A Clinical Trial for Transcatheter Aortic Valve Implantation in Chronic Dialysis Patients With Aortic Valve Stenosis
Phase: NA
Conditions: Aortic Stenosis
Sponsor: Edwards Lifesciences


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PROTOCOL 

 
 
A Clinical Trial for Transcatheter Aortic Valve Implantation 
in Chronic Dialysis Patients with Aortic Valve Stenosis㻌


 
Study Device ID Code: EWJ-003 
 
 
 
 
 
 
 
 
Sponsor 
Edwards Lifesciences Corporation 
 
 
 
 
 
 
Clinical Protocol ID Code: 
EW-P-003 
 
 
Edition number: 
Ver. 6.2 
 
 
Date of creation: 
January 6, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This clinical trial will be conducted in compliance with “Law for Ensuring the Quality, 
Efficacy, and Safety of Drugs and Medical Devices” (Act No. 145 of 1960, hereinafter referred 
to as "PMD Act"), ethical principles that have their origin in the Declaration of Helsinki, the 
Japan Ministerial Ordinance on Good Clinical Practice for Medical Devices (Ordinance of the 
Ministry of Health, Labour and Welfare No. 36 of 2005, hereinafter referred to as "J-GCP"), 
ministerial ordinances partially amending J-GCP and the relating regulations, and this protocol. 
 
  
The information contained in this protocol is confidential 
information of Edwards Lifesciences Corporation, and it 
may not be disclosed to any third persons not involved in 
this clinical trial or used for any other purposes without 
prior written permission from Edwards Lifesciences 
Corporation.㻌
CONFIDENTIAL 
 
List of abbreviations
Abbreviation 
English 
AATS 
American Association for Thoracic Surgery 
ACC 
American College of Cardiology 
ACE-I 
Angiotensin Converting Enzyme Inhibitor 
ACT 
Activated Clotting Time 
AHA 
American Heart Association 
ALT 
Alanine Aminotransferase 
ARB 
Angiotensin II Receptor Blocker 
AS 
Aortic Stenosis 
ASE 
American Society of Echocardiography 
AST 
Asparate Aminotransferase 
AT 
As-Treated 
BARC 
Bleeding Academic Research Consortium 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
CCB 
Calcium Channel Blocker 
CCS 
Canadian Cardiovascular Society 
CEC 
Clinical Event Committee 
CFR 
Code of Federal Regulation 
CK 
Creatine Kinase 
CKD 
Chronic Kidney Disease 
CK-MB 
Creatine Kinase MB Isoenzyme  
CRP 
C-reactive Protein 
CT 
Computed Tomography 
DMC 
Data Monitoring Committee 
e-CRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GOT 
Glutamic Oxaloacetic Transaminase 
GPT 
Glutamic Pyruvate Transaminase 
HMG-CoA 
3-Hydroxy-3-methylglutaryl-coenzyme A 
ICU 
Intensive Care Unit 
IDE 
Investigational Device Exemption 
ISO 
International Organization for Standardization 
ITT 
Intention-to-treat 
LBBB 
Left Bundle-branch Block 
LDH 
Lactate Dehydrogenase 
LVOT 
Left Ventricular Outflow Tract 
MACCE 
Major Adverse Cardiac and Cerebro-Vascular Events 
MRI 
Magnetic Resonance Imaging 
NIHSS 
National Institutes of Health 
NYHA 
New York Heart Association 
PCI 
Percutaneous Coronary Intervention 
PET 
Polyethylene Terephthalate 
PG 
Performance Goal 
QOL 
Quality of Life 
sAVR 
Surgical Aortic Valve Replacement 
SF-12 
Short Form 12-item Health Survey 
STS 
Society of Thoracic Surgeons 
TA 
Transapical 

 
Abbreviation 
English 
TAo 
Transaortic 
TAVI 
Transcatheter Aortic Valve Implantation 
TEE 
Transesophageal Echocardiography 
TF 
Tranfemoral 
URL 
Upper Range Limit 
VARC 
Valve Academic Research Consortium 
VI 
Valve Implant 
  
 
TABLE OF CONTENTS
LIST OF ABBREVIATIONS ..................................................................................................................... 3 
TABLE OF CONTENTS ........................................................................................................................... I 
PROTOCOL SYNOPSIS ......................................................................................................................... 7 
1 
INTRODUCTION ........................................................................................................................... 22 
1.1 
BACKGROUND OF DEVELOPMENT .............................................................................................. 22 
1.1.1 
Background of development of Transcatheter aortic valve implantation ........................ 22 
1.1.2 
AS treatment in chronic dialysis patients ....................................................................... 23 
1.1.3 
TAVI development for chronic dialysis patients .............................................................. 24 
1.2 
VALIDITY OF THE TRIAL CONDUCT .............................................................................................. 24 
1.2.1 
Nonclinical study results ................................................................................................. 24 
1.2.2 
Clinical trial results.......................................................................................................... 26 
1.2.2.1 
Clinical trial results of the investigational device .................................................................................... 26 
1.2.2.2 
Treatment results in advanced medical care ............................................................................................. 30 
1.2.2.3 
Referenced literature reports .................................................................................................................... 31 
1.2.3 
Validity of the trial conduct .............................................................................................. 32 
2 
STUDY OBJECTIVE ..................................................................................................................... 32 
3 
OUTLINE OF STUDY DEVICE ...................................................................................................... 33 
3.1 
STRUCTURE OR COMPOSITION OF STUDY DEVICE ...................................................................... 33 
3.2 
DIRECTIONS FOR USE ............................................................................................................... 38 
4 
STUDY DESIGN ............................................................................................................................ 39 
4.1 
STUDY DESIGN ......................................................................................................................... 39 
4.2 
PERFORMANCE GOAL ............................................................................................................... 40 
4.2.1 
Rationales for the performance goal setting .................................................................. 40 
4.2.2 
Clinical validity of performance goal ............................................................................... 45 
4.3 
TARGET SAMPLE SIZE ............................................................................................................... 46 
4.4 
CONTINUED ACCESS REGISTRY ................................................................................................. 49 
5 
SELECTION OF SUBJECTS ........................................................................................................ 50 
5.1 
SUBJECTS ................................................................................................................................ 50 
5.2 
SCREENING .............................................................................................................................. 50 
5.2.1 
Inclusion criteria .............................................................................................................. 51 
5.2.2 
Exclusion criteria ............................................................................................................ 52 
5.2.3 
Inclusion criteria for continued access registry .............................................................. 57 
5.2.4 
Exclusion criteria for continued access registry ............................................................. 58 
 
5.3 
CASE REVIEW PROCESS ........................................................................................................... 60 
5.4 
SUBJECT ENROLLMENT ............................................................................................................. 61 
6 
CONSIDERATIONS CONCERNING SUBJECT’S INFORMED CONSENT................................. 63 
7 
TREATMENT OF SUBJECTS ....................................................................................................... 64 
7.1 
BASELINE TESTS ...................................................................................................................... 64 
7.2 
STUDY PROCEDURE .................................................................................................................. 64 
7.3 
POST-PROCEDURAL FOLLOW-UP OBSERVATION.......................................................................... 65 
7.4 
BAILOUT TREATMENT REGISTRY ................................................................................................ 65 
8 
CONCOMITANT THERAPY .......................................................................................................... 67 
8.1 
ANTICOAGULATION/ANTIPLATELET THERAPY .............................................................................. 67 
8.2 
PROPHYLACTIC ADMINISTRATION OF ANTIBIOTICS ...................................................................... 68 
8.3 
PRECAUTIONS FOR CONCOMITANT DRUGS ................................................................................. 68 
8.4 
PERIPROCEDURAL HEMODIALYSIS ............................................................................................. 69 
8.5 
OTHER DRUGS/THERAPIES ....................................................................................................... 69 
8.6 
PRECAUTIONS FOR CONCOMITANT DRUGS/CONCOMITANT THERAPY AND INPUT PROCEDURE IN 
ELECTRONIC CASE REPORT FORMS ...................................................................................................... 69 
8.6.1 
Anticoagulant/antiplatelet drugs and antibiotics ............................................................. 69 
8.6.2 
Blood purification ............................................................................................................ 70 
8.6.3 
Other concomitant drug/therapy ..................................................................................... 70 
9 
STUDY ENDPOINTS ..................................................................................................................... 72 
9.1 
PRIMARY ENDPOINTS ................................................................................................................ 72 
9.2 
SECONDARY ENDPOINTS ........................................................................................................... 72 
9.2.1 
Secondary safety endpoints ........................................................................................... 72 
9.2.2 
Secondary efficacy endpoints ........................................................................................ 73 
9.2.3 
Secondary valve performance endpoints ....................................................................... 73 
10 
TEST/OBSERVATION DATA COLLECTION ............................................................................ 73 
10.1 
TEST/OBSERVATION SCHEDULE ................................................................................................. 73 
10.2 
TESTS/OBSERVATIONS .............................................................................................................. 77 
10.2.1 
Baseline .......................................................................................................................... 77 
10.2.2 
During procedure ............................................................................................................ 79 
10.2.3 
Immediately after procedure ........................................................................................... 79 
10.2.4 
Hospital discharge .......................................................................................................... 80 
10.2.5 
At 30 days post-procedural follow-up observation ......................................................... 81 
10.2.6 
At 6 months post-procedural follow-up ........................................................................... 82 
10.2.7 
At 1 year post-procedural follow-up observation ............................................................ 83 
10.2.8 
Years 2 through 5 annual post-procedure visits ............................................................. 84 
 
10.2.9 
At trial discontinuation .................................................................................................... 85 
10.2.10 Unscheduled visit ........................................................................................................... 85 
10.3 
TEST/OBSERVATION ITEMS FOR THE CONTINUED ACCESS REGISTRY ........................................... 86 
10.3.1 
Baseline .......................................................................................................................... 86 
10.3.2 
During procedure ............................................................................................................ 88 
10.3.3 
Immediately after procedure ........................................................................................... 88 
10.3.4 
Hospital discharge .......................................................................................................... 89 
10.3.5 
At 30 days post-procedural follow-up observation ......................................................... 89 
10.3.6 
At 6 months post-procedural follow-up ........................................................................... 91 
10.3.7 
At 1 year post-procedural follow-up observation ............................................................ 92 
10.3.8 
Years 2 through 5 annual post-procedure visits ............................................................. 93 
10.3.9 
At trial discontinuation and unscheduled visits ............................................................... 94 
11 
ADVERSE EVENT/DEVICE DEFICIENCY ............................................................................... 95 
11.1 
DEFINITION OF ADVERSE EVENTS .............................................................................................. 95 
11.2 
DEFINITION OF SERIOUS ADVERSE EVENTS ............................................................................... 95 
11.3 
ADVERSE EVENTS ASSOCIATED WITH LABORATORY TEST ABNORMAL VARIATIONS ....................... 96 
11.4 
DEVICE DEFICIENCIES ............................................................................................................... 96 
11.5 
SERIOUS ADVERSE EVENT REPORTING...................................................................................... 96 
11.6 
RECORDS OF ADVERSE EVENTS ................................................................................................ 97 
11.7 
FOLLOW-UP INVESTIGATION OF ADVERSE EVENTS ...................................................................... 99 
12 
MONITORING OF THE CLINICAL TRIAL BY DATA MONITORING COMMITTEE ............... 101 
13 
EVALUATION BY THIRD-PARTY JUDGMENT ORGANIZATION ......................................... 101 
13.1 
CLINICAL EVENT ADJUDICATION COMMITTEE ............................................................................ 101 
13.2 
ECHO CORE LABORATORY ...................................................................................................... 102 
14 
SUBJECT TREATMENT DISCONTINUATION ....................................................................... 103 
14.1 
SUBJECT TREATMENT DISCONTINUATION ................................................................................. 103 
14.2 
SUBJECT TREATMENT DISCONTINUATION PROCEDURE ............................................................. 103 
14.3 
FOLLOW-UP INVESTIGATION OF SUBJECTS WITH MISSING VISITS ............................................... 103 
15 
STATISTICAL ANALYSIS ........................................................................................................ 104 
15.1 
SAFETY AND EFFICACY ANALYSIS OF EWJ-003 ........................................................................ 104 
15.1.1 
Analysis sets ................................................................................................................. 104 
15.1.1.1 
Intent-to-treat analysis set ...................................................................................................................... 104 
15.1.1.2 
As-treated analysis set ............................................................................................................................ 104 
15.1.1.3 
Valve implant analysis set ...................................................................................................................... 104 
15.1.2 
Statistical analysis plan and statistical method ............................................................ 104 
15.2 
BAILOUT TREATMENT REGISTRY STATISTICAL ANALYSIS ............................................................ 105 

 
15.3 
STATISTICAL ANALYSIS OF THE CONTINUED ACCESS REGISTRY ................................................. 105 
15.4 
CREATION/CHANGES TO STATISTICAL ANALYSIS PLAN............................................................... 105 
16 
ELECTRONIC CASE REPORT FORM ................................................................................... 107 
16.1 
PROCEDURE FOR ELECTRONIC CASE REPORT FORM CREATION AND PRECAUTIONS .................. 107 
16.2 
CHANGES OR CORRECTIONS TO ELECTRONIC CASE REPORT FORMS ........................................ 107 
16.3 
INCONSISTENCY BETWEEN ELECTRONIC CASE REPORT FORM AND SOURCE DOCUMENT ........... 107 
17 
PROTOCOL DEVIATIONS OR MODIFICATION .................................................................... 108 
18 
TRIAL DISCONTINUATION/SUSPENSION AND TERMINATION ......................................... 108 
18.1 
DISCONTINUATION/SUSPENSION OF THE ENTIRE TRIAL ............................................................. 108 
18.2 
DISCONTINUATION/SUSPENSION AT INDIVIDUAL STUDY SITES .................................................... 109 
18.3 
TERMINATION OF THE CLINICAL TRIAL ....................................................................................... 110 
19 
RECORD RETENTION ............................................................................................................ 110 
19.1 
STUDY SITE ............................................................................................................................. 110 
19.2 
SPONSOR ................................................................................................................................ 111 
20 
TRAINING ................................................................................................................................. 111 
21 
DIRECT ACCESS TO SOURCE DOCUMENTS ..................................................................... 113 
21.1 
IDENTIFICATION OF SOURCE DOCUMENTS ................................................................................. 113 
21.2 
PROCEDURE FOR DIRECT ACCESS ........................................................................................... 113 
22 
CLINICAL TRIAL QUALITY CONTROL AND QUALITY ASSURANCE ................................ 113 
22.1 
QUALITY CONTROL .................................................................................................................. 113 
22.1.1 
Clinical trial monitoring .................................................................................................. 113 
22.2 
QUALITY ASSURANCE .............................................................................................................. 114 
23 
STUDY DEVICE MANAGEMENT ........................................................................................... 114 
24 
ETHICAL CONSIDERATIONS AND REGULATORY REQUIREMENTS ............................... 116 
24.1 
COMPLIANCE WITH J-GCP ....................................................................................................... 116 
24.2 
CREATION OF WRITTEN PATIENT INFORMATION AND INFORMED CONSENT FORM ......................... 116 
24.3 
CHANGES TO THE PROTOCOL, WRITTEN PATIENT INFORMATION, AND INFORMED CONSENT FORM117 
24.4 
INSTITUTIONAL REVIEW BOARD ................................................................................................ 117 
24.5 
CONSIDERATIONS CONCERNING SUBJECT’S PRIVACY ................................................................ 118 
24.6 
COMPENSATION AVAILABLE TO THE SUBJECTS .......................................................................... 118 
24.7 
PAYMENT TO REDUCE FINANCIAL BURDEN ON THE SUBJECTS .................................................... 118 
25 
AGREEMENT TO PROTOCOL ............................................................................................... 118 
26 
USE OF STUDY RESULTS OR PUBLICATION POLICY ....................................................... 118 
 
27 
SCHEDULED TRIAL DURATION ........................................................................................... 119 
28 
CONSIDERATION AFTER MARKETING APPROVAL ........................................................... 119 
29 
GENERAL STUDY ORGANIZATION ...................................................................................... 120 
30 
GLOSSARY ............................................................................................................................. 121 
31 
REFERENCES ......................................................................................................................... 134 
 
List of Appendices 
Appendix 1 
NIHSS 
Appendix 2 
Modified Rankin Scale 
Appendix 3 
Six-minute Walk Test 
Appendix 4 
Euro QOL Assessment Form 
Appendix 5 
SF-12 Assessment Form 
 
List of Attachments 
Attachment 1 
General Study Organization 
Attachment 2 
Instructions for Use 
 
 
 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 7 - 
PROTOCOL SYNOPSIS 
 
Study Title: 
A Clinical Trial for Transcatheter Aortic Valve Implantation in Chronic 
Dialysis Patients with Aortic Valve Stenosis 
Study Device ID Code: 
EWJ-003 
Clinical Protocol ID Code: 
EW-P-003 
 
Item 
Content 
Study Objective 
The study objective of this trial is to evaluate safety and effectiveness of 
Edwards SAPIEN 3 Transcatheter Heart Valve System in the treatment of 
symptomatic severe aortic stenosis patients on chronic dialysis, who are 
determined by the heart team to be unable to undergo safe open surgical 
therapy and have the benefits of the study valve implantation. 
Study Design 
A single arm, prospective, open, non-randomized, Japanese multicenter study 
Study Device 
Edwards SAPIEN 3 Transcatheter Heart Valve System (EWJ-003) 
x 
Transcatheter heart valve (THV) (Size: 20, 23, 26, 29 mm) 
x 
Delivery system (transfemoral approach)㻌
ż 
Delivery system 
ż 
Introducer sheath set 
ż 
Balloon catheter 
x 
Delivery system (transapical/transaortic approach) 
ż 
Delivery system 
ż 
Introducer sheath set 
ż 
Balloon catheter 
x 
Other components 
ż 
Crimper 
ż 
Crimping accessory 
ż 
Inflation device/inflation syringe 
<THV Sizes of the Investigational Device Available for the Trial> 
Native 
Annulus Size 
(TEE) 
Native Annulus Size (CT) 
THV 
Size 
Valve  
Height 
Native Annulus 
Area 
Area-derived 
Diameter 
16 - 19 mm 
273 - 345 mm2 
18.6 - 21.0 mm 
20 mm 
15.5 mm 
18 - 22 mm 
338 - 430 mm2 
20.7 - 23.4 mm 
23 mm 
18 mm 
21 - 25 mm 
430 - 546 mm2 
23.4 - 26.4 mm 
26 mm 
20 mm 
24 - 28 mm 
540 - 683 mm2 
26.2 - 29.5 mm 
29 mm 
22.5 mm 
Access Approach 
Transfemoral (TF), transapical (TA) or transaortic (TAo) approach 
Patient Population 
Chronic dialysis patients with symptomatic severe aortic stenosis, who are 

Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 8 - 
Item 
Content 
judged by the heart team to be unable to undergo safe open surgical therapy 
and have the benefits of the study valve implantation. 
Inclusion Criteria 
1. Patients determined by the heart team to be unable to undergo safe open 
surgical therapy and have the benefits of the study valve implantation. 
Specifically, considering the followings as risk factors, the risk should be 
comprehensively determined. 
• 
Porcelain aorta 
• 
History of mediastinal radiotherapy 
• 
History of mediastinitis 
• 
Remarkable thoracic deformity 
• 
Previous open heart surgery or coronary-artery bypass grafting (CABG) 
• 
Chronic obstructive pulmonary disease 
2. Patient has senile degenerative aortic valve stenosis (AS) with one of the 
following echocardiographic criteria. Measurement of aortic valve area (AVA) 
at baseline must be acquired within 60 days prior to the study procedure . 
(a) 0HDQSUHVVXUHJUDGLHQWPP+J 
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3. 3DWLHQWKDVV\PSWRPVDVVRFLDWHGZLWK$61<+$FODVV,, 
4. The subject has been informed of the nature of the study, agrees to its 
provisions and has provided written informed consent as approved by the 
Institutional Review Board (IRB) of the respective clinical site. 
5. The subject and the investigator agreed to comply with all required 
post-procedural follow-up visits. 
6. Patient has been on dialysis (hemodialysis or peritoneal dialysis) in stable 
FRQGLWLRQIRUPRQWKV 
7. Patient has any one of the following native aortic valve annulus sizes as 
measured by transesophageal echocardiography (TEE) or 3D-computed 
tomography (CT). 
(a) Native anQXOXVVL]HPPDQGPPE\7(( 
(b) 1DWLYHDQQXOXVDUHDPP2 DQGPP2 by 3D-CT 
(c) Area-GHULYHGGLDPHWHUPPDQGPPE\'-CT 
8. Patient is verified by the Case Review Process that the treatment with 
EWJ-003 will likely benefit the patient. 
Exclusion Criteria 
1. Patient has an evidence of an acute myocardial infarction (MI) within 1 
month (30 days) prior to the study procedure . Acute MI is defined as; Q 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 9 - 
Item 
Content 
wave MI, or non-Q-wave MI with elevation of creatine kinase MB isoenzyme 
(CK-MB) or troponin, together with the evidence of myocardial ischemia 
with at least one of the following findings: 
• 
Symptoms of ischemia 
• 
Electrocardiogram (ECG) changes indicative of new ischemia (ST-T 
changes, left bundle-branch block [LBBB]) 
• 
Imaging evidence of a new loss of viable myocardium or new wall 
motion abnormality. 
2. Patient has a congenital unicuspid or bicuspid aortic valve, or a non-calcified 
aortic valve. 
3. Patient has severe aortic valve regurgitation. 
4. Patient has severe mitral valve regurgitation. 
5. Patient has an evidence of any therapeutic invasive cardiac procedures within 
30 days prior to the study procedure . However, implantation of a permanent 
pacemaker or balloon valvuloplasty for bridging to procedure after a 
qualifying echocardiography are excluded. 
6. Patient with planned concomitant surgical or transcatheter ablation for atrial 
fibrillation. 
7. Patient has pre-existing prosthetic valve in any position. 
8. Patient is at a high risk of bleeding, difficult to have appropriate treatment, or 
unable to receive appropriate anticoagulation or antiplatelet therapy. 
• 
Leukopenia (white blood cell < 3,000 cells/mm3) 
• 
Thrombocytopenia (platelet < 50,000 cells/mm3) 
• 
Bleeding diathesis or coagulopathy 
• 
Active gastro-intestinal ulceration, or upper gastro-intestinal bleeding 
within the past 3 months 
• 
Refuse blood transfusion 
• 
Receiving anticoagulant and/or antiplatelet medication unable to 
interrupt for the study procedure  
• 
Concluded by investigator that appropriate anticoagulation or antiplatelet 
therapy is difficult for any other reasons 
9. Patient has untreated clinically significant coronary artery disease requiring 
revascularization. 
10. Patient has hemodynamic instability requiring inotropic support or 
mechanical heart assistance. Patient has respiratory instability requiring 
mechanical ventilation. 
11. Patient requires an emergency surgery for any reason. 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 10 - 
Item 
Content 
12. Patient has hypertrophic cardiomyopathy with or without obstruction. 
13. Patient has severe ventricular dysfunction with left ventricular ejection 
fraction (LVEF) < 20%. 
14. Patient has echocardiographic evidence of intracardiac mass, thrombus, or 
vegetation. 
15. Patient has hypersensitivity to or a known contraindication of heparin and/or 
aspirin, which cannot be adequately pre-medicated. Patient has a known 
hypersensitivity to contrast media. 
16. Patient has hypersensitivities to cobalt, chromium, nickel, molybdenum, 
titanium, manganese, silicon, or polymeric materials. 
17. Patient has had a cerebrovascular accident or transient ischemic attack within 
6 months prior to the study procedure . Except cases with an event associated 
with AS. 
18. Patient with poorly controlled blood pressure. 
19. Patient has serum albumin < 3.0 g/dL or body mass index (BMI) < 18. 
20. Patient has uncontrollable diabetes mellitus. 
21. Patient has active bacterial endocarditis or other active infection. 
22. Patient has life expectancy < 12 months due to pre-operative non-cardiac 
comorbidity (e.g., cancer, chronic liver disease). 
23. Patient is currently participating in an investigational drug or another device 
study. [Note: Trials requiring extended follow-up for products that were 
investigational, but have become commercially available, are not considered 
investigational trials]. 
24. Cardiovascular surgeons and cardiologists concluded that the patient is 
inappropriate for participating in this trial. 
 
<TF approach> 
25. Patient has significant tortuous aorta, diseases including abdominal aortic or 
thoracic aneurysm, or significant atheroma in the femoral artery or iliac artery 
that would prevent from proper placement of delivery system. 
26. Patient has iliofemoral vessel characteristics that would preclude safe 
placement of 14F or 16F introducer sheath such as severe obstructive 
calcification and severe tortuosity, or minimum average vessel size less than 
5.5 mm (6.0 mm for 16F introducer sheath). 
 
Study Endpoints 
Primary Endpoint 
All-cause mortality at 1 year post-procedure (noninferiority verification) 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 11 - 
Item 
Content 
 
Secondary Endpoints 
<Secondary Safety Endpoints> 
x 
Composite endpoint: 30 days, 6 months, 1 year, and 2 to 5 years annually 
ż 
Death and stroke 
x 
Single endpoints: 30 days, 6 months, 1 year, and 2 to 5 years annually 
ż 
Death (cardiovascular, non-cardiovascular) 
ż 
MI (periprocedural, spontaneous) 
ż 
Stroke (disabling, non-disabling) 
ż 
Bleeding (life-threatening or disabling, major, minor) 
ż 
Vascular access site/access-related complications 
ż 
Major vascular complications 
ż 
Conduction disturbance/arrhythmia 
ż 
Conduction disturbance requiring new pacemaker implantation 
ż 
Aortic valve re-intervention 
ż 
Coronary obstruction 
ż 
Endocarditis 
ż 
Valve explants 
ż 
Structural valve deterioration 
ż 
Nonstructural valve dysfunction 
 
<Secondary Efficacy Endpoints> 
x 
Device success: 30 days 
x 
Length of hospitalization /ICU stay: Discharge 
x 
NYHA Classification: 30 days, 6 months, 1 year, and 2 to 5 years annually 
x 
Six-minute walk test: 30 days and 1 year 
x 
Quality of Life (QOL): 30 days, 6 months, 1 year, and 2 to 5 years annually 
 
<Secondary Valve Performance Endpoints> 
x 
Echocardiography: 30 days, 6 months, 1 year, and 2 to 5 years annually 
ż 
Mean pressure gradient 
ż 
Peak gradient 
ż 
Effective orifice area (EOA) 
ż 
Effective orifice area index (EOAi) 
ż 
Aortic valve regurgitation (paravalvular, transvalvular) 
ż 
Left Ventricular Ejection Fraction (LVEF) 

Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 12 - 
Item 
Content 
ż 
Left ventricular mass 
ż 
Left ventricular mass index (LVMI) 
Target Sample Size 
A total of 30 subjects 
x 
At least 2 subjects for each approach (TF, TA, and TAo) should be enrolled. 
x 
At least 1 subject each for THV sizes. 
x 
Enrollment will be closed when the number of patients enrolled in the study 
reaches the target sample size even when the above-mentioned number of 
patients are not ensured. 
x 
Additional subjects will not be included for discontinued subjects. 
 
 
Target sample size by approach 
Target sample size 
Transfemoral 
VXEMHFWV 
A total of 30 
subjects 
Transapical 
VXEMHFWV 
Transaortic 
VXEMHFWV 
Target sample size by valve size 
20 mm 
VXEMHFW 
23 mm 
VXEMHFW 
26 mm 
VXEMHFW 
29 mm 
VXEMHFW 
Sample Size 
Calculation 
The sample size for this trial was calculated based on the number of subjects 
required to verify noninferiority of the study treatment to the standard therapy by 
comparing the primary endpoint of all-cause mortality at 1 year post-procedure 
with the performance goal (PG). With the predicted mortality (true value) at 1 
year post-procedure of 20% and PG of 45%, the number of subjects required to 
reject the null hypothesis (H0: Mortality at 1 year post-SURFHGXUHLVZLWK
one-sided alpha of 0.05 was calculated as 24 subjects. A sample size of 24 
subjects will provide 81.1% power by one-sided Fisher’s exact test. To account 
for the drop-out, a total of 30 subjects was determined for the target sample size 
for this trial. 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 13 - 
Item 
Content 
Bailout Treatment 
Registry 
In this trial, a subject who received valve implantation with non-nominal balloon 
inflation volume as a result of the medical judgment will be considered “bailout 
subject” and registered to the Bailout Treatment Registry at the end of the study 
procedure . Bailout subjects will not be counted as the study target population (30 
subjects), so that they will be excluded from the analysis population to evaluate 
the safety and effectiveness of EWJ-003. Post-procedure follow-up for them is the 
same as subjects with nominal valve implantation. 
 
Study sites 
Maximum 3 sites in Japan 
Study procedure  
TF Approach 
1. Using the crimper, crimp the THV on the valve crimping site of the delivery 
system after the THV rinsing. 
2. Puncture the iliac-femoral artery by the standard procedure, and advance the 
guidewire to the left ventricle. Advance the balloon catheter from the 
femoro-iliac artery, and predilate the stenosed native aortic valve under the 
rapid pacing. 
3. As maintaining guidewire position, remove the balloon catheter and 
subsequently expand the access site by using the introducer to place the 
introducer sheath. 
4. Insert the delivery system through the sheath and advance it until descending 
aorta. 
5. Initiate valve alignment by pulling the balloon shaft of delivery system, and 
transfer the THV on the balloon. Then advance the THV until the predilated 
native aortic valve. 
Dilatation at a non-nominal volume
Bailout Treatment Registry
Informed consent
Screening
Case review
Enrollment
Index procedure
Dilatation at a nominal volume
EWJ-003 analysis set 
(30 subjects)
Safety and efficacy evaluation  
(at 1 year post-procedure)
Follow-up until at 5 years post-procedure
Protocol 
 
Edition number: 
Date of creation: 
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Jaunuary 6, 2020 
 
- 14 - 
Item 
Content 
6. Continuing the rapid pacing, dilate the balloon on the stenosed native aortic 
valve, and deploy the THV. 
 
TA Approach 
1. Using the crimper, crimp the THV on the balloon of the delivery system after 
the THV rinsing. 
2. Access the apex through an anterior mini thoracotomy at the appropriate site. 
Incise the pericardium to expose the left ventricular apex. 
3. Place a reinforced double purse string on the left ventricle apex, and insert the 
guidewire to the left ventricle through standard transapical techniques. 
4. Advance the balloon catheter over the guidewire, predilate the stenosed 
native aortic valve under the rapid pacing. 
5. Remove the balloon catheter, leaving the guidewire in place in the left 
ventricle. Subsequently, insert the introducer sheath over the guidewire and 
advance it to the left ventricular outflow tract (LVOT). 
6. Insert the delivery system through the sheath and advance it until the 
predilated native aortic valve. 
7. Continuing the rapid pacing, dilate the balloon on the stenosed native aortic 
valve, and deploy the THV. 
 
TAo Approach 
1. Using the crimper, crimp the THV on the balloon of the delivery system after 
the THV rinsing. 
2. Access to the ascending aorta using standard surgical technique. 
3. Place purse string sutures at the intended access site in the ascending aorta 
and insert the guidewire through standard transapical techniques. 
4. Advance the balloon catheter over the guidewire, predilate the stenosed 
native aortic valve under the rapid pacing. 
5. Remove the balloon catheter, leaving the guidewire in place in the left 
ventricle. Subsequently, insert the introducer sheath over the guidewire into 
the aorta to approximately 2 cm. 
6. Insert the delivery system through the sheath and advance it until the 
predilated native aortic valve. 
7. Continuing the rapid pacing, dilate the balloon on the stenosed native aortic 
valve, and deploy the THV. 
Concomitant 
Medication/Procedur
Recommended Antiplatelet/Anticoagulation Regimen 
< Pre-procedural antiplatelet therapy> 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 15 - 
Item 
Content 
e 
Considering bleeding risk, pre-procedural antiplatelet is not applied as a general 
rule. If a patient was taking an antiplatelet or anticoagulant before procedure 
(excluding anticoagulant administration for dialysis), these medications should be 
discontinued at least 14 days prior to the study procedure . 
 
<Intraprocedural anticoagulation therapy> 
After intravenous administration of heparin 5000 IU, heparin will be given to 
achieve and maintain activated clotting time (ACT) VHFonds. 
 
<Post-procedural antiplatelet therapy> 
Aspirin 75 to 100 mg/day will be given as a monotherapy for an indefinite period 
after study procedure . 
 
Periprocedural dialysis 
<Pre-procedural dialysis> 
x 
For hemodialysis patients, perform hemodialysis until achievement of this 
dry weight on the day before study procedure  as a general rule. Do not 
change the anticoagulant therapy. 
x 
For peritoneal dialysis patients, continue peritoneal dialysis as usual until the 
day before study procedure . 
 
<Post-procedural dialysis> 
x 
Considering post-procedural hemodynamics, resume dialysis at the 
discretion of the investigator. 
x 
In case of the hemodialysis, it is recommended to use anticoagulant with 
shorter half-life (e.g. nafamostat mesilate) to reduce bleeding risk. 
x 
Do not change dialysis conditions until 1 year post-procedure as a general 
rule. However, the dialysis conditions may be changed if it is based on the 
medical judgement. 
Follow-up Duration 
For 5 years post-procedure 
Schedule of Tests and 
Observations 
As shown in Table I 
Continued Access 
Registry 
During a time period from the end of subject entry into the EWJ-003 analysis set 
until acquisition of marketing approval of the study device (EWJ-003), up to a 
maximum of 50 dialysis patients with severe AS requiring treatment with 
EWJ-003 will be included into the Continued Access Registry. Patients eligible 
for this registry must be verified that they meet all inclusion criteria for the 

Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 16 - 
Item 
Content 
Continued Access Registry and do not fall under any of the exclusion criteria. The 
duration of post-procedural follow-up observation will be for 5 years 
post-procedure similarly to those for the EWJ-003 analysis set and bailout 
treatment registry, and tests/observations required for the Continued Access 
Registry will be performed. Subjects enrolled in this registry will not be included 
in the analysis set for the safety and efficacy evaluation of EWJ-003. 
Inclusion Criteria for 
Continued Access 
Registry 
1. Patients determined by the heart team to be unable to undergo safe open 
surgical therapy and have the benefits of the study valve implantation. 
Specifically, considering the followings as risk factors, the risk should be 
comprehensively determined. 
• 
Porcelain aorta 
• 
History of mediastinal radiotherapy 
• 
History of mediastinitis 
• 
Remarkable thoracic deformity 
• 
Previous open heart surgery or CABG  
• 
Chronic obstructive pulmonary disease 
2. Patient has senile degenerative AS with one of the following 
echocardiographic criteria. Measurement of AVA at baseline must be acquired 
within 60 days prior to the study procedure . 
(a) 0HDQSUHVVXUHJUDGLHQWPP+J 
(b) $RUWLFIORZYHORFLW\PV 
(c) $9$DWEDVHOLQHFP2 
(d) $9$LQGH[FP2/m2 
3. 3DWLHQWKDVV\PSWRPVDVVRFLDWHGZLWK$61<+$FODVV,, 
4. The subject has been informed of the nature of the study, agrees to its 
provisions and has provided written informed consent as approved by the IRB 
of the respective clinical site. 
5. The subject and the investigator agreed to comply with all required 
post-procedural follow-up visits. 
6. Patient on maintenance dialysis (hemodialysis or peritoneal dialysis). 
7. Patient has any one of the following native aortic valve annulus sizes as 
measured by TEE or 3D-CT. 
(a) 1DWLYHDQQXOXVVL]HPPDQGPPE\7(( 
(b) 1DWLYHDQQXOXVDUHD273 mm2 DQGPP2 by 3D-CT 
(c) Area-GHULYHGGLDPHWHUPPDQGPPE\'-CT 
Exclusion Criteria for 
Continued Access 
1. Patient has an evidence of an acute MI within 1 month (30 days) prior to the 
study procedure . Acute MI is defined as; Q wave MI, or non-Q-wave MI 
Protocol 
 
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Date of creation: 
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Jaunuary 6, 2020 
 
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Item 
Content 
Registry 
with elevation of CK-MB or troponin, together with the evidence of 
myocardial ischemia with at least one of the following findings: 
• 
Symptoms of ischemia 
• 
ECG changes indicative of new ischemia (ST-T changes, LBBB) 
• 
Imaging evidence of a new loss of viable myocardium or new wall 
motion abnormality. 
2. Patient has a congenital unicuspid or bicuspid aortic valve, or a non-calcified 
aortic valve. 
3. Patient has severe aortic valve regurgitation. 
4. Patient has severe mitral valve regurgitation. 
5. Patient has an evidence of any therapeutic invasive cardiac procedures within 
30 days prior to the study procedure . However, implantation of a permanent 
pacemaker or balloon valvuloplasty for bridging to procedure after a 
qualifying echocardiography are excluded. 
6. Patient with planned concomitant surgical or transcatheter ablation for atrial 
fibrillation. 
7. Patient has pre-existing prosthetic valve in any position. 
8. Patient is at a high risk of bleeding, difficult to have appropriate treatment, or 
unable to receive appropriate anticoagulation or antiplatelet therapy. 
• 
Leukopenia (white blood cell < 3,000 cells/mm3) 
• 
Thrombocytopenia (platelet < 50,000 cells/mm3) 
• 
Bleeding diathesis or coagulopathy 
• 
Active gastro-intestinal ulceration, or upper gastro-intestinal bleeding 
within the past 3 months 
• 
Refuse blood transfusion 
• 
Receiving anticoagulant and/or antiplatelet medication unable to 
interrupt for the study procedure  
• 
Concluded by investigator that appropriate anticoagulation or antiplatelet 
therapy is difficult for any other reasons 
9. Patient has untreated clinically significant coronary artery disease requiring 
revascularization. 
10. Patient has hemodynamic instability requiring mechanical heart assistance. 
Patient has respiratory instability requiring mechanical ventilation. 
11. Patient requires an emergency surgery for any reason. 
12. Patient has hypertrophic cardiomyopathy with or without obstruction. 
13. Patient has severe ventricular dysfunction with LVEF < 20%. 
14. Patient has echocardiographic evidence of intracardiac mass, thrombus, or 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
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Item 
Content 
vegetation. 
15. Patient has hypersensitivity to or a known contraindication of heparin and/or 
aspirin, which cannot be adequately pre-medicated. Patient has a known 
hypersensitivity to contrast media. 
16. Patient has hypersensitivities to cobalt, chromium, nickel, molybdenum, 
titanium, manganese, silicon, or polymeric materials. 
17. Patient has had a cerebrovascular accident or transient ischemic attack within 
6 months prior to the study procedure . Except cases with an event associated 
with AS. 
18. Patient with poorly controlled blood pressure. 
19. Patient has serum albumin < 2.8 g/dL or BMI < 16. 
20. Patient has uncontrollable diabetes mellitus. 
21. Patient has active bacterial endocarditis or other active infection. 
22. Patient has life expectancy < 12 months due to pre-operative non-cardiac 
comorbidity (e.g., cancer, chronic liver disease). 
23. Patient is currently participating in an investigational drug or another device 
study. [Note: Trials requiring extended follow-up for products that were 
investigational, but have become commercially available, are not considered 
investigational trials]. 
24. Cardiovascular surgeons and cardiologists concluded that the patient is 
inappropriate for participating in this trial. 
 
