investigation Purpose  
Evaluate long term safety and effectiveness of 17 mm size Avalus Aortic 
Valve (stented bovine aortic bioprosthesis valve) in patients undergone 
SAVR in MDT-2215 study  
Product Status 
Post approval 
Study Design 
Long term follow-up (3 to 5 years) for subjects undergone surgical 
aortic valvereplacement with Avalus bioprosthesis  
Sample Size  
10 subjects 
Number of Sites 
8 clinical sites 
Inclusion/Exclusion Criteria 
Inclusion Criteria: 
Enrolled and still being followed up in MDT-2215 study (Protocol 
identification No. MDT2-15-14) 
Exclusion Criteria: 
Research investigator determined it is difficult to continue being 
followed up because of medical reasons 
Study Procedures and 
Assessments  
Subjects will be evaluated at the research site at 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. SAE/Device related Adverse events/device deficiency 
Safety and Effectiveness 
Assessments  
1. 
Assessment of NYHA classification will be evaluated annually up 
to 5 years.   
2. 
EOAI will be evaluated annually through 5 years.       
3. 
Hemodynamic performance annually up to 5 years including: 
a. 
effective orifice area (EOA) 
b. 
peak pressure gradient 
c. 
mean pressure gradient 
d. 
valvular regurgitation 
e. 
performance index 
f. 
cardiac output 

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g. 
cardiac index  
Safety endpoints: The following valve-related adverse events as 
defined by ISO5840:2009 will be evaluated in this study: 
1. 
Thromboembolism  
2. 
Thrombosis  
3. 
Hemorrhage (all and major)  
4. 
Paravalvular leak (PVL, all and major)  
5. 
Endocarditis  
6. 
Hemolysis  
7. 
Structural valve deterioration  
8. 
Non-structural dysfunction  
9. 
Reintervention 
10. Explant 
11. Death 
 Statistics  
Primary cohort is all the subjects meet all inclusion criteria and no 
exclusion criteria and also provide written informed consent. 
Statistical  analysis  will  be  performedin  accordance  with  Statistical 
Analysis Plan (SAP).  
 
4. 
Introduction 
4.1. Background  
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). 1-4 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%.5 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.6 The Magna Ease 
uses the Magna design, with a lower profile and contoured sewing ring to enhance implantability.7   The 
Perimount valves utilize anti-calcification treatments to inhibit the binding of calcium to the prosthetic 
leaflets. 
Medtronic has developed the MDT-2215 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.8-9 

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The purpose of this study is to evaluate the safety and effectiveness of the Medtronic 17mm Avalus aortic 
valve bioprosthesis [herein referred to as MDT-2215 valve] in a patient population undergone SAVR. 
Regulatory approval was granted before 5-year subject follow-up period is over. The rest of the follow-up 
period will be conducted under Ethical Guidelines for Medical and Health Research Involving Human 
Subjects. 
4.2. Purpose 
The purpose of this research is to confirm the long term (3-5 years) safety and effectiveness for subjects 
undergone SAVR with Avalus bioprosthesis valve 17 mm.  
 
5. 
Objectives and Endpoints 
5.1. Objectives 
 
Primary Objective(s) 
The purpose of this study is to evaluate the safety and effectiveness of the Medtronic 17mm Avalus aortic 
valve bioprosthesis in a patient population undergone SAVR in the preceded MDT-2215 trial. Regulatory 
approval was granted before 5-year subject follow-up period is over. The follow-up period after 
regulatory approval is granted will be conducted under Ethical Guidelines for Medical and Health Research 
Involving Human Subjects. 
5.1.1.1 
Primary Endpoint 
The primary endpoints are as follows:  
Efficacy - Functional and Anatomical;  
Changes in New York Heart Association (NYHA) Class and effective orifice area (EOA) from 
baseline to 1 year. 
The primary endponts were achieved with preceded trial. The primary endpoints are not applicable to 
PERIGON Japan research, which is a long term follow-up study. 
5.1.1.2 
Secondary Endpoint 
The Secondary Endpoints are as follows: 
1. 
Assessment of NYHA classification will be evaluated annually up to 5 years.  
2. 
EOAI will be evaluated annually through 5 years.       
3. 
Hemodynamic performance annually up to 5 years including: 
a. 
effective orifice area (EOA) 
b. 
peak pressure gradient 
c. 
mean pressure gradient 
d. 
valvular regurgitation 

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e. 
performance index 
f. 
cardiac output 
g. 
cardiac index  
 
Safety endpoints: The following valve-related adverse events as defined by ISO5840:2009 will be 
evaluated in this study: 
 
1. 
Thromboembolism  
2. 
Thrombosis  
3. 
Hemorrhage (all and major)  
4. 
Paravalvular leak (PVL, all and major)  
5. 
Endocarditis  
6. 
Hemolysis  
7. 
Structural valve deterioration  
8. 
Non-structural dysfunction  
9. 
Reintervention 
10. Explant 
11. Death 
Safety of the valve will be evaluated by the incidence of valve-related adverse events, reintervention, 
explant, and death. The endpoints will be summarized and the number of events as well as number and 
proportion of subjects experiencing an event will be reported. The endpoint is descriptive and no 
statistical hypothesis test will be performed.  
 