<TF approach> 
25. Patient has significant tortuous aorta, diseases including abdominal aortic or 
thoracic aneurysm, or significant atheroma in the femoral artery or iliac artery 
that would prevent from proper placement of delivery system. 
26. Patient has iliofemoral vessel characteristics that would preclude safe 
placement of 14F or 16F introducer sheath such as severe obstructive 
calcification and severe tortuosity, or minimum average vessel size less than 
5.5 mm (6.0 mm for 16F introducer sheath). 
Schedule of Tests and 
Observations for 
Continued Access 
Registry 
As shown in Table II 
Study Duration 
September 2016 to September 2025 
<EWJ-003 Analysis Population/Bailout Treatment Registry> [Enrollment closed] 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 19 - 
Item 
Content 
September 2016 to December 2022 
The estimated period of subject enrollment into the EWJ-003 analysis population 
is from September 2016 to October 2017 (14 months). Clinical study report will 
be prepared after the completion of 1 year-data collection and utilized for the 
regulatory submission.  
< Continued Access Registry > 
January 2018 to September 2025 
Subject entry into the Continued Access Registry will start from January 2018 to 
July 2020 (2 years and 6 months), after the completion of subject entry into the 
EWJ-003 analysis population. 
 
 

Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 20 - 
Table I: Schedule of Tests and Observations 
*1 
Calculate STS score, Logistic EuroSCORE, and EuroSCORE II. 
*2 
For patient who has suffered a stroke, mRS must be evaluated within 30 to 90 days and beyond 90 days as earlier as from the onset of stroke. 
*3 
Perform within 48 hours prior to entering the operating room. 
*4 
Perform within 14 days prior to the study procedure. 
*5 
Perform within 90 days prior to the study procedure. 
*6 
Perform CT, MRI, or X-ray within 90 days prior to the study procedure . 
*7 
Start assessment from 7 days pre-procedure. 
*8 
Measure the aortic annulus diameter, and perform observation items of cardiac catheterization according to the situation. 
*9 
Perform pre- and post-study procedure . May be performed by echocardiography according to the situation. 
*10 Assess dialysis information performed from the latest date prior to the study procedure  to discharge (at discharge date or 7 days post-procedure, 
whichever came earlier). 
*11 Baseline BSA value must be used for calculation of EOAi and LVMI. 
*12 Assess other concomitant medication/therapy used within 1 year post-procedure, excluding anticoagulation/antiplatelet, antibiotic, and 
hemodialysis. 
 
Timing 
 
 
 
 
 
 
 
Tests/observations 
Baseline 
(Within 60 
days 
pre-procedure) 
During procedure 
Immediately after procedure 
(Within 72 hours 
pre-procedure) 
Discharge or 7 days 
post-procedure 
(± 2 days) 
30 days post-procedure 
(- 7 days, + 14 days) 
6 months post-procedure 
(± 30 days) 
1 year post-procedure 
(± 30 days) 
2 - 5 years post-procedure 
(± 45 days) 
Discontinued 
Unscheduled visit 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Patient background 
X 
 
 
 
 
 
 
 
 
 
Surgical risk assessment*1 
X 
 
 
 
 
 
 
 
 
 
NYHA classification of cardiac 
performance 
X 
 
 
X 
X 
X 
X 
X 
 
 
CCS status of stable angina 
X 
 
 
X 
X 
X 
X 
X 
 
 
Neurological assessment*2 
(NIHSS, mRS) 
X 
 
 
 
X 
X 
X 
 
 
 
Blood pressure 
X 
 
 
X 
X 
X 
X 
 
 
 
12-lead ECG 
X*3 
 
X 
X 
X 
X 
X 
 
 
 
Chest X-ray 
X 
 
X 
X 
X 
X 
X 
 
 
 
Head CT 
X 
 
 
 
X 
X 
X 
 
 
 
6-minute walk test 
X 
 
 
 
X 
 
X 
 
 
 
Clinical 
laboratory test 
Hematology 
X*4 
 
 
 
X 
X 
X 
 
 
 
Biochemistry 
X*4 
 
 
 
X 
X 
X 
 
 
 
Coagulation 
X*4 
 
 
 
X 
X 
X 
 
 
 
Cardiac enzyme 
X*4 
 
X 
X 
X 
X 
X 
 
 
 
Echocardiography 
X 
X*8 
 
X*11 
X*11 
X*11 
X*11 
X*11 
 
 
Cardiac CT 
X 
 
 
 
 
 
 
 
 
 
Coronary angiography 
X*5 
 
 
 
 
 
 
 
 
 
Aortofemoral imaging 
X*6 
 
 
 
 
 
 
 
 
 
Cardiac catheterization 
 
X*9 
 
 
 
 
 
 
 
 
QOL questionnaire 
(EuroQOL, SF-12) 
X 
 
 
 
X 
X 
X 
X 
 
 
Procedure information 
 
X 
 
 
 
 
 
 
 
 
Anticoagulant/antiplatelet drugs 
X*7 
X 
Antibiotic 
X*7 
X 
 
 
 
 
 
 
Blood purification 
X*10 
 
 
X 
 
 
 
Other concomitant medication/therapy 
 
X 
 
X*12 
X*12 
Adverse event/device deficiency 
 
X 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 21 - 
Table II:  Schedule of Tests and Observations for Continued Access Registry 
*1 
Calculate STS score, Logistic EuroSCORE, and EuroSCORE II. 
*2 
For patient who has suffered a stroke, mRS must be evaluated within 30 to 90 days and beyond 90 days as earlier as from the onset of stroke. 
*3 
Subjects who developed stroke only. 
*4 
Perform within 48 hours prior to entering the operating room. 
*5 
Perform within 14 days prior to the study procedure. 
*6 
Except cases that may be clinically valid, perform within 1 year prior to the study procedure. 
*7 
Perform CT, MRI, or X-ray within 90 days prior to the study procedure. 
*8 
Start assessment from 7 days pre-procedure. 
*9 
Measure the aortic annulus diameter, and perform observation items of cardiac catheterization according to the situation. 
*10 Perform pre- and post-study procedure . May be performed by echocardiography according to the situation. 
*11 Assess dialysis information performed from the latest date prior to the study procedure  to discharge (at discharge date or 7 days post-procedure, 
whichever came earlier). 
*12 Baseline BSA value must be used for calculation of EOAi and LVMI. 
*13 Subjects who were included in the continued access registry under Protocol ver. 5 will require no post-procedural QOL questionnaire. 
*14 Where possible, assess other concomitant medication/therapy used within 1 year post-procedure, excluding anticoagulation/antiplatelet, antibiotic, 
and hemodialysis. 
 
 
 
Timing 
 
 
 
 
 
 
 
Tests/observations 
Baseline 
(Within 60 days 
pre-procedure) 
During procedure 
Immediately after procedure 
(Within 72 hours 
pre-procedure) 
Discharge or 7 days 
post-procedure 
(± 2 days) 
30 days post-procedure 
(- 7 days, + 14 days) 
6 months post-procedure 
(± 30 days) 
1 year post-procedure 
(± 30 days) 
2 - 5 years post-procedure 
(± 45 days) 
Discontinued 
Unscheduled visit 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria for Continued 
Access Registry 
X 
 
 
 
 
 
 
 
 
 
Patient background 
X 
 
 
 
 
 
 
 
 
 
Surgical risk assessment*1 
X 
 
 
 
 
 
 
 
 
 
NYHA classification of cardiac 
performance 
X 
 
 
X 
X 
X 
X 
X 
 
 
CCS status of stable angina 
X 
 
 
X 
X 
X 
X 
X 
 
 
Neurological assessment*2 
(NIHSS, mRS) 
X 
 
 
 
X 
X*3 
X*3 
 
 
 
Blood pressure 
X 
 
 
X 
X 
X 
X 
 
 
 
12-lead ECG 
X*4 
 
X 
X 
X 
X 
X 
 
 
 
Chest X-ray 
X 
 
X 
X 
X 
X 
X 
 
 
 
Head CT 
X 
 
 
 
X 
X*3 
X*3 
 
 
 
Clinical 
laboratory test 
Hematology 
X*5 
 
 
 
X 
X 
X 
 
 
 
Biochemistry 
X*5 
 
 
 
X 
X 
X 
 
 
 
Coagulation 
X*5 
 
 
 
X 
X 
X 
 
 
 
Cardiac enzyme 
X*5 
 
X 
X 
X 
X 
X 
 
 
 
Echocardiography 
X 
X*9 
 
X*12 
X*12 
X*12 
X*12 
X*12 
 
 
Cardiac CT 
X 
 
 
 
 
 
 
 
 
 
Coronary angiography 
X*6 
 
 
 
 
 
 
 
 
 
Aortofemoral imaging 
X*7 
 
 
 
 
 
 
 
 
 
Cardiac catheterization 
 
X*10 
 
 
 
 
 
 
 
 
QOL questionnaire 
(EuroQOL, SF-12) 
X 
 
 
 
X*13 
X*13 
X*13 
X*13 
 
 
Procedure information 
 
X 
 
 
 
 
 
 
 
 
Anticoagulant/antiplatelet drugs 
X*8 
X 
Blood purification 
X*11 
 
 
X 
 
 
 
Other concomitant medication/therapy 
 
X*14 
 
X*14 
X*14 
Adverse event/device deficiency 
 
X 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 22 - 
1 
INTRODUCTION 
1.1 
Background of Development 
1.1.1 Background of development of Transcatheter aortic valve implantation 
Aortic stenosis (AS) is a disease condition in which constriction is developed in the aortic valve due to 
degeneration of the aortic valve, congenital bicuspid aortic valve, rheumatism, or inflammatory changes. In 
the recent aging population, the cause of AS has shifted from inflammatory changes due to rheumatic fever 
to degeneration by aging and arteriosclerosis, and the incidence in the elderly is predicted to be growing in 
the future. In degenerative AS progressive calcification of the cusp restricts normal cusp opening during 
systole. As a result, the left ventricle receives a chronic pressure load, leading to afferent left ventricular 
hypertrophy, reduced systemic and coronary blood flow. Typically, patients with AS are free from clinical 
symptoms, such as angina pectoris, syncope, or heart failure, for a long period of time in the course of the 
disease. However, once these symptoms manifest, the prognosis is poor; the mean life expectancy of 5 
years after onset of angina pectoris, 3 years after syncope, and 2 years after heart failure.[1] Therefore, 
symptomatic and severe AS patients should receive surgery as soon as practicable. 
 
The standard treatment for AS is surgical aortic valve replacement (sAVR) with which the hardened native 
cusp is removed under open-heart surgery and replaced with artificial valve. However, since sAVR requires 
extracorporeal circulation, and general anesthesia is essential, very old patients, patients with severe 
preoperative complication, and patients with significantly impaired cardiopulmonary function have a higher 
risk of periprocedural mortality and severe postoperative complication, and therefore sAVR is not 
applicable. Such patients receive drug therapies, including diuretics and vasodilator, only to alleviate the 
symptom. Other treatments for patients who cannot be treated with sAVR include percutaneous balloon 
aortic valvuloplasty that has been performed since around 1980. However, since many patients developed 
re-stenosis within 1 year after the procedure, percutaneous balloon aortic valvuloplasty is not presently 
performed as an active treatment means. 
 
Under such circumstances, as a minimally invasive treatment for patients at a higher surgical risk and not 
eligible for sAVR, transcatheter aortic valve implantation (TAVI) has been developed in the recent years, 
with which a bioprosthetic valve is placed through a catheter. TAVI using balloon expandable device, which 
was clinically applied for the first time by Cribier, et al. in 2002,[2] followed by the 1st generation SAPIEN 
bioprosthetic valve system (hereinafter “SAPIEN”) gaining CE mark in EU in 2007, and in 2011 approved 
by the FDA in the US. Subsequently, the 2nd generation SAPIEN XT bioprosthetic valve system 
(hereinafter “SAPIEN XT”) was developed, with improved functions based on the findings obtained in the 
clinical use. SAPIEN XT gained CE mark in 2010, approved by the FDA in 2014, and in Japan sizes 
23 mm and 26 mm were approved in 2013, and sizes 20 mm and 29 mm were approved by partial change 
application in 2015 (Approval No.: 22500BZX00270000). At present, in order to further minimize the risk 
of paravalvular regurgitation and vascular complication, the 3rd generation bioprosthetic valve system 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 23 - 
(EWJ-003) with an additional back-flow prevention mechanism and reduced diameter has been developed, 
gaining CE mark in 2014, and approved by the FDA in 2015. Also in Japan, it was approved in March 2016 
(Approval No.: 22800BZX00094000; transfemoral (TF) approach only), and expected to be widely usd in 
clinical practice in the near future. 
 
1.1.2 AS treatment in chronic dialysis patients 
In Japan, the number of chronic dialysis patients is growing every year, and according to the investigation 
by The Japanese Society for Dialysis Therapy,[3] the number reached 320,448 patients at the end of 2014. 
The annual crude death rate in 2014 was 9.6%, and as the cause of deaths, cardiovascular deaths, 
combining the largest number of heart failure (26.3%), cerebrovascular disorder (7.1%), and myocardial 
infarction (MI) (4.3%), accounted for 37.7%. AS is one of the major complications in dialysis patients, and 
compared with non-dialysis patients higher prevalence can be found in dialysis patients, with a reportedly 
higher complication prevalence rate of 3% to 15%.[4-8] In addition, it is known that since dialysis patients 
develop AS earlier,[9] and prone to develop ectopic calcification due to secondary hyperparathyroidism, AS 
is aggravated in about twice as faster than that in non-dialysis patients with progression of aortic valve 
calcification.[6, 10] Moreover, dialysis patients are susceptible to infective endocarditis associated with 
paracentesis at hemodialysis and their susceptibility to infection,[11] and often complicated with coronary 
artery disease. 
 
Currently, of the treatments for AS in dialysis patients, the 1st line of treatment is sAVR. There is no 
difference in the indication of sAVR for AS between dialysis patients and non-dialysis patients, and in 
Japan it is based on “Guidelines for Surgical and Interventional Treatment of Valvular Heart Disease”[12] 
created by joint study group of 4 medical societies, including The Japanese Circulation Society, in 2012. 
However, compared with non-dialysis patients, dialysis patients have poor prognosis after sAVR.[13, 14] In 
addition, since early calcification of bioprosthetic valve and structural valve deterioration are concerned in 
dialysis patients because calcification is more likely to occur, for selection of prosthetic valve for dialysis 
patients, the use of mechanical valves has been typically recommended to date. However, since there is no 
difference in the long-term outcome results between dialysis and non-dialysis patients[15-17] and the 
incidence of valve-related complications is smaller with bioprosthetic valves, it was reported that 
bioprosthetic valves were favorable.[18, 19] Therefore, at present, it is recommended that valves be selected 
according to the patient’s condition, taking primary disease and complications into consideration.[12, 20] 
 
Chronic dialysis patients have multiple complications in general, with poor general condition due to a 
bleeding tendency and increased susceptibility to infection, and have a higher surgical risk, and therefore 
compared with non-dialysis patients, dialysis patients are often not eligible for sAVR. As described above, 
TAVI may be considered in patients not eligible for sAVR; however in Japan the approved indication of 
SAPIEN XT and EWJ-003 is limited to non-dialysis patients with symptomatic severe AS associated with 

Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 24 - 
sclerosis of the native aortic cusp, not eligible for surgery and deemed best treated with these devices, and 
hence chronic dialysis patients are not included. Because of this, chronic dialysis patients not subject to 
sAVR have no choice other than palliative symptomatic treatment with drug therapy at present, and 
inclusion of chronic dialysis patients into the indication of TAVI has been demanded. 
 
1.1.3 TAVI development for chronic dialysis patients 
To date, TAVI development for chronic dialysis patients in Japan has been initiated mainly by Osaka 
University Hospital. Osaka University Hospital performed TAVI using the 1st generation SAPIEN and 2nd 
generation SAPIEN XT in chronic dialysis patients with symptomatic severe AS, who were not eligible for 
sAVR under advanced medical care, and in 2015 Maeda et al. reported good results in 17 chronic dialysis 
patients up to 1 year after the procedure. [21] As of March 2016, the results in 24 chronic dialysis patients up 
to 1 year after the procedure have been obtained, and the treatment results are compared favorably with 
sAVR, the standard therapy. Therefore, TAVI could be a safe and effective treatment method in chronic 
dialysis AS patients who were not indicated for sAVR, and with no radical treatment available. 
 
As described above, the safety and efficacy of TAVI using SAPIEN and SAPIEN XT in chronic dialysis 
patients in advanced medical care were evident. However, since newly introduced 3rd generation EWJ-003 
has a paravalvular regurgitation preventing mechanism, with reduced diameter, it may serve as a safer and 
more effective treatment to chronic dialysis patients with multiple complications, bleeding tendency, and 
increased susceptibility to infection. In order to support the safety and efficacy of TAVI in chronic dialysis 
patients observed in advanced medical care, hypothesis should be tested in a statistically basis, and further 
by performing a long-term follow-up for 5 years after the procedure, long-term safety and efficacy need to 
be confirmed. 
 
Based on the above, we planned this clinical trial to evaluate the safety and efficacy of TAVI using 
EWJ-003 in chronic dialysis patients. 
 
1.2 
Validity of the Trial Conduct 
1.2.1 Nonclinical study results 
Similarly to the already approved SAPIEN XT, the investigational valve is a device that combines a balloon 
expandable stent and bioprosthetic valve technology. Similarly to the existing device, to achieve an 
adequate hemodynamic improvement in AS patients, a moderate valve area should be ensured, and the 
shape should be maintained withstanding strong external load on the fibrous annular. Therefore, in order to 
evaluate the characteristics of the investigational device, nonclinical studies were conducted, considering 
not only valve performance but also functionality of the frame to fix the valve by expansion of a balloon. 
The studies conducted and specifications applied or referred to are presented in Table 1-1. 
(For details see Investigator's Brochure)㻌
Protocol 
 
Edition number: 
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Table 1-1: 
Conducted nonclinical studies and specifications 
Studied item 
Specifications applied or referred to 
Risk management 
z 
ISO 14971: Application of risk management to medical devices 
(ISO 14971 is the same as JIST 14971 “Medical devices - Application of risk management 
to medical devices.”) 
Physical and chemical property 
study 
z 
FDA Replacement Heart Valve Guidance Version 4.1 (dated October 14, 1994) 
z 
ISO 5840: Cardiovascular implants - Artificial heart valve 
z 
FDA Guidance for Intravascular Stents and Associated Delivery Systems (dated 
January 13, 2005) 
z 
ISO 14630: Non-active surgical implants - General requirements 
z 
ISO 25539-1: Cardiovascular implants - Intravascular devices - Part 1: Intravascular 
aids 
z 
ISO 10555-1: Disposable sterile vascular catheter - Part 1: General requirements 
z 
ISO 10555-4: Disposable sterile vascular catheter - Part 4: Balloon dilatation catheters 
z 
ISO 11070: Disposable sterile vascular catheter inducer 
Hydrodynamic study 
z 
FDA Replacement Heart Valve Guidance Version 4.1 (dated October 14, 1994) 
z 
ISO 5840: Cardiovascular implants - Artificial heart valve 
Accelerated durability study 
z 
FDA Replacement Heart Valve Guidance Version 4.1 (dated October 14, 1994) 
z 
ISO 5840: Cardiovascular implants - Artificial heart valve 
Biological safety study 
z 
ISO 10993-1: Biological evaluation of medical devices - Part 1: Evaluation and tests 
Animal study 
z 
FDA 21 CFR part 58 GLP 
z 
ISO 5840: Cardiovascular implants - Artificial heart valve 
 
The investigational valve and delivery system were individually tested with application or in reference to 
the specifications shown in the above table, and the results confirmed the performance and safety of the 
investigational valve. 
 
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1.2.2 Clinical trial results 
1.2.2.1 Clinical trial results of the investigational device 
Clinical trials of this investigational device are listed in Table 1-2. 
 
Table 1-2: 
List of clinical trials of this investigational device 
 
Study title 
Study objective 
Study design 
Country/ 
region 
Study device 
(size) 
Implantation 
procedure 
Target 
sample 
size 
Number 
of study 
sites 
Study 
progression 
status 
1 First-in-man trial Feasibility study 
Prospective, 
multi-center study Canada 
EWJ-003 
(26) 
TF 
15 
subjects 
2 sites Completed 
2 
PARTNER II 
Trial 
(2010-12-US) 
To evaluate the 
safety and 
efficacy of a 
bioprosthetic 
valve and 
delivery system 
A prospective, 
single arm, 
non-randomized, 
historical control 
comparative 
study 
US 
EWJ-003 
(20, 23, 26, 
29) 
TF, TA, TAo 
583 
subjects* 
(TF: 491 
subjects) 
29 sites 
Follow-up 
observation 
is 
underway 
3 EU clinical trial 
(2012-07) 
To evaluate the 
safety and 
efficacy of a 
bioprosthetic 
valve and 
delivery system 
Prospective, 
non-randomized, 
multi-center study 
EU, 
Canada 
EWJ-003 
(20, 23, 26, 
29) 
TF, TA, TAo 
102 
subjects* 
(TF: 57 
subjects) 
14 sites 
Follow-up 
observation 
is 
underway 
* The number of subjects valid for analysis of results in patients not eligible for surgery and at a higher risk used for approval 
application of EWJ-003 in Japan. 
 
<First-in-man trial> 
A first-in-man trial of EWJ-003 was conducted in Canada[22] from January to June 2012, 15 patients with 
symptomatic severe AS (including 1 chronic dialysis patient) were enrolled in this clinical trial from 2 trial 
sites. The average patient age was 80.3 ± 11.2 years, and male patients accounted for 100%, with the 
Society of Thoracic Surgeons (STS) score of 5.4 ± 3.2%. All patients received the procedure by TF 
approach, and the investigational valve was successfully implanted. There were no death cases within 30 
days post-procedure, and no incidence of stroke, vascular complications, or bleeding was observed. No 
cases with moderate to severe paravalvular regurgitation within 30 days post-procedure were reported, and 
all subjects were assessed as New York Heart Association (NYHA) Class I or Class II. Also the effective 
orifice area (EOA) and mean pressure gradient determined by echocardiography were significantly 
improved from the baseline at 30 days after the procedure, and post-procedural good hemodynamics was 
confirmed. 
 
<PARTNER II Trial> 
PARTNER II Trial conducted in the US evaluated the safety and efficacy of EWJ-003 in severe AS patients 
with symptomatic calcification (excluding chronic dialysis patients). From October 2013 to July 2014, 586 
subjects who were not eligible for surgery and at a higher risk were enrolled from 29 study sites, of which 
583 subjects received investigational valve implantation. The implantation procedures included TF 
approach in 491 subjects, transapical (TA) approach in 57 subjects, and transaortic (TAo) approach in 35 
(For details see Investigator's Brochure)㻌
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subjects. For this trial, a long-term follow-up is still underway, and at this time point, the results up to 1 
year after the procedure have been obtained. 
 
The average patient age of these 583 subjects who received implantation of the investigational valve was 
82.6 ± 8.1 years, and a proportion of male patients was 58.0%, with the mean STS score and Euro SCORE 
II of 8.6 ± 3.7% and 8.6 ± 7.1%, respectively. Of 583 subjects, 581 subjects (99.7%) received the 
investigational valve implantation as assigned, and only 1 subject was switched to surgery. The remaining 1 
subject was transferred from TF approach to TA approach due to an intraoperative complication. The 
incidence of nonhierarchical composite events consisting of the primary endpoints; all-cause mortality, all 
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group and 15.6% in the historical control SAPIEN group. The difference was -9.0% (90% confidence 
interval [CI]: -13.1%, -5.2%). Since the upper limit of the 90% CI of -5.2 was lower than the noninferiority 
margin of 7.5%, the noninferiority of EWJ-WR6$3,(1ZDVYHULILHG$OOLQFLGHQFHRI moderate aortic 
valve regurgitation and severe vascular complications at 30 days post-procedure were significantly lower 
with EWJ-003 compared with SAPIEN, and thus the concept of EWJ-003 development was achieved 
[Aortic valve regurgitation: SAPIEN group, 14.3%; EWJ-003 group, 3.0%, p < 0.0001, severe vascular 
complication: SAPIEN group, 10.1%; EWJ-003 group, 5.0%, p = 0.0006]. The incidence determined by the 
Kaplan-Meier estimates for all-cause mortality and stroke at 30 days post-procedure were 2.2% and 1.4%, 
respectively, and at 1 year post-procedure 14.4% and 4.3%, respectively. At 30 days post-procedure 87.3% 
RI VXEMHFWV VKRZHG LPSURYHPHQW RI  1<+$ &ODVV , DQG DOVR DW  \HDU SRVW-procedure sustained 
improvement was observed. Also long-term outcome of hemodynamics was good, the EOA, mean pressure 
gradient, and maximum pressure gradient determined by echocardiography were significantly improved 
from the baseline at 30 days after the procedure, and at 1 year post-procedure sustained improvement was 
observed. 
 
[By approach] 
TF Approach 
The background of 491 subjects who received the procedure via TF approach was comparable to that of the 
overall subject population; the average patient age of 82.8 ± 8.2 years, and a proportion of male patients 
was 56.4%, with the mean STS score and Euro SCORE II of 8.4 ± 3.5% and 8.2 ± 6.8%, respectively. Of 
491 subjects, 78 subjects (15.9%) received the procedure with conscious sedation method, and the average 
duration of procedure was shorter with TF approach, compared with TA/TAo approaches. The 
investigational valve was implanted at the intended position in 99.4% of subjects, and postprocedural 
dilatation was required in 14.9% of subjects. The length of postprocedural hospitalization was 6.1 ± 4.3 
days, which was shorter than that of TA/TAo approaches. Late clinical outcome showed the same trend as 
that of overall subjects. The incidence determined by the Kaplan-Meier estimates for all-cause mortality 
and stroke at 30 days post-procedure were 1.6% and 1.4%, respectively, and at 1 year post-procedure 
12.3% and 4.1%, respectively, which were lower than those of TA/TAo approaches. On the other hand,  

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vascular access site/access-related complications that are concerned with TF approach were common 
compared to those of TA/TAo approaches, but the incidence of severe vascular complications was 
equivalent. 
 
TA Approach 
The average age of 57 subjects who received the procedure via TA approach was 80.0 ± 7.2 years, which 
was comparable to that of overall subjects. On the other hand, the male ratio (77.2%) was higher than that 
of overall subjects, and the STS score and EuroSCORE II were also higher as 9.3 ± 3.9% and 11.3 ± 8.4%, 
respectively. All subjects received the procedure with general anesthesia, and the average duration of 
procedure was longer than that of TF approach but shorter than that of TAo approach. The investigational 
valve was implanted at the intended position in 96.5% of subjects, and postprocedural dilatation was 
required in 14.0% of subjects. The length of postprocedural hospitalization was 9.8 ± 6.2 days, which was 
longer than that of TF approach. As for late clinical outcome, compared with TF approach, its prognosis 
was poorer; the incidence determined by the Kaplan-Meier estimates for all-cause mortality at 30 days 
post-procedure and 1 year post-procedure were 3.5% and 22.8%, respectively. The incidence of stroke at 30 
days post-procedure was 1.8%, and at 1 year post-procedure 8.4%. Hemorrhage had been reported in 
38.6% of subjects at 30 days post-procedure, which was higher than that with TF approach, but the 
incidence of life-threatening or disabling bleeding event was 5.3%, which was equivalent to that with TF 
approach. 
 
TAo Approach 
The average age of 35 subjects who received the procedure via TAo approach was 84.5 ± 7.1 years, which 
was comparable to that of overall subjects. On the other hand, a proportion of male subjects (48.6%) was 
lower than that of overall subjects, and the STS score and EuroSCORE II were higher as 11.1 ± 4.7% and 
9.8 ± 7.7%, respectively. All subjects received the procedure with general anesthesia, and the longest 
average duration of procedure was observed with TAo approach, compared with other approaches. The 
investigational valve was implanted at the intended position in all subjects, and postprocedural dilatation 
was required in 14.3% of subjects. The length of postprocedural hospitalization was 11.4 ± 3.7 days, which 
was the longest duration, while the length of intensive care unit (ICU) stay was comparable to that with TA 
approach. As for late clinical outcome, compared with other approaches, its prognosis was poorer; the 
incidence determined by the Kaplan-Meier estimates for all-cause mortality at 30 days post-procedure and 
1 year post-procedure were 8.6% and 29.2%, respectively. TAo approach resulted in a higher incidence of 
hemorrhage, which was reported in 51.4% of subjects at 30 days post-procedure, and 17.1% was assessed 
as life-threatening or disabling hemorrhage. On the other hand, no stroke had been reported at 1 year 
post-procedure. 
 
<EU clinical trial> 
EU clinical trial conducted in Europe and Canada evaluated the safety and efficacy of EWJ-003 in severe 
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AS patients with symptomatic calcification (excluding chronic dialysis patients). In this trial, 50 patients 
who were not eligible for surgery and at a higher risk were sequentially enrolled first, followed by 
HQUROOPHQWRISDWLHQWVPRGHUDWHVXUJHU\ULVNAt this timepoint, the results up to 1 year after the 
procedure analyzing 102 subjects not eligible for surgery and at a higher risk who completed the follow-up 
observations at 1 year post-procedure as of September 4, 2014 are available. From January to October 2013, 
102 subjects valid for analysis were enrolled in this clinical trial from 14 study sites, and all subjects 
received implantation of the investigational valve. The implantation procedures included TF approach in 57 
subjects, and TA approach or TAo approach in 45 subjects. 
 
The average age of these 102 subjects valid for analysis was 84.1 ± 5.0 years, and a ratio of male patients 
was 39.2%, with the mean STS score and Euro SCORE II of 8.0 ± 4.7% and 24.1 ± 13.0%, respectively. Of 
102 subjects, 101 subjects (99.0%) received implantation of the investigational valve with no problem, and 
the procedure was switched to surgery in only 1 subject. The incidence of nonhierarchical composite events 
consisting of the primary endpoints; all-FDXVH PRUWDOLW\ DOO VWURNH DQG  PRGHUDWH DRUWLF YDOYH
regurgitation, was 14.8% at 30 days after the procedure and 30.5% at 1 year post-procedure. The proportion 
RI VXEMHFWV ZLWK  PRGHUDWH DRUWLF YDOYH UHJXUJLWDWLRQ ZDV  DW EDVHOLQH ZKHUHDV LW VLJQLILFDQWO\
decreased to 3.7% at 30 days, and 1.6% at 1 year post-procedure. Also the incidence of severe vascular 
complications was low; the rate at 30 days post-procedure was 4.9%. The incidence determined by the 
Kaplan-Meier estimates for all-cause mortality and stroke at 30 days post-procedure were 7.8% and 3.0%, 
respectively, and at 1 year post-procedure 19.9% and 5.4%, respectively. At 30 days post-procedure 92.1% 
RI VXEMHFWV VKRZHG LPSURYHPHQW RI  1<+$ &ODVV , DQG DOVR DW  \HDU SRVW-procedure sustained 
improvement was observed. Also long-term outcome of hemodynamics was good, the EOA, mean pressure 
gradient, and maximum pressure gradient determined by echocardiography were significantly improved 
from the baseline at 30 days after the procedure, and at 1 year post-procedure sustained improvement was 
observed. 
 
 
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[By approach] 
TF Approach 
The background of 57 subjects who received the procedure via TF approach was comparable to that of the 
overall subject population; the average patient age of 85.1 ± 4.6 years, and a proportion of male patients 
was 40.4%, with the mean STS score and mean Logistic EuroSCORE of 8.2 ± 4.2% and 22.3 ± 11.3%, 
respectively. Of 57 subjects, 13 subjects (22.8%) received the procedure with conscious sedation method, 
and the average duration of procedure was slightly longer, compared with TA/TAo approaches, as 86.1 ± 
88.1 minutes, this may be because affected by that the procedure was switched to surgery in 1 subject. The 
investigational valve was implanted at the intended position in 98.2% of subjects, and postprocedural 
dilatation was required in 5.3% of subjects. The length of postprocedural hospitalization was 12.0 ± 7.8 
days, which was shorter than that of TA/TAo approaches. Late clinical outcome showed the same trend as 
that of overall subjects. The incidence determined by the Kaplan-Meier estimates for all-cause mortality 
and stroke at 30 days post-procedure were 3.5% and 1.8%, respectively, and at 1 year post-procedure 
12.4% and 3.6%, respectively, which were lower than those of TA/TAo approaches. Also for the vascular 
access site/access-related complications that are generally concerned with TF approach, a lower incidence 
was observed than those of TA/TAo approaches as 7.1%. 
 
TA/TAo Approaches 
The background of 45 subjects who received the procedure via TA/TAo approaches was comparable to that 
of the overall subject population; the average age of 83.0 ± 5.3 years, and a proportion of male patients was 
37.8%, with the mean STS score and mean Logistic EuroSCORE of 7.9 ± 5.2% and 26.4 ± 14.7%, 
respectively. All subjects received the procedure with general anesthesia, and the average duration of 
procedure was 84.4 ± 28.8 minutes. The investigational valve was implanted at the intended position in all 
subjects, and postprocedural dilatation was required in 2.2% of subjects. The length of postprocedural 
hospitalization was 17.6 ± 11.3 days, which was longer than that of TF approach. As for late clinical 
outcome, compared with TF approach, the prognosis was poorer. The incidence determined by 
Kaplan-Meier estimates for all-cause mortality and stroke at 30 days post-procedure were 13.3% and 4.6%, 
respectively, and at 1 year post-procedure 29.2% and 7.9%, respectively. Hemorrhage had been reported in 
35.8% of subjects at 30 days post-procedure, which was higher than that with TF approach, but the 
incidence of life-threatening or disabling bleeding event was 6.7%, which was equivalent to that with TF 
approach. 
 
1.2.2.2 Treatment results in advanced medical care 
Osaka University Hospital performed TAVI using the 1st generation SAPIEN and 2nd generation SAPIEN 
XT in chronic dialysis patients with symptomatic severe AS, who were not eligible for sAVR under 
advanced medical care. At present, the results in 24 Japanese chronic dialysis patients up to 1 year after the 
procedure have been obtained. 
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The mean age of 24 chronic dialysis patients who received TAVI was 76.7 ± 5.1 years, significantly lower 
than non-dialysis patients, and the proportion of male was 41.7%. The STS score was 15.0 ± 10.7%, and 
Logistic EuroSCORE was 27.3 ± 17.8%; compared with non-dialysis patients, surgical risk was higher. The 
average dialysis period was 11.8 ± 9.3 years. Of 24 subjects, 10 subjects received the procedure by TF 
approach, 14 subjects received TA approach, and the median length of postprocedural hospitalization and 
ICU stay were 13.8 days and 3.0 days, respectively. There were no death cases within 30 days 
post-procedure, and stroke was reported in 1 subject (4.1%). The survival rate at 1 year post-procedure 
determined by Kaplan-Meier survival analysis was as good as 89.3%, and also the event-free rate of major 
adverse cardiovascular and cerebral events (MACCE) at 1 year post-procedure of 71.4% was favorable in 
comparison with the event-free rate (60.5%) at sAVR in dialysis patients reported by Umezu et al. .[23] Also 
long-term outcome of hemodynamics was good, the effective orifice area index (EOAi) and mean pressure 
gradient, significantly improved from the baseline at 30 days post-procedure, and also at 1 year 
post-procedure sustained improvement was observed. 
 