6. 
Study Design  
Long term follow-up (3 to 5 years) will be conducted for subjects undergone surgical aortic 
valvereplacement with Avalus bioprosthesis at 3, 4 and 5 years after implant in preceded MDT-2215 
study (Investigation Plan identifier: MDT2-15-14). This is an observational study which is not physically or 
mentally invasive to subjects. This study will be conducted within the regular practice. No new subject 
will be enrolled in this study.  
MDT-2215 study was a prospective, interventional, non-randomized, multi-center trial, with each site 
following a common protocol.  The design of the trial was based on the recommendations by the FDA 
Heart Valve guidance (2010) and EN ISO 5840:2009 standard for cardiac valve prostheses. 
6.1. Duration 
Planned start date of the study is November 2019 and the subject follow-up will be completed in July 
2023. Clinical Study Report will be completed  in December 2023. 
6.2. Rationale 
Refer to Section 4.1 Background and Rationale. 

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7. 
Product Description 
Avalus aortic valve bioprosthesis (17 mm size) is indicated for the replacement of a diseased, damaged, 
or malfunctioning native or prosthetic aortic valve. 
Avalus aortic valve bioprosthesis (17 mm size) shown in Figure 1 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 1: Avalus 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. Avalus aortic valve bioprosthesis (17 mm size) 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. 
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.  
 
8. 
Selection of Subjects 
8.1. Study Population 
Subjects who had  aortic valve replacement (AVR) in preceded MDT-2215 study may be considered for 
this study if they meet all of the inclusion and none of the exclusion criteria. Written consent should be 
provided.  

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8.2. Subject Enrollment 
The point of enrollment for this study is once the EC-approved patient informed consent form has been 
signed and dated by all of the required parties. 
8.3. Inclusion Criteria 
Subject enrolled in the MDT-2215 study and being followed up continuously. 
8.4. Exclusion Criteria 
Subjects will be excluded if study investigator considers it is difficult for the subject to participate in the 
study because of medical reasons.  
 
9. 
Study Procedures 
Subjects implanted with Avalus prosthetic valve will be evaluated at research site at 3, 4 and 5 years (± 
60 days) post-procedure.  
9.1. Subject follow-up schedule 
The following table indicates the parameters expected to be routinely evaluated by physicians 
participating in the study. 
Table 1:  Schedule of assessments 
Data Collection Requirement 
Assessment Intervals 
3-year 
4-year 
5-year 
Unscheduled Visits 
Exit 
Visit Window 
± 60 days 
± 60 days 
± 60 days 
As necessary 
Date of Exit 
Physical Examination 
 
 
 
×* 
 
NYHA Classification 
× 
× 
× 
×* 
 
12-Lead ECG 
× 
× 
× 
×* 
 
Blood Labs 
× 
× 
× 
×* 
 
Transthoracic Echo (TTE) 
× 
× 
× 
×* 
 
Adverse Event/Device Deficiency 
×** 
×** 
×** 
×** 
×** 
Relevant Medications 
× 
× 
× 
×* 
×* 

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Vital Status 
 
 
 
 
× 
*Any assessments for unscheduled visits are done at the discretion of the Investigator.  
**Only SAE/device related adverse events/device deficiencies will be collected 
 
Subjects will be evaluated at the research site at 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. SAE/Device related Adverse events/device deficiency 
 
Unscheduled Follow-up Visits 
If a subject returns to the institution for an unplanned visit between the protocol-required follow-up visits 
specifically for a problem related to their Avalus valve (17mm), the visit will be treated as an unscheduled 
visit. 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 Unscheduled 
Follow-up eCRF and AE data on the AE eCRF.  
 
Missed Follow-up Visits 
Every effort should be made to ensure subjects return to the clinic for all protocol required follow-up 
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 9.8.  The Investigator should also make every 
effort to contact the subject within the visit window, to collect the subject’s information including 
potential adverse events. 
9.2. SUBJECT EXIT FROM STUDY 
Table 2 below details how the data will be handled for each scenario.   
Table 2: Study exit scenarios 
Scenario 
Follow-up Required 
CRFs Required 
Subject enrolled, implanted with 
Avalus valve, and exits the study 
early due to explant 
30 days post-
explant for safety 
only 
-All required/ Unscheduled Follow-up eCRFs 
through last visit completed 
-Valve Reintervention eCRF 
-AE eCRF (as applicable) 
-Trial Exit eCRF 

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Scenario 
Follow-up Required 
CRFs Required 
Subject enrolled, implanted with 
Avalus valve, and exits the study 
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 Follow-up eCRFs 
through last visit completed 
-AE eCRF (as applicable) 
-Trial Exit eCRF 
Subject enrolled, implanted and 
completes the study 
requirements 
Through 5 year 
follow-up 
-All required/ Unscheduled Follow-up eCRFs 
-AE eCRF (as appropriate) 
-Trial Exit eCRF 
9.3. TRIAL ASSESSSMENTS 
 
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 all in-office follow-up visits, and the results recorded on the 
appropriate eCRF.  The NYHA classification should be assessed by a medical doctor.  
 
12-Lead ECG 
A standard 12-Lead ECG should be taken at 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. 

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The Investigator or Sub-Investigator should review and sign/date each 12-lead ECG recording conducted 
as part of the study 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. 
 
Echocardiography 
Transthoracic echocardiography (TTE) is required at all in-office scheduled follow up visits.  The site will 
record echocardiography data on the Site Echo 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 C: Echocardiography procedure. 
Additional information regarding the Echo Core Lab can be found in Section エラー! 参照元が見つかりま
せん。. 
 
Hematology/Chemistry 
This section describes the laboratory parameters required at baseline and at each postoperative in-office 
interval.   
 
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 
 
Reticulocytes Count  
 
Haptoglobin 
 
Serum lactate dehydrogenase (LDH) 
*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. 
 
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. 

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9.4. Medications 
Use of the following medications will be collected at each postoperative interval and recorded on the 
appropriate eCRF: 
 
Anticoagulants 
 
Antiplatelets 
 
Aspirin  
9.5. Subject Consent 
 
Informed Consent Form 
PI/ICF used for this study includes items described in section of “Article 5-(12)-3 Ethical Guidelines for 
Medical and Health Research Involving Human Subjects. PI/ICF may be modified per requirement of 
respective investigational site. 
Site EC shall approve all informed consent documents prior to implementation in the study.  EC must pre-
approve all language changes to the PI/ICF throughout the course of the study prior to implementation; 
this includes initial submission, annual reviews (if applicable) and protocol amendment reviews.  
Medtronic will provide any important new information that impacts the health, safety or welfare of study 
subjects, for inclusion in PI/ICF updates as it becomes available.   Sites should following any EC 
requirements for disseminating new information and re-consenting subjects during the course of the 
study. 
9.5.2. 
Informed Consent Process 
The Investigator or authorized designee must administer the approved PI/ICF to each prospective study 
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 study, using native non-technical language that is understandable to the patient.   The 
patient must be informed about their right to withdraw from the study 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 study will not jeopardize their future medical care.  The patient must also be 
informed that by participating in the study, they are not waiving their legal rights.  The patient must have 
ample time and opportunity to inquire about details of the study, and to decide whether or not to 
participate in the clinical study. All questions about the study should be answered to the satisfaction of 
the patient.  All items discussed in the 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 Section 
9.5.3) will be documented in the patient’s medical record prior to any study-specific procedures.  Patient 
informed consent must be obtained in accordance with the national and local laws, regulations and 
guidelines of each site.   The institutional standard procedure consent form does not replace the study 
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 
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form will be retained in the patient’s study records.  A copy of the signed informed consent will be 
provided to the patient. 
Informed consent should not be obtained from legally authorized representative. 
9.5.3. 
Special Cercumstances 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.  
9.6. Assessment of Safety 
Refer to  Section 11, Adverse Event and Device Deficiency. 
9.7. Recording Data 
Same subject ID number (SID) designated in the preceded MDT-2215 study will be used in the PERIGON 
Japan study. SID for each subject was recorded on the subject log created for the preceded MDT-2215 
study. Subject log is stored only at investigational sites and Medtronic will not collect the subject log.  
9.7.1. 
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 study will be maintained for the life of Medtronic, 
according to corporate policy and record retention schedule.  
9.7.2. 
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 Sub-investigator and study collaborator list (RC) or the Delegation of Tasks List. The 
eCRFs must be completed and/or updated to reflect the latest observations on the subjects participating 
in the study.   
The primary investigator or delegated 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 or delegated sub-
investigator shall re-sign this eCRF. 

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9.7.3. 
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.  
Study 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. 
9.7.4. 
Source Documents 
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 study). 
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.。 
9.8. Deviation Handling 
A study deviation is any event in which the study 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 study 
 
Required testing and/or measurements not done or incorrectly done 
 
Subject did not attend follow-up visit  
 
Follow-up visit was completed outside window 
 
Source data permanently lost 
 
Enrollment of subjects during lapse of Ethics Board approval 

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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.  Study 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 
requirements.  
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.   
9.9. Subject Withdrawal or Discontinuation 
When a subject voluntarily withdraw his or her consent to participate in the study, the subject’s will 
should be respected and  the subject should be exited from the study. At the last point of contact (if 
outside a study-required visit), the subject’s status of any ongoing adverse events.  Subject withdrawal 
should be documented per the clinical site’s SOP if applicable. 
No additional subject will be enrolled to replace a subject withdrawn. 
 