1.2.2.3 Referenced literature reports 
It has been reported that the early and long-term mortality risk after TAVI increase depending on the 
severity of chronic kidney disease (CKD).[24 - 27] According to the report by Dumonteil et al.,[24] the 
mortality within 30 days post-procedure was 1.8% in non-CKD patients, whereas it was 6.7%, 8.3%, and 
8.3% in mild, moderate, and severe CKD patients, respectively, and it was as high as 15.2% in dialysis 
patients. Also Allende et al.[25] classified 2075 patients undergone TAVI into 5 groups by the severity of 
CKD, and reported that higher early and medium-term mortality was found in severe CKD patients (Stage 
H*)5P/PLQP2 and < 30 mL/min/1.73 m2, and Stage 5: eGFR < 15 mL/min/1.73 m2 or 
requiring dialysis), and the death-free rate at 1 year post-procedure was significantly lower in Stage 5 
patients (64.5%). Moreover, recently conducted 2 European large-scale registry studies; FRANCE-2 
registry[26] and UK TAVI registry[27], also examined the impact of CKD on TAVI treatment results, and 
reported that poor prognosis after TAVI was observed with advance in CKD. The mortality rate in the Stage 
5 patient group including dialysis patients at 1 year post-procedure in FRANCE-2 registry[26] was 39.9% (of 
96 Stage 5 patients, 82 patients were requiring dialysis), and in UK TAVI registry[27] it was 39.4% (of 99 
Stage 5 patients, 81 patients were requiring dialysis). On the other hand, Rau et al.[28] reported that there 
was no difference in the Kaplan-Meier estimate mortality at 6 months after the procedure between 116 
non-dialysis patients and 10 dialysis patients, who received TAVI due to ineligibility for surgery. Kobrin et 
al.[29] adjusted propensity score, and then compared the results between TAVI and sAVR in chronic dialysis 
patients. The mortality at 30 days post-procedure was 10% for TAVI and 8% for sAVR, with no statistically 
significant difference between these 2 treatment groups (p = 0.47). Also for the survival rate at 1 year 
post-procedure determined by Kaplan-Meier survival analysis, no difference was found between 2 groups; 
60% for TAVI and 63.6% for sAVR (Logrank p = 0.99). According to the study by Alqahtani et al. in 

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2017[30], the hospital mortality adjusted for propensity score was 6.1% for TAVI and 13.7% for sAVR, with 
a significantly lower rate for TAVI (p = 0.021). The hospital mortality by approach was 5.1% for TF 
approach (vs. 13.8% for sAVR, p = 0.007) and 10% for TA approach (vs. 14% for sAVR 14%, p = 0.52). 
Based on these reports, it is predicted that TAVI in chronic dialysis patients may lead to poorer prognosis 
compared with that in non-dialysis patients, but has the comparable safety and efficacy to those of sAVR, 
the standard treatment. 
 
1.2.3 Validity of the trial conduct 
Based on the fact that the quality, performance, and safety of this study device EWJ-003 were verified by 
non-clinical studies, a first-in-man trial of EWJ-003 was conducted in Canada. The first-in-man trial 
exploratory evaluated feasibility of EWJ-003 implantation by TF approach, and confirmed the basic safety 
and efficacy of EWJ-003. Subsequently, PARTNER II Trial conducted as a US IDE pivotal study and an 
EU clinical trial aiming at acquisition of CE mark showed the safety and efficacy of EWJ-003, and CE 
mark was granted in 2014, followed by FDA approval in 2015. Also in Japan, the TF approach was 
approved in March 2016 (Approval No.: 22800BZX00094000), and therefore it will be widely used in 
clinical practice in the near future. For the safety and efficacy of TAVI in Japanese chronic dialysis patients, 
advanced medical care performing TAVI with the 1st generation SAPIEN and 2nd generation SAPIEN XT 
confirmed the safety and efficacy up to 1 year after the procedure. In addition, since the study device 
EWJ-003 has a paravalvular regurgitation preventing mechanism, with reduced diameter of the system, this 
clinical trial of EWJ-003 is expected to show the results equal to or better than the results of advanced 
medical treatments using previous generation of the study device. Furthermore, chronic dialysis patients 
outside Japan are not excluded from the indications of TAVI devices including EWJ-003, and in view of the 
literature data on TAVI in chronic dialysis patients that have been reported outside Japan to date, it is 
predicted that TAVI in chronic dialysis patients may lead to poorer prognosis compared with that in 
non-dialysis patients, but has the comparable safety and efficacy to those of sAVR, the standard treatment. 
 
Based on the above, it was determined that the conduct of this clinical trial for the purpose of evaluation of 
the safety and efficacy of EWJ-003 in chronic dialysis patients with symptomatic severe AS associated with 
sclerosis of the native cups of aortic valve is scientifically and ethically reasonable. 
 
2 
STUDY OBJECTIVE 
The objective of this trial is to evaluate the safety and efficacy of EWJ-003 in chronic dialysis patients with 
symptomatic severe AS associated with sclerosis of the native cusp of aortic valve, who are deemed not to 
tolerate open surgery, and judged EWJ-003 is the best available treatment. 
 
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3 
OUTLINE OF STUDY DEVICE 
This clinical trial will use EWJ-003, the 3rd generation balloon expandable transcatheter bovine pericardial 
tissue valve developed by Edwards Lifesciences, as the study device. EWJ-003 is comprised of the 
transcatheter heart valve (THV), delivery system (for TF approach or TA/TAo approaches), and other 
components (crimper, crimping accessories, and inflation device/inflation syringe). The sizes of THV 
available in the trial are 20, 23, 26, and 29 mm. 
 
Native valve annulus 
size 
(TEE) 
Native valve annulus size (CT) 
THV size 
Valve height 
Area 
Area derived 
diameter 
16 - 19 mm 
273 - 345 mm2 
18.6 - 21.0 mm 
20 mm 
15.5 mm 
18 - 22 mm 
338 - 430 mm2 
20.7 - 23.4 mm 
23 mm 
18 mm 
21 - 25 mm 
430 - 546 mm2 
23.4 - 26.4 mm 
26 mm 
20 mm 
24 - 28 mm 
540 - 683 mm2 
26.2 - 29.5 mm 
29 mm 
22.5 mm 
Table 3-1: 
THV sizes available in the trial 
 
 
3.1 
Structure or Composition of Study Device 
 
Components 
Outline 
Investigational valve (common to TF, TA/TAo approaches) 
1 
THV 
 
 
 
The investigational valve (THV) is a device that combines 
a balloon expandable stent and bioprosthetic valve 
technology. Four valve sizes (20 mm, 23 mm, 26 mm, and 
29 mm) are available, and designed for implantation by 
TF approach or TA/TAo approaches in severe AS patients. 
THV is comprised of a cusp (1) and a radiopaque, 
cobalt-chromium supporting structure (frame) to maintain 
the valve structure (2), and the frame is equipped with 
inner and outer polyethylene terephthalate (PET) fabric 
skirts (3,4) to prevent paravalvular regurgitation. These 
PET skirts are sewn on the frame by suture (5). The valve 
tissue is fabricated from bovine pericardium that have 
been preserved in low concentration solutions of buffered 
glutaraldehyde to fully crosslink the tissue, while 
preserving its flexibility and strength, molded into three 
equal cusps. 
 
 
(1) 
Cusp 
(2) Frame 
(3) PET skirt 
(inside) 
(4) PET skirt 
(outside) 
(5) Suture (white) 
(6) Suture (green) 
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Delivery system (TF approach) 
1 
Delivery system 
<Delivery catheter> 
 
 
 
1 
Stylet 
2 
Tapered tip 
3 
Marker band 
4 
Balloon 
5 
Marker band 
6 
Crimp balloon 
7 
Flex catheter 
8 
Flex wheel 
9 
Flex indicator 
10 Handle 
11 Fine adjustment wheel 
12 Balloon lock 
13 Balloon catheter 
14 Strain relief 
15 Y-connector 
16 Extension tube 
17 Three-way stopcock 
The delivery catheter is used to aid in insertion of the 
THV from the sheath along the guidewire into the body 
and allow to pass the aortic arch. The flex wheel enables 
the distal end of the catheter to curve, and the flex 
indicator allows us to know the angle at the curving. The 
tapered tip of the catheter facilitates easier passing 
through the native valve, and the balloon is used to deploy 
the THV. The THV is attached to the crimp site, and 
guided to the accurate site by the fine adjustment wheel. 
2 
Introducer sheath set 
<Sheath (expandable)> 
 
 
An introducer sheath set is comprised of a sheath, an 
introducer, and a loader. A radiopaque marker in the distal 
end of the sheath is provided to visualize the position of 
the tip of sheath under X-ray fluoroscopy. The loader is 
used to insert the crimped THV mounted on the delivery 
system through the sheath. 
 
<Introducer> 
 
 
 
 
<Loader> 
 
 
 
 
[1] 
[2] 
[3] 
[3] 
[4] 
[6] 
[5] 
[7] 
[9] 
[8] 
[10] 
[16] 
[11] 
[12] 
[14] 
[13] 
[17] 
[15] 
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3 
Balloon catheter 
 
 
 
 
The balloon catheter is utilized for balloon predilatation to 
help with THV delivery through the native valve. A 
radiopaque marker in the balloon is provided to visualize 
the position under X-ray fluoroscopy. 
Delivery system (TA/TAo approach) 
1 
Delivery system 
<Delivery catheter> 
 
 
1 
Stylet 
2 
Tapered tip 
3 
Balloon 
4 
Marker band 
5 
Balloon catheter 
6 
Catheter knob 
7 
Handle 
The delivery system is comprised of a delivery catheter, a 
loader, and an extension tube. The balloon has 2 
radiopaque markers, which play a role of indicator not 
only in visualizing the balloon but also in visualizing the 
position of the THV during crimping. The catheter is 
equipped with a curving mechanism for positioning of the 
balloon. The loader is one of delivery system’s 
components, and is intended to pass the valve mounted on 
the delivery catheter through a hemostasis valve located 
on the sheath introducer. 
 
<Loader> 
 
 
 
y
[1] 
[2] 
[3] 
[5] 
[4] 
Effective length A 
[6] 
[7] 

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<Extension tube> 
 
 
2 
Introducer sheath set 
<Sheath> 
 
 
The introducer sheath set is comprised of a sheath and an 
introducer. A radiopaque marker in the distal end of the 
sheath is provided to visualize the position of the tip of 
sheath under X-ray fluoroscopy. 
 
<Introducer> 
 
 
 
 
3 
Balloon catheter 
(for all 23/26/29 mm sizes) 
 
The balloon catheter is utilized for balloon predilatation to 
help with THV delivery through the native valve. A 
radiopaque marker in the balloon is provided to visualize 
the position under X-ray fluoroscopy. 
The balloon catheter (20 mm) for the size 20 mm THV is 
the same product as the balloon catheter for 20 mm THV 
in the TF system. 
 
(20 mm) 
 
 
 
 
 
Other components (common to TF and TA/TAo approaches) 
1 
Crimper 
The crimper is a device for single use that does not come 
into contact with the patient, which reduces the diameter 
of the THV symmetrically from expanded size to 
attaching size to mount it to the delivery balloon catheter. 
The crimper is comprised of a compression mechanism 
䐟
䐠
䐡
[1] 
[2] 
[3] 
[5] 
[4] 
[6] 
[1] 
[7] 
Protocol 
 
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that is closed with a handle located on the housing. 
The crimper includes a crimp stopper (packaged with the 
delivery system) to correctly crimp the THV to the 
appropriate size. 
 
 
[1] 
[2] 
[3] 
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2 
Crimping accessories 
 
Type A 
Type B 
 
 
 
 
 
 
 
The crimping accessories (packaged with the delivery 
system) are utilized to protect the cusps during 
compression of the THV. Type A that corresponds with 
the size of the THV and Type B that is independent from 
the size are available. 
3 
Inflation device/inflation syringe 
 
 
 
Inflation device 
Inflation syringe 
 
The inflation device (20, 23, and 26 mm) and inflation 
syringe (29 mm only) are utilized to expansion/deflation 
of the balloon for predilatation and deployment of the 
THV. 
 
3.2 
Directions for Use 
Deliver a transcatheter heart valve (THV), the investigational valve, from the femoral artery, apex, or aorta 
to a lesion where the valve is deployed and implanted. The balloon inflation volume at deployment of THV 
is as shown in Table 3-2. For further descriptions of the study device see Attachment 2 “Instructions for 
Use.” 
 
Table 3-2: 
Balloon inflation volume required for deployment of THV 
Delivery system 
THV 
Nominal volume 
Transfemoral Approach 
Model 9610TF20 
20 mm 
11 mL 
Model 9610TF23 
23 mm 
17 mL 
Model 9610TF26 
26 mm 
23 mL 
Model 9610TF29 
29 mm 
33 mL 
Transapical/Transaortic 
Approaches 
Model 9620TA20 
20 mm 
14 mL 
Model 9620TA23 
23 mm 
17 mL 
Model 9620TA26 
26 mm 
23 mL 
Model 9620TA29 
29 mm 
30 mL 
 
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4 
STUDY DESIGN 
4.1 
Study Design 
This clinical trial is a prospective, open, non-randomized, multi-center, single arm study. 
 
This trial evaluate the safety and efficacy of EWJ-003 in patients who were deemed medically 
inappropriate for sAVR and EWJ-003 therapy would be the best treatment available by the heart team, 
among chronic dialysis patients with symptomatic severe AS. Since the standard therapy of chronic dialysis 
patients with symptomatic severe AS is sAVR, the performance goal (PG) will be set based on the clinical 
research results of sAVR in chronic analysis patients, and non-inferiority of this clinical trial results of 
EWJ-003 to the standard therapy will be verified. 
 
In this clinical trial, patients in whom deployment of the THV by balloon dilatation at a nominal volume 
was impossible for a medical reason during study procedure will be regarded as bailout cases, and these 
cases will be included in the bailout treatment registry at the end of the study procedure. The bailout cases 
will be enrolled separately from the target sample size of this trial, and will not be included in the analysis 
set for the safety and efficacy evaluation of EWJ-003. 
 
In this clinical trial, on humanitarian grounds, subject enrollment will be continued as an continued access 
until EWJ-003 gains marketing approval, so that the subjects will be able to receive EWJ-003 therapy 
continuously even after completion of subject entry into the EWJ-003 analysis set. For the continued access 
registry, see Section 4.4. 
 
 
 
Figure 4-1: Study design of this clinical trial 
Chronic dialysis patients with symptomatic severe AS 
Case study by the heart team 
Not indicated for surgery 
A prospective, open, 
non-randomized, multi-center, 
single arm study 
Application of surgery 
Whether TF approach 
is applicable or not 
Non-Inferiority 
analyses 
Ineligible for the 
clinical trial 
TF approach is 
applicable 
TF approach is not 
applicable 
TF Approach 
TA Approach 
Tao Approach 
Bailout treatment registry 
Continued Access Registry 
Primary endpoint: Mortality at 1 year post-procedure 

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<Rationales for the setting> 
The standard therapy for chronic dialysis patients with symptomatic severe AS is sAVR. Therefore chronic 
dialysis patients deemed medically inappropriate for sAVR have no choice other than palliative 
symptomatic treatment with drug therapy at present. Based on that the clinical positioning of the treatment 
with EWJ-003 where EWJ-003 therapy may make curative therapy not inferior to the standard therapy 
sAVR possible in such chronic dialysis patients who were deemed medically inappropriate for sAVR, this 
clinical trial was designed to verify non-inferiority of EWJ-003 therapy to sAVR. The patients subject to 
EWJ-003 therapy are chronic dialysis patients at a higher surgical risk and cannot tolerate sAVR, and 
compared with patients undergoing sAVR, they have poorer general condition and therefore poor prognosis 
can be predicted. However, according to the report by Kobrin et al.[29] who adjusted patient background by 
propensity score adjustment method and compare the results of TAVI in chronic dialysis patients and the 
results of sAVR, but no statistically significant difference was found in these results, and therefore it was 
determined that for verification of non-inferiority of EWJ-003 therapy to sAVR, the difference may be 
clinically permissible. 
 
Furthermore, since this clinical trial will be conducted in chronic dialysis patients who cannot receive 
sAVR, setting a control group of patients undergoing sAVR for randomized comparison is ethically not 
possible. Therefore, this clinical trial is designed as a single arm of EWJ-003 therapy, and for a control 
sAVR treatment results, PG will be set based on the results of Japanese clinical research reports. 
 
4.2 
Performance Goal 
4.2.1 Rationales for the performance goal setting 
The PG was established by estimating mortality at 1 year post-procedure from the clinical research results 
of sAVR in chronic dialysis patients in Japan. 
 
In the dialysis treatment between Japan and Europe and the US, there are some differences in physique of 
the patients, formulation of dialysis volume and duration of dialysis, patient control, and treatment 
compliance, and it is generally known that prognosis is better in Japan relative to Europe and the US. 
According to a large-scale global observation epidemiologic cohort research on medical care process and 
outcome of patients on maintenance dialysis (Dialysis Outcomes and Practice Patterns Study [DOPPS]), 
when the relative death risk adjusted for age, gender, race, and 15 concomitant diseases in Japan is assumed 
to be 1, it was 3.78 in the US, and 2.84 in Europe[31]. Compared with non-dialysis patients, chronic dialysis 
patients have poorer prognosis after sAVR; it has been reported that the survival rate at 1 year 
post-procedure in the US was approximately 60%, at 3 years post-procedure approximately 40%, and at 5 
years post-procedure approximately 30%,[9, 13] whereas in Japan good long-term results have been reported; 
at 1 year post-procedure 75% to 90%, at 3 years post-procedure 40% to 80%, and at 5 years post-procedure 
30% to 60%.[14, 17, 32-35] Therefore, upon estimating the mortality at 1 year post-procedure in chronic 
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dialysis patients underwent sAVR, the impact of the difference in the medical environment for dialysis 
between Japan and Europe and the US cannot be ignored, and thus the mortality at 1 year post-procedure 
was estimated based on the results of Japanese clinical research. 
 
As shown in Table 4-1, there was no difference in the results of sAVR in chronic dialysis patients by type of 
artificial valve (bioprosthetic or mechanical valve) ,[17, 32] for the setting of PG, regardless of bioprosthetic 
or mechanical, the results of both valves were used. 
 
Table 4-1: 
Comparison of sAVR results in chronic dialysis patients by type of prosthetic valve 
Author 
(year of 
publication/ 
country) 
Valve 
position 
Implantation 
valve 
Treatment results 
30-day mortality 
5-year survival rate *3 
Structural 
valve 
deterioration 
K. Tanaka, et al[32] 
(2009/Japan) 
Aortic 
valve 
Bioprosthetic 
valve (N=22) 1/22 (4.5%)*1 
--- 
55.7 ± 7.6% 
p < 
0.001*4 
0 subjects 
(FU: 42 ± 31 
m) 
Mechanical 
valve (N=51) 4/51 (7.8%)*1 
--- 
S. Fukui, et al[17] 
(2012/Japan) 
Aortic 
valve 
Bioprosthetic 
valve (N=23) 3/23 (13.0%)*2 
p = 0.94 
35.7% 
p = 0.33 
0 subjects 
(FU: 2.3 ± 
4.0 y*5) 
Mechanical valve 
(N=15) 
2/15 (13.3%)*2 
29.2% 
---: No reports 
*1 Hospital death 
*2 Operative mortality (hospital death or death within 30 days post-procedure) 
*3 Kaplan-Meier estimated survival rate 
*4 The respective 5-year survival rate (numerical value) for bioprosthetic valve and mechanical valve were not reported. 
Report by Tanaka et al. suggested that compared with mechanical valve, bioprosthetic valve showed significantly lower 
5-year survival rate, but there was no significant difference in the valve-related event-free rate by type of prosthetic valve 
(p = 0.202). 
*5 Mean follow-up observation period in all subjects (N = 38) 
 
The results of sAVR in Japanese chronic dialysis patients referenced for the PG setting are presented in 
Table 4-2. According to these Japanese clinical research reports, the mortality at 1 year post-procedure 
ranged between 8% and 25.5%. However, since the annual crude mortality of dialysis patients in Japan is 
approximately 10%,[3] based on the report by Azuma et al. and Yamamura et al., 21% to 25.5% were chosen 
for the mortality at 1 year post-procedure, and since the weighted mean was calculated as 24.4%, the 
estimated mortality at 1 year post-procedure was determined to be 25%. 
 
Table 4-2: 
The results of Japanese clinical researches referenced for the PG setting 
Author 
(year of publication) 
Type of prosthetic 
valve 
Number of 
subjects 
30-day 
mortality 
1-year survival 
rate *1 
1-year 
mortality *2 
K. Tanaka, et al[32] 
(2009) 
Bioprosthetic 
valve/Mechanical 
valve 
73 subjects 
Hospital death 
5/73 (6.8%) 
--- 
--- 
S. Fukui, et al[17] 
(2012) 
Bioprosthetic 
valve/Mechanical 
valve 
38 subjects 
Operative death 
5/38 (13.2%) 
--- 
--- 
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S. Azuma, et al[33] 
(2013) 
Bioprosthetic 
valve/Mechanical 
valve 
75 subjects 
Operative death 
5/75 (6.6%) 
74.5% 
25.5% 
Y. Okamoto, et al[34] 
(2013) 
Bioprosthetic 
valve/Mechanical 
valve 
40 subjects 
Hospital death 
2/40 (5%) 
92% 
8% 
N. Okada, et al[14] 
(2015) 
Bioprosthetic 
valve/Mechanical 
valve 
89 subjects 
Hospital death 
6/89 (6.7%) 
--- 
--- 
M. Yamamura, et al[35] 
(2009) 
Bioprosthetic 
valve/Mechanical 
valve 
24 subjects 
Hospital death 
3/24 (12.5%) 
79% 
21% 
---: Not applicable 
*1 Kaplan-Meier estimation 
*2 Calculated from the 1-year survival rate 
 
However, since this clinical trial will be conducted in a group of patients in a poor general condition not 
eligible for sAVR, for PG setting the impact of differences in the patient background on the treatment 
results should be taken into consideration. Then, we compared the patient background in advanced medical 
care with which a group of patients similar to that of this clinical trial underwent TAVI at Osaka University 
Hospital and the patient background in the results of Japanese clinical researches shown in Table 4-3.
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Table 4-3: 
Comparison of patient background 
 
Advanced  
medical care 
The results of Japanese clinical research reports referenced for the PG setting 
K. Tanaka, et al [32] 
S. Fukui, et al [17] 
S. Azuma, et al [33] 
Y. Okamoto, et al [34] 
N. Okada, et al [14] 
M. Yamamura, et al [35] 
Patient 
population 
Chronic dialysis AS 
patients for whom 
sAVR is not indicated 
Chronic dialysis AS patients for whom sAVR is indicated 
Treatment 
procedure 
TAVI 
sAVR 
Number of 
subjects 
24 subjects 
73 subjects 
38 subjects 
75 subjects 
40 subjects 
89 subjects 
76 subjects*1 
(sAVR alone: 24 
subjects) 
Type of 
prosthetic 
valve 
Bioprosthetic valve 
(SAPIEN/SAPIEN 
XT) 
Mechanical valve 51 
patients/Bioprosthetic 
valve 22 patients 
Mechanical valve 23 
patients/Bioprosthetic 
valve 15 patients 
Mechanical valve 40 
patients/Bioprosthetic 
valve 35 patients 
Mechanical valve 33 
patients/Bioprosthetic 
valve 7 patients 
Mechanical valve 50 
patients/Bioprosthetic 
valve 39 patients 
Mechanical valve 14 
patients/Bioprosthetic 
valve 10 patients 
Age (year) 
76.7 ± 5.1 
65.5 ± 8.3 
69.1 ± 9.4 
66.7 ± 8.5 
65.8 ± 8.3 
66 ± 8 
63 ± 11*1 
Proportion of 
male patients 
41.7% 
60.3% 
50% 
70.7% 
77.5% 
67.4% 
60.5%*1 
NYHA Class 
III/IV 
50.0% 
--- 
5.3% 
--- 
85.0% 
--- 
--- 
LVEF (%) 
58.8 ± 11.3 
--- 
--- 
54.2 
53 ± 13 
--- 
--- 
STS score 
(%) 
15.0 ± 10.7 
--- 
--- 
--- 
--- 
--- 
--- 
Length of 
dialysis (year) 
11.8 ± 9.3 
12.0 ± 7.7 
12.2 ± 9.7 
8.1 ± 6.2 
11.2 ± 7.8 
12.0 ± 7.2 
9 ± 9*1 
*1 Including patients who received CABG and mitral valve replacement 
㻌
㻌
 
 

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As shown in Table 4-3, the results of comparison between the group of patients who received sAVR and the 
group of patients treated with TAVI showed a significant difference in the age of patients (sAVR group, < 
70 years; TAVI, 76.7 years), and thus age may be the important factor in determination whether sAVR can 
be applied or not. Then, considering patient’s age as the difference in patient background between the group 
of patients subject to this clinical trial and the patient group treated with sAVR shown in Table 4-2, the 
impact on the mortality at 1 year post-procedure was examined. 
 
Herzog et al. reported that[15] the age of patients was a significant risk factor for long-term death in chronic 
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had a relative risk of 1.18 (95% CI: 1.08, 1.29), ages 65 to 74 had 1.45 (95% CI: 1.31, DQG\HDUV
had 1.72 (95% CI: 1.52, 1.95). Generally the use of mechanical valve is considered for patients < 65 years, 
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aged 45 to 64 for mechanical valve implantation, and 65 to 74 for bioprosthetic valve implantation in the 
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PRUWDOLW\ULVNRISDWLHQWV\HDUVYHUVus patients 45 to 64 years and 65 to 74 years, respectively, was 
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patients 45 to 64 years, and 1.5 times that of patients 65 to 74 years, and the weighted mean considering 
ratio of subjects with mechanical and bioprosthetic valves (211 : 128) in the clinical research reports shown 
in Table 4-2 was calculated as 1.7 times. Therefore, if the same patient group as this clinical trial receives 
sAVR, the mortality at 1 year post-procedure would be 42.5%, 1.7 times 25%, the estimated value from the 
clinical research results shown in Table 4-2, and hence the PG in this clinical trial was set as 45%. 
 
Table 4-4: 
Relative mortality risk by age 
 
Relative mortality risk [15] 
(95% CI) 
Maximum ratio*1 of 
relative mortality risk 
versus ages 45 to 64 
Maximum ratio*1 of 
relative mortality risk 
versus ages 65 to 74 
\HDUV 
1 
45 to 64 years 
1.18 (1.08, 1.29) 
65 to 74 years 
1.45 (1.31, 1.60) 
\HDUV 
1.72 (1.52, 1.95) 
1.8 
1.5 
*1 7KHUDWLRVZHUHFDOFXODWHGXVLQJWKH&,XSSHUOLPLWIRU\HDUVDQGWKH&,ORZHUOLPLWVIRUWR\HDUVDQGto 74 years. 
 
Therefore, when the 95% CI upper limit for the mortality at 1 year post-procedure, the primary endpoint, 
was lower than the PG (45%), non-inferiority of EWJ-003 therapy to the standard therapy would be 
verified, and this clinical trial can be considered as success. 
 
Null hypothesis (H0) and alternative hypothesis (HA) are as follows: 
 
H0: Mortality at 1 year post-SURFHGXUH 
HA: Mortality at 1 year post-procedure < 45% 
 
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4.2.2 Clinical validity of performance goal 
Subjects in this clinical trial are chronic dialysis AS patients at a higher operative risk and deemed to be 
inappropriate for sAVR, and by estimating the mortality at 1 year post-procedure based on the clinical 
research results, assuming that the same subjects receive sAVR, the PG in this clinical trial was set as 45%. 
However, the existing treatment for these patients is drug therapy or percutaneous balloon aortic 
valvuloplasty, and for evaluation of the safety and efficacy of TAVI, the study treatment, it is required that 
the PG is clinically acceptable even in light of the drug therapy results. 
 
Cohort B in PARTNER-US study in non-dialysis patients deemed inappropriate for sAVR showed the 
mortality at 1 year post-treatment of 50.2% for 181 subjects in the drug therapy group. However, in 
PREVAIL-JAPAN study conducted in the similar patient group, compared with the drug therapy group in 
PARTNER-US study, lower baseline STS score was shown (PARTNER-US study, 11.85 ± 4.86; 
PREVAIL-JAPAN study, TF group 7.79 ± 3.43, TA group 10.55 ± 5.28), with a difference in patient 
background. Then, in order to estimate the mortality at 1 year after drug therapy in Japanese non-dialysis 
patients, a patient group equivalent to the interquartile range of STS score (5.35 to 11.475) in 
PREVAIL-JAPAN study (Japanese subset) was extracted from the drug therapy group of PARTNER-US 
study, and was analyzed. As a result, as shown in Table 4-5, the Kaplan-Meier estimate mortality at 1 year 
post-procedure in the Japanese subset of 51.2% exceeded the PG of this clinical trial (45%). 
 
Table 4-5: 
Kaplan-Meier estimate mortality at 1 year post-procedure in the Japanese subset 
Mortality at 1 year post-procedure 
Number of 
subjects 
Number of 
events 
Kaplan Meier 
estimate mortality 
Kaplan Meier SE 
PARTNER-US study Cohort B 
Drug therapy Japanese subset 
69 
35 
51.2% 
6.1% 
 
As for reports in Japan, Ohno et al. reported that 26 Japanese AS patients who received drug therapy 
(including 2 dialysis patients) showed the mortality at 1 year post-treatment of 53.1%[36]. That was nearly 
consistent with the above-mentioned PARTNER-US study results, and the mortality at 1 year post-drug 
therapy in Japanese non-dialysis patients was estimated as approximately 50%. Ohara et al. reported that 12 
out of 16 Japanese chronic dialysis AS patients (75%) died during mean follow-up period of 32 ± 17 
months,[10] and considering that among 16 patients only 2 patients received sAVR, the mortality in 14 
patients who received drug therapy may be at least 71.4% (10/14). This was similar to 3-year mortality 
(70.7%) in 26 AS patients (including 2 dialysis patients) reported by Ohno et al., but the mean age of 
patients 68 ± 10 years was significantly lower than that reported by Ohno et al. (mean age 84.1 ± 5.3 years). 
In addition, considering that the mean patient age in the advanced medical care given at Osaka University 
Hospital was 76.7 ± 5.1 years, the prognosis in the drug therapy group assumed for this clinical trial can be 
predicted as poorer than that reported by Ohara et al., and the 1-year mortality may be over 50%. 
 
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Therefore, for evaluation of the safety and efficacy of TAVI in chronic dialysis AS patients deemed 
inappropriate for sAVR, the setting PG of 45% was determined to be clinically acceptable even in light of 
the drug therapy results. 
 
Table 4-6: 
Results of drug therapy in patients with AS 
 
PARTNER-US study Cohort B drug therapy 
group 
M. Ohno, et al.[36] 
T. Ohara, et al.[10] 
Overall 
Japanese subset 
Country 
US 
Japan 
Japan 
Subjects 
Non-dialysis AS patients for whom sAVR is 
not indicated 
AS patients who refused 
sAVR or for whom sAVR 
is not indicated 
(including 2 dialysis 
patients) 
Dialysis AS patients 
Number of 
subjects 
181 subjects 
69 subjects 
26 subjects 
14 subjects 
1-year mortality 
50.2% 
51.2% 
53.1% 
N/A 
3-year mortality 
80.9% 
N/A 
70.7% 
71.4% (10/14)-85.7% (12/14) 
(Mean duration of FU period: 
32 ± 17 months) 
 
4.3 
Target Sample Size 
This clinical trial aims at enrollment of 30 subjects in total. At least 2 subjects for each approach, and at 
least 1 subject for each size should be enrolled, so that the safety and efficacy for the TF, TA, and TAo 
approaches and all THV sizes (20, 23, 26, and 29 mm) could be evaluated. Enrollment will be closed when 
the number of patients enrolled in the study reaches the target sample size even when the above-mentioned 
number of patients are not ensured. Additional subjects will not be included for discontinued subjects. 
 
Table 4-7: 
Target Sample Size 
Target sample size by approach 
Target Sample Size 
Transfemoral approach 
VXEMHFWV 
A total of 30 subjects 
Transapical approach  
VXEMHFWV 
Transaortic approach  
VXEMHFWV 
Target sample size by valve size 
20 mm 
VXEMHFW 
23 mm 
VXEMHFW 
26 mm 
VXEMHFW 
29 mm 
VXEMHFW 
 
<Rationales for the setting> 
The sample size for this clinical trial was calculated based on the number of subjects required to verify 
noninferiority of the study treatment to the standard therapy by comparing the primary endpoint of 
all-cause mortality at 1 year post-procedure with the PG. Based on the results of the advanced medical care 
given in Osaka University Hospital, PREVAIL-JAPAN study, and SAPIEN XT post-marketing surveillance, 
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the predicted mortality at 1 year post-procedure (true value) in this clinical trial was set as 20%. As 
previously mentioned, the PG was set as 45%, and the number of subjects required to reject the null 
hypothesis (H0: Mortality at 1 year post-SURFHGXUHLVZLWKRQH-sided D = 0.05 was calculated as 24 
subjects. A sample size of 24 subjects will provide 81.1% power by one-sided Fisher’s exact test. To 
account for the drop-out, a total of 30 subjects was determined for the target sample size for this trial. The 
sample size was computed using PASS 11 software. 
 
x 
PG = 45% 
x 
Predicted mortality at 1 year post-procedure (true value) = 20% 
x 
H0: Mortality at 1 year post-SURFHGXUH 
x 
HA: Mortality at 1 year post-procedure < 45% 
x 
One-sided Fisher’s exact test. 
x 
Level of significance D = 0.05 
 
Rationale for the setting of predicted mortality at 1 year post-procedure (true value) 
The mortality at 1 year post-procedure was 10.7% in the advanced medical care given at Osaka University 
Hospital. However, this result was observed in a single medical institution, and since the mortality at 1 year 
post-procedure in PREVAIL-JAPAN study conducted in non-chronic dialysis AS patients and SAPIEN XT 
post-marketing surveillance was 14.9% and 11.3%, respectively, the predicted mortality at 1 year 
post-procedure (true value) in this clinical trial should be estimated higher than these results. Therefore, 
maximum mortality at 1 year post-procedure in chronic dialysis patients was assumed from the results of 
PREVAIL JAPAN study and SAPIEN XT post-marketing surveillance. The weighted mean mortality of 
11.7% was calculated for the results of PREVAIL JAPAN study and SAPIEN XT post-marketing 
surveillance. Kobrin et al.[29] reported that the hazard ratio of medium-term mortality by dialysis was 1.7, 
with the 95% CI upper limit of 2.3. Although there is a medical environmental difference for dialysis 
patients between in and out of Japan, the reported mean follow-up duration was 6.2 months (IQR: 2.8 to 
10.8), and the impact of medical environmental difference may be small during this follow-up period. Then, 
assuming the maximum mortality at 1 year post-procedure of 26.9%, equivalent to 2.3 times 11.7%, the 
mortality at 1 year post-procedure in this clinical trial was estimated as between 10.7% and 26.9%. Since 
the median is determined to be 18.8%, the predicted mortality at 1 year post-procedure (true value) in this 
clinical trial was set as 20%. 
 

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Table 4-8: 
TAVI treatment results at 1 year post-procedure 
 
Advanced medical care 
PREVAIL JAPAN study Post-marketing surveillance 
Subjects 
Chronic dialysis AS 
patients for whom sAVR is 
not indicated 
Chronic dialysis AS patients for whom sAVR is not 
indicated 
Device used 
SAPIEN/SAPIEN XT 
SAPIEN XT 
Number of subjects 
24 subjects 
64 subjects 
594 subjects 
Survival rate at 1 year 
post-procedure*1 
89.3% 
85.1% 
88.7% 
Mortality at 1 year 
post-procedure*2 
10.7% 
14.9% 
11.3% 
Weighted mean 
11.7% 
The hazard ratio*3 of medium-term mortality by dialysis 
was taken into consideration 
26.9% 
*1 Kaplan-Meier estimation 
*2 Calculated from the 1-year survival rate 
*3 The hazard ratio of medium-term mortality by dialysis 1.7 (95% CI: 1.3, 2.3)㻌
㻌
When the PG was established in this clinical trial, the mortality at 1 year after sAVR in Japanese chronic 
dialysis patients was estimated as 25%, and considering that the mortality at 1 year post-procedure in 
Europe and the US is approximately 40%, when the mortality in Japanese patients is counted as 1, the 
relative mortality risk is 1.6 for Europe and the US. If this ratio is applied to the mortality at 1 year after 
TAVI, the predicted mortality in this clinical trial (true value) of 20% versus 32% in Europe and the US can 
be determined, which was compared favorably with the results in Europe and the US as shown in Table 4-9. 
Therefore, setting the predicted mortality at 1 year post-procedure (true value) in this clinical trial as 20% is 
determined to be clinically valid. 
 