10. Risks and Benefits 
10.1. Potential Risks 
10.1.1. 
Description of Risk Analysis 
10.1.1.1 
Risk 
Risks associated with any surgical procedure were identified and they were carefully monitored 
throughout the MDT-2215 study. No additional risks are expected for patients to participate in PERIGON 
Japan study. Risks associated with the Avalus aortic valve bioprosthesis are expected to be similar to 
commercially available tissue heart valves.  Refer to Section 11 for adverse events and device 
deficiencies.  
The following measures have been implemented to minimize risks to study subjects: 
 
Investigators will have expertise in aortic heart valve replacement procedures. 

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 
Investigative sites will have comprehensive cardiology and surgery programs. 
 
Subjects receiving the Avalus valve will be rigorously followed over the course of the study.  The 
protocol includes regular follow-up visits to assess device safety and effectiveness. These visits 
will enable detection of deterioration in Avalus 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. 
Instruction for use (IFU) for the device will be utilized to address forseeable risks. Updated IFU will be 
distributed to the clinical sites. 
10.1.1.2 
Potential Benefits 
There is no direct benefit associated to participation in this study, but the information obtained during 
this study will be used scientifically. The results of this study can help physicians understand the safety 
and effectiveness of the heart valve. 
 
11. Adverse Event and Device Deficiencies 
11.1. Definitions/Classifications 
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 Japan Study 
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) 
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  

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Event Type 
Definition 
(EN 
ISO14155:2011 
3.37) 
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.  
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 
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. 
11.2. Potential Adverse Events 
Potential failures/or adverse events associated with the heart valve replacement may include the 

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following: 
 
Device Failures/Adverse Events of significance 
o 
Thromboembolism,  
o 
Valve Thrombosis 
o 
Dehiscence of valve’s basal portion or valve commissure 
o 
Endocarditis and other infection 
o 
Hemolysis 
o 
Hemolytic anemia 
o 
Hemorrhage, anticoagulant/antiplatelet-related 
o 
Leak, transvalvular or paravalvular  
o 
Nonstructural dysfunction (leaflet entrapment/impingement, obstructive pannus 
ingrowth, suture dehiscence, inappropriate sizing, other) 
o 
Prosthesis regurgitation 
o 
Structural deterioration (calcification, leaflet tear, stenosis, other) 
o 
Reintervention 
o 
Reoperation 
o 
Explant 
o 
Permanent disability 
o 
Death 
 
 
Device Failures/Adverse Events of others 
o 
Abrasion/or perforation which influenced suture or fabric covered stent 
o 
Damage with equipment handling 
o 
Patient - prosthesis mismatch 
o 
Native tissue injury for implantation treatment 
o 
Obstruction of coronary ostia by the stent and sewing ring 
o 
Ventricle rupture 
o 
Increase of transvalvular pressure gradient 
o 
Angina 
o 
Cardiac dysrhythmias 
o 
Heart failure 
o 
Myocardial infarction 
o 
Stroke 
11.3. Reporting of Adverse Events 
11.3.1. 
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 study subjects until they are no longer participating in the 
study.   
Suspected or confirmed device related adverse events, all SAE’s regardless of device relatedness, and 
device deficiencies that occur during the study 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 

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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.  
The general process for reporting Adverse Events is as follows:  
 
Report the event to Medtronic as soon as possible. Table 5 provides recommended reporting 
timeframes. These timeframes are not considered protocol requirements. Sites will be provided 
with the contact information of the appropriate Medtronic Safety designee for event reporting.  
 
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. 
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 Avalus valve 
 
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 
When possible and not otherwise prohibited by local regulation, 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 12.1. 
11.3.2. 
Classification of Causal Relationships 
For each reported AE, the causal relationship between the AE and the study devices and implant 
procedure will be classified as related, not related or unknown. Definition of  the causal relationship 
between the AE and Avalus aortic valve bioprosthesis 17mm is 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. 
11.3.3. 
Adverse Events and Device Deficiency Reporting 
Requirement 
Adverse events and device deficiencies that occur during this study are required to be reported to 
Medtronic via the AE or device deficiency eCRF, as soon as possible after the event occurs. Table 5 
provides recommended reporting timeframes. These timeframes are not considered protocol 
requirements. 
Table 5: Timeframes for Adverse Event reporting to Medtronic 

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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 24 hours of the 
investigator’s / site’s first knowledge of the event 
Adverse Device Effect (ADE) or Device 
Related Adverse Event 
No later than 10 working days of the investigator’s / site’s 
first knowledge of the event 
Serious Adverse Device Effect (SADE) 
Immediately, but no later than 24 hours of the investigator’s 
/ site’s first knowledge of the event 
Unanticipated Serious Adverse Device 
Effect (USADE) 
Immediately, but no later than 24 hours of the investigator’s 
/ site’s first knowledge of the event 
Device Deficiency 
No later than 48 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 24 hours of the investigator’s 
/ site’s first knowledge of the event 
In addition, Investigators are obligated to report adverse events in accordance with the requirements of 
their reviewing Ethics Board and local regulations. 
Marketing approval was obtained for Avalus aortic valve bioprosthesis 17mm and this study is an 
observational study not involving invasive treatment, adverse events listed in Section 11.3.4 will be 
reported to the head of institution. 
11.3.4. 
Regular Reporting of Adverse Event and Device 
Deficiencies (Annual Report) 
The Sponsor is obligated to report adverse events and device deficiencies that occur during this study to 
the Regulatory Authorities and Ethics Board as per local requirements. Additionally the Sponsor should 
report adverse events reported from the clinical sites to the head of clinical department per internal 
procedure. 
11.3.5. 
Documentation and Reporting of Device Deficiencies 
Device deficiency information will be collected throughout the study and reported to Medtronic.  Device 
deficiencies that led to an AE are reported on the AE eCRF only.   
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.  

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Any device or accessory involved with a device deficiency should be returned to Medtronic (unless 
implanted) for analysis. 
11.3.6. 
Emergency Contact Details for Reporting Events and 
Device Deficiencies 
Investigators should contact the Medtronic Study 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. 
 
12. Data Review Committees 
12.1. 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 PMDA 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 
 
Medtronic will conduct audit to MedStar Health Research Institute if it is required based on annual audit 
plan. Also, annual business evaluations are conducted and improvements are requested as necessary. If 
non-compliance and / or deviations are identified, discuss immediately and develop appropriate 
improvements. 
12.2. Pathology Lab 
All explanted study valves will be independently analyzed by CVPath Institute, Inc., 19 Firstfield Road, 
Gaithersburg, MD 20878.   
 

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Medtronic will conduct audit to CVPath Institute if it is required based on annual audit plan. Also, annual 
business evaluations are conducted and improvements are requested as necessary. If non-compliance 
and / or deviations are identified, discuss immediately and develop appropriate improvements. 
12.3. Clinical Event Committee (CEC) 
An independent Clinical Events Committee (CEC) will be established prior to the first enrollment of the 
study.  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 study 
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 study.  Additional specialists, such as echocardiologists, may also be selected 
as part of the CEC.  
Prior to the onset of the study, the CEC charter will be drafted to establish explicit rules outlining the 
minimum amount of data required and the algorithm followed in order to classify/adjudicate a study 
endpoint related clinical event.  The charter will be approved by Medtronic. 
All deaths and potential endpoint events will be reviewed and adjudicated by CEC as described in CEC 
Charter. CEC decisions will be documented in meeting minutes, which will be maintained in the study 
master file.   
Additional details about the CEC will be outlined in the CEC charter. 
12.4. Data Safety and Monitoring Board (DSMB) 
A DSMB will be established to review accumulating data from the study, and advise Medtronic on the 
continuing safety of current and future study participants, and the continuing validity and scientific merit 
of the study.  The board will be independent of Medtronic and the study 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 study termination recommendations if safety concerns warrant. These DSMB 
recommendations may include recommendations on study status such as continuing the study 
without modifications, continuing the study with modifications, stopping the enrollment in the 
study, or recommendations about study conduct including recommendations around enrollment 
or protocol deviations.  
 
Frequency of meetings 
 
Handling of emergency situations 
 
Documentation procedures of the DSMB meetings 
The DSMB will meet at least 2 times during the study 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 study.  The DSMB may call additional 
meetings if, at any time, there is concern about any aspect of the study.  All data presented at the 
meetings will be considered confidential and returned to the study statistician at the closure of the DSMB 
meeting. 
Additional details about the DSMB will be outlined in the DSMB charter. 

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13. 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 study report, along with justification for 
the deviation(s). 
13.1. 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. 
 
14. Ethics 
14.1. Statement(s) of Compliance 
14.1.1. 
Applicable Laws and Regulations 
The PERIGON Japan Study was designed to reflect the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects (Ministry of Education and Ministry of Health, Labor and Welfare notification 
No. 3 in 2014) and Law for Ensuring the Quality, Efficacy, and Safety of Drugs and Medical Devices (The 
law No. 145 in 1960). 
The following items in “Article 8-(1), Ethical Guidelines for Medical and Health Research Involving Human 
Subjects” are not applicable. 
⑯ Procedure regulated by Article 13 (including procedure of explanation) when obtaining informed 
assent 
⑰ How to deem if the all requirements in Article 12-6 are met when the research regulated by the Article 
is performed 
㉑ Provision of medications to subjects after the research specific activities on the research exceed to 
regular treatment 
㉒ Handing of the research results (including accidental findings) when an important knowledge as to 
subjects’ health and genetic characteristics etc. which can be inherited by descendants can be obtained 
 

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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 (PIC) 
process, Ethics Board approval, study training, clinical study registration, pre-clinical testing, risk benefit 
assessment, and publication policy. In addition, the study will be conducted in compliance with FDA 21 
CFR Part 11 and 54.  
Ethics Board notification/approval to conduct the study is required at all participating sites.  
Investigational sites will be not be activated, nor begin enrolling subjects until the required 
approval/favorable opinion from the respective Ethics Board 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 Declaration of 
Helsinki on http://clinicaltrials.gov (PL 110-85, Section 810(a)).  
14.1.2. 
Investigational Site Initiation and Management 
14.1.2.1 Investigator Selection 
The following criteria will be used to select investigators and sites for participation: 
 
The presence or capacity of establishing an investigative team capable of managing the duties of 
the clinical study 
 
Access to the necessary cardiovascular facilities and services to complete protocol required study 
procedures and follow-up. 
 