Table 4-9: 
Results of TAVI in chronic dialysis patients 
Author 
(year of 
publication/country) 
Device 
Number 
of 
subjects 
Mortality 
30 days 
post-procedure 
6 months 
post-procedure 
1 year 
post-procedure 
Advanced medical care 
SAPIEN/SAPIEN 
XT 
24 
subjects 
0% 
4.3% 
10.7% 
M. Szerlip, et al[37] 
(2016/US) 
SAPIEN 
43 
subjects 
14.0% 
25.6% 
--- 
D.M. Kobrin, et al[29] 
(2015/US) 
--- 
224 
subjects 
13% 
--- 
42.6% 
Y. Ohno[38] 
(2015/Italy) 
CoreValve/ 
SAPIEN XT 
44 
subjects 
9.1% 
--- 
34.1% 
N. Dumonteil, et al[24] 
(2013/Europe) 
CoreValve/33 
subjects 
SAPIEN 
33 
subjects 
15.2% 
--- 
45.2% 
S. Rau, et al[28] 
(2011/Germany) 
CoreValve 
10 
subjects 
0% 
20% 
--- 
---: No reports 
 
Rationale for the setting of registered number of subjects by approach 
Based on the percentage of TF approach (approximately 40%) in the advanced medical care with TAVI 
given to chronic dialysis patients and the ratio of TA/TAo approaches of 2 : 1 in PARTNER II study, the 
ratio of TF, TA, and TAo approaches in this clinical trial was predicted to be 2 : 2 : 1. In comparison with 
this ratio, the enrollment of approximately 5 to 6 patients may be expected for TF approach; however, when 
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subjects are limited to chronic dialysis patients, literatures[24, 37] suggested that the ratio of TAo approach 
versus TA approach may be lower than the predicted ratio. In SAPIEN XT post-marketing surveillance 
currently underway in Japan, approximately 30% of the registered 134 subjects treated with TA approach 
were reported advanced calcification in the aorta. Such patients are not recommended to be treated with 
TAo approach. Since in chronic dialysis patients a higher morbidity may be expected due to abnormal 
calcium metabolism, etc., only limited number of patients may be treated with TAo approach in this clinical 
trial. Therefore, setting the number of subjects for each approach as at least 2 subjects was determined to be 
valid from the stand point of feasibility. 
The manufacturer standard for introducing CoreValve[39] for which TAo approach has been already 
introduced in Japan, specifies at least 2 subjects for subclavian artery/direct TAo approaches, and therefore 
enrollment of at least 2 subjects in this clinical trial may also verify to have no technological concern in 
THV implantation by TAo approach. The safety of TAo approach may be comparable to that of TA also in 
chronic dialysis patients similarly to non-chronic dialysis patients, and therefore it was determined that a 
small number of subjects could verify that there is no safety concern requiring new risk evaluation in 
chronic dialysis patients. Therefore, also to verify the efficacy and safety of TAo approach, which was not 
included in the advanced medical care, in chronic dialysis patients, it was determined that setting the 
number of subjects as at least 2 subjects may be acceptable. 
 
Rationale for the setting of registered number of subjects by THV size 
Based on the results of SAPIEN XT post-marketing surveillance, distribution of THV in this clinical trial 
was predicted as 20 mm : 23 mm: 26 mm : 29 mm = 1 : 14 : 9 : 2. In comparison with this predicted ratio, 
about 1 to 2 subjects are expected to be registered for 20 mm. Therefore, setting the number of subjects for 
each size as at least 1 subject was determined to be valid from the stand point of feasibility. 
 
4.4 
Continued Access Registry 
During a time period from the end of subject entry into the EWJ-003 analysis set until acquisition of 
marketing approval of the study device (EWJ-003), up to a maximum of 50 dialysis patients with severe AS 
requiring treatment with EWJ-003 (a maximum of 25 subjects per study site) will be included into the 
continued access registry. Patients eligible for this registry must be verified that they meet all inclusion 
criteria for the continued access registry and do not fall under any of the exclusion criteria. The duration of 
post-procedural follow-up observation will be for 5 years post-procedure similarly to that for the EWJ-003 
analysis set and bailout treatment registry, and tests/observations required for the continued access registry 
will be performed. Subjects enrolled in this registry will not be included in the analysis set for the safety 
and efficacy evaluation of EWJ-003. For the inclusion and exclusion criteria for the continued access 
registry, see Sections 5.2.3 and 5.2.4, and for test/observation items, see Section 10.3. 
 
Protocol 
 
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Figure 4-2: Clinical trial flow for continued access registry 
 
<Rationales for the setting> 
Once clinical symptoms, such as angina pectoris, syncope, or heart failure, manifest, the prognosis of AS is 
poor; the mean life expectancy of 5 years after onset of angina pectoris, 3 years after syncope, and 2 years 
after heart failure.[1] Furthermore, AS progresses approximately twice faster in chronic dialysis patients 
compared with non-dialysis patients, [6, 10] and therefore chronic dialysis patients with symptomatic severe 
AS should be treated as soon as possible. However, chronic dialysis patients not subject to sAVR have no 
choice other than palliative symptomatic treatment with drug therapy at present, because no other effective 
treatments are available. Therefore, on humanitarian grounds, it is required that even after completion of 
subject enrollment in the EWJ-003 analysis set, treatment with EWJ-003 should be continued in chronic 
dialysis patients. To date no concerned events from the safety and efficacy standpoints have been observed 
in this clinical trial, and hence it was determined that there is no problem in conducting the continued 
access registry and continuously providing EWJ-003 to chronic dialysis patients. 
 
5 
SELECTION OF SUBJECTS 
5.1 
Subjects 
Subjects in this clinical trial are chronic dialysis patients with symptomatic severe AS associated with 
sclerosis of the native cusp of aortic valve, who are determined to be unable to undergo safe open surgical 
therapy, and judged EWJ-003 is the best available treatment. 
 
5.2 
Screening 
The principal investigator or subinvestigators will give an explanation about this clinical trial to a subject, 
Informed consent to the continued access 
registry
Screening
(Inclusion/exclusion criteria for continued access 
registry)
Registration to the continued 
access registry 
 (a maximum of 50 subjects)
Study procedure
Follow-up until at 5 years post-procedure
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obtain written informed consent, and check the subject’s eligibility for participation in the trial. Patients 
eligible for this clinical trial must be verified that they meet all inclusion criteria and do not fall under any 
of the exclusion criteria. 
 
Each study conducting medical institution must create and maintain subject enrolment log. 
5.2.1 Inclusion criteria 
Candidates for this study must meet all of the following inclusion criteria: 
 
(1) 
Patients determined by the heart team to be unable to undergo safe open surgical therapy, and judged 
EWJ-003 is the best available treatment. Specifically, considering the followings as risk factors, the 
risk should be comprehensively determined. 
• 
Porcelain aorta㻌
• 
History of mediastinal radiotherapy㻌
• 
History of mediastinitis㻌
• 
Remarkable thoracic deformity㻌
• 
Previous open heart surgery or coronary-artery bypass grafting㻌
• 
Chronic obstructive pulmonary disease
(2) 
Patient has senile degenerative AS with one of the following echocardiographic criteria. 
Measurement of aortic valve area (AVA) at baseline must be acquired within 60 days prior to the 
study procedure. 
a. 
0HDQSUHVVXUHJUDGLHQWPP+J 
b. 
$RUWLFIORZYHORFLW\PV 
c. 
$9$DWEDVHOLQHFP2 
d. 
$9$LQGH[0.6 cm2/m2 
(3) 
3DWLHQWKDVV\PSWRPVDVVRFLDWHGZLWK$61<+$FODVV,, 
(4) 
The subject has been informed of the nature of the study, agrees to its provisions and has provided 
written informed consent as approved by the Institutional Review Board (IRB) of the respective 
clinical sites. 
(5) 
The subject and the investigator agreed to comply with all required post-procedural follow-up visits. 
(6) 
3DWLHQWKDVEHHQRQGLDO\VLVKHPRGLDO\VLVRUSHULWRQHDOGLDO\VLVLQVWDEOHFRQGLWLRQIRUPRQWKV 
(7) 
Patient has any one of the following native aortic valve annulus sizes as measured by 
transesophageal echocardiography (TEE) or 3D- computed tomography (CT). 
a. 
1DWLYHDQQXOXVVL]HPPDQGPPE\7(( 
b. 
1DWLYHDQQXOXVDUHDPP2 DQGPP2 by 3D-CT 
c. 
Area-GHULYHGGLDPHWHUPPDQGPPE\'-CT 
(8) 
Patient is verified by the Case Review Process that the treatment with EWJ-003 is appropriate for the 
patient. 

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<Rationales for the setting> 
The inclusion criteria for this clinical trial were set up in reference to the inclusion criteria for a US clinical 
study of the study device PARTNER II study, Japanese clinical studies of previous generation SAPIEN XT 
PREVAIL JAPAN study (EW-P-001) and PREVAIL-20 JAPAN study (EW-P-002), and advanced medical 
care that evaluated TAVI with SAPIEN and SAPIEN XT in chronic dialysis patients. The rationales for the 
setting of individual inclusion criteria are as shown in the followings: 
 
(1) Set up based on the current indications for EWJ-003 in Japan. 
(2) As the diagnostic criteria for severe AS for which EWJ-003 therapy is indicated, set up based on the 
American College of Cardiology (ACC)/American Heart Association (AHA) guideline[20] and 
Japanese Guidelines for Surgical and Interventional Treatment of Valvular Heart Disease.[12] 
(3) Since the ACC/AHA guideline[20] and Japanese Guidelines for Surgical and Interventional 
Treatment of Valvular Heart Disease[12] recommend aortic valve replacement for patients with 
symptomatic severe AS, similarly to the past clinical trials, symptomatic was defined as NYHA 
Class II and over. 
(4) Set up to ensure human rights of subjects. 
(5) Set up to ensure the quality of trial. 
(6) Guidelines for Clinical Evaluation of Therapeutic Drugs for Renal Anemia issued on September 30, 
2011[40] (Notification No.0930-2 of the Evaluation and Licensing Division, PFSB) recommend that 
patients who have past at least 3 months after introduction of dialysis and in a stable condition be 
included in clinical trials. In order to avoid difficulty in data interpretation for evaluation of the 
safety and efficacy of EWJ-003 therapy in chronic dialysis patients, also this clinical trial will 
include dialysis patients who have past at least 3 months after introduction of dialysis and in a 
stable condition. In addition, the recommendations for valvular disease surgery in dialysis patients 
in Guidelines for Surgical and Interventional Treatment of Valvular Heart Disease[12] do not classify 
the type of dialysis (hemodialysis or peritoneal dialysis), and based on the reports that there was no 
difference in the mortality at 1 year post-procedure between hemodialysis patients and peritoneal 
dialysis patients[41] and that both hemodialysis and peritoneal dialysis could be adequately managed 
for periprocedural control,[42] both hemodialysis and peritoneal dialysis patients could be included. 
(7) Set up based on the applicable aortic annulus size of EWJ-003. 
(8) Set up because upon inclusion in this clinical trial a patient should be verified by the Case Review 
Process that the treatment with EWJ-003 is appropriate for the patient. 
 
5.2.2 Exclusion criteria 
Candidates for this clinical trial must not fall under any one of the following exclusion criteria: 
 
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(1) 
Patient has an evidence of an acute MI within 1 month (30 days) prior to the study procedure. Acute 
MI is defined as; Q wave MI, or non-Q-wave MI with elevation of creatine kinase MB isoenzyme 
(CK-MB) or troponin, together with the evidence of myocardial ischemia with at least one of the 
following findings: 
• 
Symptoms of ischemia 
• 
Electrocardiogram (ECG) changes indicative of new ischemia (ST-T changes, left 
bundle-branch block [LBBB]) 
• 
Imaging evidence of a new loss of viable myocardium or new wall motion abnormality. 
(2) 
Patient has a congenital unicuspid or bicuspid. Or patient has a non-calcified aortic valve. 
(3) 
Patient has severe aortic valve incompetence. 
(4) 
Patient has severe mitral valve incompetence. 
(5) 
Patient has an evidence of any therapeutic invasive cardiac procedures within 30 days prior to the 
study procedure. However, implantation of a permanent pacemaker or balloon valvuloplasty for 
bridging to procedure after a qualifying echocardiography are excluded. 
(6) 
Patient with planned concomitant surgical or transcatheter ablation for atrial fibrillation. 
(7) 
Patient has pre-existing prosthetic valve in any position. 
(8) 
Patient is at a high risk of bleeding, difficult to have appropriate treatment, or unable to receive 
appropriate anticoagulation or antiplatelet therapy. 
• 
Leukopenia (white blood cell < 3,000 cells/mm3) 
• 
Thrombocytopenia (platelet < 50,000 cells/mm3) 
• 
Bleeding diathesis or coagulopathy 
• 
Active gastro-intestinal ulceration, or upper gastro-intestinal bleeding within the past 3 
months 
• 
Refuse blood transfusion 
• 
Receiving anticoagulant and/or antiplatelet medication and can’t stop them for the study 
procedure 
• 
Concluded by investigator that appropriate anticoagulation or antiplatelet therapy is difficult 
for any other reasons 
(9) 
Patient has untreated clinically significant coronary artery disease requiring revascularization.㻌
(10) Patient has hemodynamic instability requiring inotropic support or mechanical heart assistance. 
Patient has respiratory instability requiring mechanical ventilation. 
(11) Patient requires an emergency surgery for any reason. 
(12) Patient has hypertrophic cardiomyopathy with or without obstruction. 
(13) Patient has severe ventricular dysfunction with left ventricular ejection fraction (LVEF) < 20%. 
(14) Patient has echocardiographic evidence of intracardiac mass, thrombus, or vegetation. 
(15) Patient has hypersensitivity to or a known contraindication of heparin and/or aspirin, which cannot 
be adequately pre-medicated. Patient has a known hypersensitivity to contrast media. 
(16) Patient has hypersensitivities to cobalt, chromium, nickel, molybdenum, titanium, manganese, 
Protocol 
 
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silicon, or polymeric materials. 
(17) Patient has had a cerebrovascular accident or transient ischemic attack within 6 months prior to the 
study procedure. Except cases with an event associated with AS. 
(18) Patient with poorly controlled blood pressure. 
(19) Patient has serum albumin < 3.0 g/dL or body mass index (BMI) < 18. 
(20) Patient has uncontrollable diabetes mellitus. 
(21) Patient has active bacterial endocarditis or other active infection. 
(22) Patient has life expectancy < 12 months due to pre-operative non-cardiac comorbidity (e.g., cancer, 
chronic liver disease). 
(23) Currently participating in an investigational drug or another device study. [Note: Trials requiring 
extended follow-up for products that were investigational, but have since become commercially 
available, are not considered investigational trials.] 
(24) Cardiovascular surgeons and cardiologists concluded that the patient is inappropriate for 
participating in this trial. 
 
< TF approach> 
(25) Patient has significant tortuous aorta, diseases including abdominal aortic or thoracic aneurysm, or 
significant atheroma in the femoral artery or iliac artery that would prevent from proper placement 
of delivery system. 
(26) Patient has iliofemoral vessel characteristics that would preclude safe placement of 14F or 16F 
introducer sheath such as severe obstructive calcification and severe tortuosity, or minimum average 
vessel size less than 5.5 mm (6.0 mm for 16F introducer sheath). 
 
<Rationales for the setting> 
The exclusion criteria for this clinical trial were set up in reference to the inclusion criteria for a US clinical 
study of the study device PARTNER II study, Japanese clinical studies of previous generation SAPIEN XT 
PREVAIL JAPAN study (EW-P-001) and PREVAIL-20 JAPAN study (EW-P-002), and advanced medical 
care that evaluated TAVI with SAPIEN and SAPIEN XT in chronic dialysis patients. The rationales for the 
setting of individual exclusion criteria are as shown in the followings: 
 
(1) 
The infarction site after onset of MI is vulnerable due to necrosis, and it is difficult to tolerate 
increased cardiac stress, which may induce myocardial rupture or papillary muscle rupture. 
Therefore, considering the safety and the impact of higher incidence of serious adverse events 
(SAEs) on evaluation of the study device, these patients were excluded. 
(2) 
Since patients with congenital unicuspid or bicuspid may have a theoretical risk of paravalvular 
regurgitation and expansion failure of the device, these patients were excluded. Patients with no 
calcification were also excluded, as the THV may not be properly fixated. 
(3) 
AS patients complicated with severe aortic valve incompetence are expected to have very poor 
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Jaunuary 6, 2020 
 
- 55 - 
morbidity of the cusp and with significant calcification, leading to difficulty in predilatation and 
THV implantation. 
(4) 
Disruption of blood flow may occur in patients complicated with severe mitral valve incompetence 
due to released AS by the study procedure. 
(5) 
Excluded because of the possible impact on proper evaluation of the study device. If pacemaker 
implantation, and balloon aortic valvuloplasty was performed as a role of bridging before the study 
procedure, the patient could be included in this clinical trial. However, since the mortality risk 
after treatment with an implantable cardioverter defibrillator in chronic dialysis patients is 
significantly high,[43] patients with implantable cardioverter defibrillator were excluded. 
(6) 
When surgery for atrial fibrillation is simultaneously given, interpretation of data may be difficult 
and that affects proper evaluation of the study device. In addition, it has been reported that 
concomitant procedure with sAVR in chronic dialysis patients was a significant risk factor for 
periprocedural death[44], and it was suggested that also in the treatment with EWJ-003 concomitant 
procedure may be a risk factor for outcome of death. Therefore, from the endurance and safety 
standpoints, concomitant procedure was excluded. Patients with scheduled coronary 
revascularization at the same time were excluded by the exclusion criterion (9). 
(7) 
Excluded because of the possible impact on proper evaluation of the study device. 
(8) 
Excluded because of a higher bleeding risk, and bleeding may become severer due to the use of 
anticoagulant/anti-platelet drug, and some cases it may lead to death. 
(9) 
If severe coronary artery stenosis coexists, left ventricular myocardial ischemia may widespread 
during the procedure, which may lead to cardiogenic shock, severe arrhythmia, and cardiac arrest. 
If coronary revascularization is concomitantly or perioperatively performed, which may lead to a 
risk of significant complication. This risk may affect proper evaluation of the study device. 
(10) In patients who have hemodynamic instability requiring catecholamine inotropic agents including 
dobutamine and dopamine or mechanical heart assistance, it is difficult to implant the THV. In 
addition, patients who have respiratory instability requiring ventilator have a higher risk of 
intraoperative/post-operative complication, and hence these patients were excluded from the 
standpoint of safety. 
(11) Excluded from the safety standpoint, because of a high probability of incidence of SAEs. 
(12) Improvement by implantation of the study device cannot be expected in patients with hypertrophic 
cardiomyopathy. 
(13) In patients with significantly impaired left ventricular function, often the left ventricular 
myocardium has an irreversible change, and even after implantation of the study device it will be 
difficult to evaluate hemodynamics appropriately. In addition, likely to cause periprocedural death, 
and excluded from the endurance and safety standpoints. 
(14) It may be released during operations in the heart, causing embolism. 
(15) Patients intolerance to the anticoagulant/antiplatelet drugs that are recommended in this clinical 
trial, and patients who have a known hypersensitivity to contrast agents are generally 