Willingness to comply with the requirements described in this CIP 
14.1.2.2 Research Agreement and Conflict of Interest 
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 study activation.  The investigator is required to indicate their approval of the CIP (and 
any subsequent amendments), by signing and dating the agreement. 
14.1.2.3 Training of Investigative Staff 
Medtronic will provide training to the investigative team, according to the Training Plan, on the study 
requirements and EN ISO 14155:2011.  Training required per local law will occur prior to site activation at 
each site, and will include the following topics: 
 
CIP overview and study procedures  
o 
Investigator and sponsor responsibilities  
o 
Procedures for obtaining informed consent  
o 
Adverse event/device deficiency reporting procedures  
o 
Deviation reporting procedures 
o 
Site record maintenance and retention 
 
Ethics Board requirements  
 
Monitoring requirements and expectations  
 
Case report form (CRF) completion and management, including electronic data entry  

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 
Potential regulatory inspections and audits by the regulatory authorities  
 
Investigational site and subject compensation  
 
Any additional regulatory requirements  
14.1.2.4 Site Activation 
Investigational sites will receive a formal letter of site activation, upon receipt of or completion of the 
following: 
 
A signed research agreement 
 
Disclosure of Conflict of Interest from the investigators 
 
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 
 
Sub-investigator and study collaborator list (RC) or DTL 
 
Lab certificate and lab normal values/ranges 
 
Confirmation of adequacy of equipment/facilities 
14.1.2.5 
Study Site Investigative Team Members – Roles and 
Responsibilities 
The following is a description of the key personnel who will form the investigative team at each study 
site.  
14.1.2.5.1 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 study at the site and for the integrity of the study 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 study-related procedures, and only 
after Ethics Board and regulatory approval of the study 
 
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  
 
Reporting adverse events and device deficiencies in accordance with the CIP and according to 
country regulations 
 
Approving all case report forms; 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 

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 
Allowing time with the study monitor and Sponsor study staff members during Sponsor site visits 
 
Managing suppliers per site’s SOP if any of the study related work is outsourced. 
14.1.2.5.2 Cardiologist/Echocardiographer 
Each site should consider having a designated cardiologist/echocardiographer as a sub-Primary 
Investigator. 
14.1.2.5.3 Other Study Support Staff 
The PI will ensure that the investigative site has the appropriate support staff to maintain the study.   
Additional staff may include sub-investigators, study coordinators, and other specialized health care 
professionals. 
14.2. Ethics Board Information 
All necessary documents (CIP and PI/ICF) 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, ICF and other written study 
materials) 
 
Any specific Ethics Board requirements relative to the study (if applicable) 
The investigator and study 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. 
The approval letter needs to be accompanied by an Ethics Board roster to allow verification that the 
investigator or other site study 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.  
 
15. Study Administration 
15.1. Management of Study Contact Information 
Medtronic (Medtronic Japan, Medtronic plc and its subsidiaries) is responsible for creating study-related 
materials, monitoring, audit, statistical analysis, data management, safety, handling of personal 
information and publication as a research representative. These study-related data are collected by using 
Medtronic’s electronic data management system for research. 
This information might be updated during the period of this research. The updated information will be 
reported to the head of research sites on regular basis. 
A list of participating investigational sites and the Investigators is provided as attachment. 

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15.2. Monitoring 
Monitoring and monitoring oversight will be provided by Medtronic Japan and detailed in a Monitoring 
Plan separate from this CIP.  Representatives of Medtronic (i.e. contractors and designees) may also act 
as the study monitors to the site.  A list of the study monitors will be kept separate from this document, 
and the Sponsor will provide updated lists to the investigative sites. 
Follow-up letter will be provided to PI at investigational site after monitoring visit is conducted. 
15.2.1. 
Site Initiation Visit 
Medtronic will conduct a site initiation visit prior to first implant, to prepare the site to conduct the study.  
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 study): 
 
Have received and understand the requirements and contents of 
o 
CIP 
o 
Patient Information/Informed Consent Form (PI/ICF) 
o 
Electronic CRFs 
o 
IFU 
o 
Any written clinical investigation agreements (as appropriate) 
 
Have access to an adequate number of investigational devices 
 
Are familiar with the responsibilities of the Principal Investigator 
15.2.2. 
Periodic Monitoring Visit 
Periodic monitoring visits will be made at all active investigational sites throughout the clinical study 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 complete records are being maintained 
 
Subject informed consent is being obtained and properly documented 
 
The CIP is being followed 
 
Appropriate and timely reports have been made to Medtronic and/or its designees and the Ethics 
Board 
 
The Investigator is carrying out all agreed activities 
The progress of the study will be monitored by: 
 
On-site review, as deemed appropriate by the sponsor 
 
Telephone communications between the site personnel (e.g., Investigator, other supporting staff) 
and study monitors 
 
Review of eCRFs and the associated clinical records 
 
Review of regulatory documents 
15.2.3. 
Study Closure 
Upon study completion Site Closeout Visits will be conducted, as outlined in the Monitoring Plan. 

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15.3. Data Management 
Refer to Section 9.7 Recording Data. 
15.4. Direct Access to Source Data/Documents 
Medtronic may conduct audits at participating clinical sites.  The purpose of an audit is to verify the 
performance of the monitoring process and the study conduct, independently of the personnel directly 
involved in the study.  Regulatory bodies, such as the MHLW, may also perform inspections at 
participating sites.  The investigator and/or institution shall permit Medtronic, monitor and regulatory 
bodies direct access to source data and documents. 
15.5. Confidentiality 
All information and data sent to parties involved in study conduct concerning subjects or their 
participation in this study will be considered confidential.  Study sites will assign a unique subject ID 
number (SID) to each subject.  Records of the subject/SID relationship will be maintained by the study 
site.  The SID number is to be recorded on all study 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. 
Data relating to the study 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.。 
15.6. Liability 
Compensation in this research is not applicable because events exceeding regular treatment, regulated 
by “Article 5‐1‐(3), Ethical guidelines of medical research for human,” are not applicable.  
15.7. Subject Compensation 
Subject compensation may be paid per agreement between Sponsor and cinical site in the research 
study. It should be documented in PD/PIC if subject compensation is payable. 
15.8. Report to the Head of Research Site 
Any revisions or amendments to the CIP or Informed Consent document, along with a statement of 
justification for the changes, will be submitted to Ethics Board, 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).  Any required approvals by regulatory agencies and Ethics Board must be obtained prior 
to implementing a CIP revision at the site. 

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15.9. Clinical Investigation Plan Amendments 
Medtronic Japan will report the following matters to the head of the research site. Each research site will 
also report the following matters to the head of the research site, depending on the site’s SOP.  
 
Case that significant concerns occurred from the point of subject’s human right and that of 
performance of this research such as study-related information leakage 
 
Case that facts or information which appropriateness of performance or reliability of research 
result are lost are obtained 
 
Case that fact or information which ethical validity and/or scientific rationality are lost are 
obtained and affect to the continuation of this research 
 
Case that Unanticipated Serious Adverse Device Effect (USADE) occurred in the research site 
 
Progress of this research, occurrence of adverse events and regular basis report of storage 
condition of study-related information (Annual report: in accordance with the SOP of Medtronic 
Japan) 
 
Case that this research is completed, suspended or stopped 
 
Case that site audit is performed (in accordance with audit plan)  
 
Approved status of performance and continuation of this research by other research site’s Ethics 
Board 
15.10. 
Records and Report 
All study-related documents must be retained for a period of at least 3 years after study closure. 
Medtronic will inform the investigator/site when these documents are no longer required to be retained. 
No study 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 study records to another party or move them to another 
location, advance written notice must be given to the Sponsor. 
The sponsor will retain the study records for the life of Medtronic, according to Medtronic corporate policy 
and record retention schedule. 
Table 6 shows record creation and retention policy for the study. Monitor will confirm subject’s informed 
consent via source data verification or alternative monitoring method (such as remote monitoring) and 
record it in monitoring report. 
 
Table 6: Method of record creation and retention 

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Record Item 
Provider 
Receiver 
(Medtronic Japan and/or Medtronic 
plc and its subsidiaries) 
Receiver’s Name: Medtronic 
Japan and/or Medtronic plc 
and its subsidiaries 
CIP and CIP Supplement (if 
necessary, notification form as 
to the provision of existing 
samples and information to 
other research institutions) to 
be stored for 3 years after the 
report date of this research 
completion (it is acceptable for 
Receiver to store instead)  
CIP to be stored permanently 
Name of responsible person of 
Receiver: Refer to CIP 
Attachment 
CIP and CIP Supplement (if 
necessary, notification form as 
to the provision of existing 
samples and information to 
other research institutions) to 
be stored for 3 years after the 
report date of this research 
completion (it is acceptable for 
Receiver to store instead) 
CIP to be stored permanently 
Provider’s Name: refer to CIP 
Attachment 
 
CIP to be stored permanently 
Researcher’s Name: refer to 
Researchers and Sponsor 
 
CIP to be stored permanently 
Data Item: refer to Sample 
Case Report Forms 
CIP and CIP Supplement (if 
necessary, notification form as 
to the provision of existing 
samples and information to 
other research institutions) to 
be stored for 3 years after the 
report date of this research 
completion (it is acceptable for 
Receiver to store instead) 
CIP to be stored permanently 
Background of obtaining 
information colleted by 
electronic data management 
system 
 
CIP to be stored permanently 

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Subjects’ personal information 
including names 
Signed informed consent form 
to be stored for 3 years after 
the report date of this 
research completion 
Provided information to be 
stored permanently in the 
electronic data management 
system in the condition not to 
be identified specific individuals 
Obtaining informed consent 
from subjects 
Signed informed consent form 
to be stored for 3 years after 
the report date of this 
research completion 
Provided information to be 
stored permanently in the 
electronic data management 
system in the condition not to 
be identified specific individuals 
Provider’s address 
 
Contract to be stored 
permanently 
Name of the head of Provider  
Contract to be stored 
permanently 
15.11. 
Publication and Use of Information 
Preceded MDT-2215 trial was registered at http://clinicaltrials.gov before first enrollment in the trial. Trial 
data and results will be made available as required per regulations. 
At the conclusion of the study, a multisite abstract reporting the primary results may be prepared in 
collaboration with Principal Investigator and with others including, but not limited to, CEC members, for 
publication in a reputable scientific journal.  The publication of the principal results from any single site 
experience within the study 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 
publications regarding the endpoints from the study requires approval by the Coordinating Principal 
Investigator. 
A separate publication plan will provide detailed information about the authorship, publication proposals, 
and requests for data. 
15.12. 
Use of Subject Data in the Future 
Medtronic should store study-related information collected from subjects strictly after completion of this 
research as well. A statistical analysis which is not planned might be performed by using the data. The data 
might be also used in newly planned research in future. 

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15.13. 
Suspension or Early Termination 
15.13.1. Planned Study Closure 
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.  
For each center, Ethics Board approval renewals are required per regulation until the study closure 
process is complete at that center. 
15.13.2. Early Termination or Suspension 
Termination of the Study is discontinuance, by sponsor or by withdrawal of Ethics Board approval before 
completion. This is possible for the whole study 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 or a single center. 
15.13.3. 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 
 
Decision by Medtronic or regulatory body (medically/ethically justifiable) where the study 
is operating under regulatory body authority 
15.13.4. 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 
 
Lack of enrollment 
 
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) 
15.13.5. Procedure for Planned Study Closure, Termination, or 
Suspension 

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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). 
15.13.5.1 
Medtronic-initiated 
In the case of study termination or suspension for reasons other than a temporary Ethics Board approval 
lapse, Medtronic will promptly inform the principal investigator and the Head of Institution (if needed, the 
Director of 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. 
15.13.5.2 
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 
15.13.5.3 
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 
 
 
16. References 
1. Suri RM, Zehr KJ, Sundt TM, 3rd, et al. Left ventricular mass regression after porcine versus 
bovine aortic valve replacement: a randomized comparison. The Annals of thoracic surgery 

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2009;88:1232-7. 
2. Banbury MK, Cosgrove DM, 3rd, White JA, Blackstone EH, Frater RW, Okies JE. Age and valve 
size effect on the long-term durability of the Carpentier-Edwards aortic pericardial bioprosthesis. 
The Annals of thoracic surgery 2001;72:753-7. 
3. Chambers JB, Rajani R, Parkin D, et al. Bovine pericardial versus porcine stented replacement 
aortic valves: early results of a randomized comparison of the Perimount and the Mosaic valves. 
The Journal of thoracic and cardiovascular surgery 2008;136:1142-8. 
4. Celiento M, Ravenni G, Milano AD, et al. Aortic valve replacement with the Medtronic Mosaic 
bioprosthesis: a 13-year follow-up. The Annals of thoracic surgery 2012;93:510-5. 
5. Aupart MR, Mirza A, Meurisse YA, Sirinelli AL, Neville PH, Marchand MA. Perimount pericardial 
bioprosthesis for aortic calcified stenosis: 18-year experience with 1133 patients. The Journal of 
heart valve disease 2006;15:768-75; discussion 75-6. 
6. Carpentier-Edwards PERIMOUNT Magna Aortic Heart Valve. Edwards Lifesciences Web site, 2013. 
(Accessed January 30, 2013, 
athttp://www.edwards.com/products/heartvalves/Pages/Magna.aspx.) 
7. Carpentier-Edwards PERIMOUNT Magna Ease Aortic Heart Valve. 2013. (Accessed January 30, 
2013, at http://www.edwards.com/products/heartvalves/Pages/magnaease.aspx.) 
8. Gott JP, Girardot MN, Girardot JM, et al. Refinement of the alpha aminooleic acid bioprosthetic 
valve anticalcification technique. The Annals of thoracic surgery 1997;64:50-8. 
9. Walther T, Falk V, Autschbach R, et al. Comparison of different anticalcification treatments for 
stentless bioprostheses. The Annals of thoracic surgery 1998;66:S249-54.28. 
17. Appendices 
Appendix A： Instruction for Use 
Appendix B： Definitions 
Appendix C： Echocardiography Procedures 
Appendix D： Informed Consent Form 
18. Version History 
Version 
Summary of Changes 
Author(s)/Title 
1.0 
Not applicable 
Mizuho Nakagaki, Sr. Clinical  
Research Specialist