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contraindicated for TAVI. 
(16) Patient has a known hypersensitivity to the components of the study device were excluded. 
(17) Patients who have a neurological event are deemed unable to be evaluated properly for the study 
device. 
(18) Guidelines for treatment of hypertension by The Japanese Society of Hypertension[45] classify 
dialysis patients in the high risk group. Since it has been reported that sudden hypotension 
V\VWROLF SUHVVXUH   PP+J DQG RUWKRVWDWLF K\SRWHQVLRQ DIWHU GLDO\VLV FRUUHODWH ZLWK SRRU
prognosis[46], patients complicated with abnormal blood pressure that cannot be appropriately 
controlled were excluded. 
(19) It is known that hypoalbuminemia in dialysis patients is a factor for difficulty in maintenance of 
blood pressure[47], and it has been reported that hemodialysis patients with serum albumin < 3.0 
JG/ FRPSDUHG ZLWK WKRVH ZLWK   JG/ KDYH D VLJQLILFDQWO\ KLJKHU PRUWDOLW\ ULVN.[48] In 
addition, it has been reported that long-term malnutrition can be suggested in patients with 
BMI < 18, and low BMI in dialysis patients after sAVR can be a significant risk factor for 
long-term death.[49] Also 2012 Critical limb ischemia field review WG report[50] recommends that 
if dialysis patients complicated with critical limb ischemia are included in a clinical trial for 
evaluation of the safety and efficacy of medical devices for revascularization of critical limb 
ischemia, maintenance dialysis patients with hypoalbuminemia (< 3.0 g/dL) or low BMI (< 18) be 
excluded. 
(20) It was reported that diabetic nephropathy is a significant risk factor for long-term mortality in 
sAVR in chronic dialysis patients,[15] suggesting that also in the treatment with EWJ-003 diabetic 
complication may be a risk factor for outcome of death. On the other hand, since it has been 
reported that good glycemic control correlates with prognosis of dialysis patients complicated with 
diabetes mellitus, especially reduced cardiovascular mortality,[51] patients complicated with poorly 
controlled blood glucose diabetes were excluded from this clinical trial. 
(21) These patients are at a higher risk of post-procedural adverse events (AEs) including sepsis, and 
dialysis patients are susceptible to infections, and therefore considering the safety they were 
excluded. 
(22) The patient is more likely to discontinue the clinical trial prior to completion of long-term 
follow-up observation. 
(23) Involvement in other clinical trial may affect evaluation of the study device in this clinical trial. 
(24) This was set up to include a group of patients with appropriate background in this clinical trial 
after considering risks versus benefits of treatment with EWJ-003. 
(25) It is difficult to deliver the THV, and patients with concurrent aneurysm are at a very high risk of 
aneurysm rupture. 
(26) When the THV is implanted via TF approach, 14F or 16F introducer sheath should be used, and 
therefore patients with difficulty in safe implantation of sheath were excluded. 
 
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5.2.3 Inclusion criteria for continued access registry 
Candidates for the continued access registry must meet all of the following inclusion criteria: 
 
(1) Patients determined by the heart team to be unable to undergo safe open surgical therapy, and judged 
EWJ-003 is the best available treatment. Specifically, considering the followings as risk factors, the 
risk should be comprehensively determined. 
• 
Porcelain aorta㻌
• 
History of mediastinal radiotherapy㻌
• 
History of mediastinitis㻌
• 
Remarkable thoracic deformity㻌
• 
Previous open heart surgery or coronary-artery bypass grafting㻌
• 
Chronic obstructive pulmonary disease
(2) Patient has senile degenerative AS with one of the following echocardiographic criteria. Measurement 
of AVA at baseline must be acquired within 60 days prior to the study procedure. 
a. 
0HDQSUHVVXUHJUDGLHQWPP+J 
b. 
$RUWLFIORZYHORFLW\PV 
c. 
$9$DWEDVHOLQHFP2 
d. 
$9$LQGH[FP2/m2 
(3) 3DWLHQWKDVV\PSWRPVDVVRFLDWHGZLWK$61<+$FODVV,, 
(4) The subject has been informed of the nature of the study, agrees to its provisions and has provided 
written informed consent as approved by the IRB of the respective clinical sites. 
(5) The subject and the investigator agreed to comply with all required post-procedural follow-up visits. 
(6) Patient on maintenance dialysis (hemodialysis or peritoneal dialysis). 
(7) Patient has any one of the following native aortic valve annulus sizes as measured by TEE or 3D-CT. 
a. 
1DWLYHDQQXOXVVL]HPPDQGPPE\7(( 
b. 
1DWLYHDQQXOXVDUHD 273 mm2 DQGPP2 by 3D-CT 
c. 
Area-GHULYHGGLDPHWHUPPDQGPPE\'-CT 
 
Protocol 
 
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Jaunuary 6, 2020 
 
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<Rationales for the setting> 
For patients deemed possible for safe treatment with EWJ-003, but do not meet all of the inclusion criteria 
described in Section 5.2.1, and therefore no chance of treatment, to make it possible to receive treatment 
with EWJ-003 on humanitarian grounds, for the continued access registry, the following changes were 
made to the inclusion criteria described in Section 5.2.1. 
 
Table 5-1: 
Changes made to inclusion criteria 
Inclusion criteria described in 
Section 5.2.1 
Inclusion criteria for continued 
access registry 
Reason for change 
(6) Patient has been on dialysis 
(hemodialysis or peritoneal 
dialysis) in stable condition for 
PRQWKV. 
(6) Patient on maintenance dialysis 
(hemodialysis or peritoneal 
dialysis). 
Based on the Guidelines for Clinical 
Evaluation of Therapeutic Drugs for Renal 
Anemia,[40] unstable patients at early stage of 
dialysis were excluded for appropriate 
evaluation of the safety and efficacy of 
EWJ-003. However, the continued access 
registry is not aiming at evaluation of the 
efficacy and safety of EWJ-003, and therefore 
not limiting a history of dialysis, and whether 
or not the patient can be treated with EWJ-003 
can be determined taking individual patient’s 
condition and safety into consideration, this 
change was made. 
(8) Patient is verified by the Case 
Review Process that the 
treatment with EWJ-003 is 
appropriate for the patient. 
(Deleted) 
Because in the continued access registry case 
review is not mandatory, this criterion was 
deleted. 
 
5.2.4 Exclusion criteria for continued access registry 
Candidates for the continued access must not fall under any one of the following exclusion criteria: 
 
(1) Patient has an evidence of an acute MI within 1 month (30 days) prior to the study procedure. Acute 
MI is defined as; Q wave MI, or non-Q-wave MI with elevation of CK-MB or troponin, together with 
the evidence of myocardial ischemia with at least one of the following findings: 
• 
Symptoms of ischemia 
• 
ECG changes indicative of new ischemia (ST-T changes, LBBB) 
• 
Imaging evidence of a new loss of viable myocardium or new wall motion abnormality. 
(2) Patient has a congenital unicuspid or bicuspid. Or patient has a non-calcified aortic valve. 
(3) Patient has severe aortic valve incompetence. 
(4) Patient has severe mitral valve incompetence. 
(5) Patient has an evidence of any therapeutic invasive cardiac procedures within 30 days prior to the study 
procedure. However, implantation of a permanent pacemaker or balloon valvuloplasty for bridging to 
procedure after a qualifying echocardiography are excluded. 
(6) Patient with planned concomitant surgical or transcatheter ablation for atrial fibrillation. 
(7) Patient has pre-existing prosthetic valve in any position. 
 
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(8) Patient is at a high risk of bleeding, difficult to have appropriate treatment, or unable to receive 
appropriate anticoagulation or antiplatelet therapy. 
• 
Leukopenia (white blood cell < 3,000 cells/mm3) 
• 
Thrombocytopenia (platelet < 50,000 cells/mm3) 
• 
Bleeding diathesis or coagulopathy 
• 
Active gastro-intestinal ulceration, or upper gastro-intestinal bleeding within the past 3 
months 
• 
Refuse blood transfusion 
• 
Receiving anticoagulant and/or antiplatelet medication and can’t stop them for the study 
procedure 
• 
Concluded by investigator that appropriate anticoagulation or antiplatelet therapy is difficult 
for any other reasons 
(9) Patient has untreated clinically significant coronary artery disease requiring revascularization.㻌
(10) Patient has hemodynamic instability requiring mechanical heart assistance. Patient has respiratory 
instability requiring mechanical ventilation. 
(11) Patient requires an emergency surgery for any reason. 
(12) Patient has hypertrophic cardiomyopathy with or without obstruction. 
(13) Patient has severe ventricular dysfunction with LVEF < 20%. 
(14) Patient has echocardiographic evidence of intracardiac mass, thrombus, or vegetation. 
(15) Patient has hypersensitivity to or a known contraindication of heparin and/or aspirin, which cannot be 
adequately pre-medicated. Patient has a known hypersensitivity to contrast media. 
(16) Patient has hypersensitivities to cobalt, chromium, nickel, molybdenum, titanium, manganese, silicon, 
or polymeric materials. 
(17) Patient has had a cerebrovascular accident or transient ischemic attack within 6 months prior to the 
study procedure. Except cases with an event associated with AS. 
(18) Patient with poorly controlled blood pressure. 
(19) Patient has serum albumin < 2.8 g/dL or BMI < 16. 
(20) Patient has uncontrollable diabetes mellitus. 
(21) Patient has active bacterial endocarditis or other active infection. 
(22) Patient has life expectancy < 12 months due to pre-operative non-cardiac comorbidity (e.g., cancer, 
chronic liver disease). 
(23) Currently participating in an investigational drug or another device study. [Note: Trials requiring 
extended follow-up for products that were investigational, but have since become commercially 
available, are not considered investigational trials.] 
(24) Cardiovascular surgeons and cardiologists concluded that the patient is inappropriate for participating 
in this trial. 
 
 

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<TF approach> 
(25) Patient has significant tortuous aorta, diseases including abdominal aortic or thoracic aneurysm, or 
significant atheroma in the femoral artery or iliac artery that would prevent from proper placement of 
delivery system. 
(26) Patient has iliofemoral vessel characteristics that would preclude safe placement of 14F or 16F 
introducer sheath such as severe obstructive calcification and severe tortuosity, or minimum average 
vessel size less than 5.5 mm (6.0 mm for 16F introducer sheath). 
 
<Rationales for the setting> 
For patients deemed possible for safe treatment with EWJ-003, but fall under one of the exclusion criteria 
described in Section 5.2.2, and therefore no chance of treatment, to make it possible to receive treatment 
with EWJ-003 on humanitarian grounds, for the continued access registry, the following changes were 
made to the exclusion criteria described in Section 5.2.2. 
 
Table 5-2: 
Changes made to exclusion criteria 
Exclusion criteria described in 
Section 5.2.2 
Exclusion criteria for continued 
access registry 
Reason for change 
(10) Patient has hemodynamic 
instability requiring inotropic 
agents or mechanical heart 
assistance. Patient has 
respiratory instability 
requiring mechanical 
ventilation. 
(10) Patient has hemodynamic 
instability requiring 
mechanical heart assistance. 
Patient has respiratory 
instability requiring 
mechanical ventilation. 
Some patients need prophylactic inotropic 
agents before and during dialysis for smooth 
dialysis although the hemodynamics does not 
interfere with safe implantation of EWJ-003, 
and therefore irrespective of with or without 
inotropic agents, whether or not the patient can 
be treated with EWJ-003 can be determined 
taking individual patient’s condition and safety 
into consideration, this change was made. 
(19) Patient has serum albumin 
< 3.0 g/dL or BMI < 18. 
(19) Patient has serum albumin < 
2.8 g/dL or BMI < 16. 
For the continued access registry, the exclusion 
criteria were set up, based on the serum 
albumin 2.8 g/dL, the physiological reference 
value that induces edema associated with 
decreased visceral protein mass due to 
malnutrition,[52] and BMI 16, the reference 
value that causes a significantly higher 
mortality risk in Japanese older adults.[53] 
 
5.3 
Case Review Process 
The results of screening conducted by the heart team in the study site confirmed that all of the inclusion 
criteria were satisfied, and none of the exclusion criteria were met, and patients who were deemed eligible 
for this clinical trial will be eventually determined for their eligibility by the case review. The case review 
should be conducted by at least one investigator and/or subinvestigator from a study site other than the 
screening site, and when eligibility of the patient is approved, the patient can be registered as a subject in 
this clinical trial. For detailed case review procedure, see the “Japan Case Review Procedure.” 
 
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Case review is not mandatory in the continued access registry. When the results of screening conducted by 
the heart team in the study site confirmed that all of the inclusion criteria were satisfied, and none of the 
exclusion criteria were met, the patient is regarded as eligible for this clinical trial. When a case review is 
performed as necessary, it should be based on the same procedure as that of the main clinical trial. 
 
5.4 
Subject Enrollment 
For patients who were eventually determined to be eligible for this clinical trial by case review, enrollment 
in this clinical trial should be completed by the document describing the patient’s eligibility. For the 
continued access registry, patients deemed eligible for this registry by screening will be enrolled in this 
registry by the start of study procedure (at the time point when an invasion such as an incision is made on 
the access site). For the subject selection/enrollment flow, see Figure 5-1. 
 
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Note: Case review is not mandatory in the continued access registry. Patients deemed eligible for the continued access registry by 
screening conducted by the heart team of the study site will be regarded as registered in this registry by the start of study procedure 
(at the time point when an invasion such as an incision is made on the access site). Even after case review, the patient will be 
regarded as completed registration in this registry by the start of study procedure. 
 
Figure 5-1: Subject selection/enrollment flow 
No consent 
Not meeting eligibility 
Not meeting eligibility 
No participation 
in the clinical trial 
No participation 
in the clinical trial 
No participation 
in the clinical trial
Discontinuation 
Not performed 
Consent 
Meeting eligibility 
Meeting eligibility 
Performed 
Study site 
The investigator or subinvestigator will 
be provided with the explanatory 
document and informed consent form 
Explanation to a patient 
Informed consent 
Eligibility review 
Final eligibility review 
Subject enrollment 
Tests at study procedure 
(immediately before the procedure) 
Procedure 
Follow-up observation 
Informed consent
Screening 
Case review 
Enrollment 
Procedure is performed
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6 
CONSIDERATIONS CONCERNING SUBJECT’S INFORMED 
CONSENT 
Subject’s informed consent should be obtained in compliance with the followings: 
 
(1) The principal investigator or subinvestigators will give an explanation about this clinical trial to 
subjects, using written patient information approved by the IRB and other appropriate documents, and 
obtain written informed consent to participation in this clinical trial voluntarily signed by the subjects. 
(2) Before informed consent may be obtained, the principal investigator or subinvestigators should 
provide the subject with ample time and opportunity to inquire about details of the trial and to decide 
whether or not to participate in the trial. 
The subject should fully understand the contents of the clinical trial, and then sign or place name and a 
seal and date the informed consent form that describes consent to participation in this clinical trial. 
The principal investigator or subinvestigators who provided an explanation to the subject should sign 
or place name and a seal and date the informed consent form. However, if a subject is unable to read 
the written patient information due to physical problem and so on, but can understand the contents of 
the written patient information given orally or other communication means, an impartial witness 
should be present during the informed consent discussion. In such a case, in addition to the subject, the 
witness should sign or place name and a seal and date the informed consent form. When a study staff 
provided a supplemental explanation, also the study staff should sign or place name and a seal and 
date the informed consent form. 
(3) The principal investigator, subinvestigators, or study staff (hereinafter referred to as “investigators”) 
should enter the date of subject’s written informed consent, and if a witness is required, the date of 
witness, in the electronic case report form (eCRF). 
(4) The principal investigator or subinvestigators must not perform tests for the purpose of this clinical 
trial until after acquisition of written informed consent. The principal investigator or subinvestigators 
should confirm whether or not the subject has other personal physician, and after an agreement with 
the subject, inform the personal physician of the subject’s participation in this clinical trial. If the 
subject may be newly consulting other hospital/department after participation in this clinical trial, the 
principal investigator or subinvestigators should instruct the subject to inform the new 
hospital/department of participation in this clinical trial. 
(5) If information becomes available that may be relevant to the subject’s willingness to continue 
participation in the trial, the principal investigator or subinvestigators should inform the subject in a 
timely manner, confirm as to whether or not the subject is willing to continue the trial, and record it in 
the medical records, etc. 
(6) If the principal investigator considers that the written patient information should be revised, the 

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written patient information should be revised promptly based on the relevant information. The 
principal investigator should notify the director of the study site of the revised written patient 
information, and obtaining IRB's approval. After approval, the principal investigator or 
subinvestigators should obtain the subject’s voluntarily signed written consent to continued 
participation in this clinical trial. If a witness is required, follow (2). 
(7) The investigators should enter the date of subject’s written informed reconsent, and if a witness is 
required, the date of witness, in the eCRF. Further, if 䡈egally acceptable representative is required, the 
investigators should enter the date of consent given by the legal representative in the eCRF. 
(8) The principal investigator or subinvestigators will provide the subject with a copy of signed or name 
and seal placed informed consent form and written information. The original informed consent form 
signed or name and a seal placed should be retained by the study site. 
 
7 
TREATMENT OF SUBJECTS 
7.1 
Baseline Tests 
The subjects enrolled in this clinical trial will receive tests to obtain baseline values before the procedure, 
so as to confirm the impact of the THV on patients, compared with follow-up observation values after the 
procedure. These test results will be entered in eCRFs and will be used for determination of eligibility of 
the subjects. If there are some data of tests carried out within the permissible time range of baseline tests 
available, even the results of tests carried out before acquisition of informed consent or to confirm subject’s 
eligibility may be used as baseline data. 
 
For baseline test/observation items and timing, see Sections 10.1 and 10.2.1. 
 
7.2 
Study Procedure 
In this clinical trial, the investigational valve may be implanted by either TF, TA, or TAo approach. 
However, TF approach should be the first line of treatment, and when TF approach is difficult to perform, 
carefully examine the subject’s clinical and anatomical characteristics, and then select appropriate access 
site (TA or TAo approach). 
 
For deployment of the THV, the balloon should be inflated at a nominal volume (see Section 3.2 Table 3-2), 
and if dilatation at a nominal volume is impossible for medical reasons, the subject should be included in 
the bailout treatment registry (see Section 7.4 “Bailout Treatment Registry”). In the continued access 
registry, irrespective of whether the THV was implanted at a nominal volume or not, subjects who received 
the study procedure will be included in this registry. For preparation of study device, THV rinsing, and 
detailed implantation procedure, see Attachment 2 “Instructions for Use.” In order to ensure and protect the 
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safety of the subjects, the sponsor should witness all procedures as much as possible and consider to be able 
to respond to questions about the study device and study procedure. 
 
If severe aortic valve regurgitation is observed after implantation of the THV, a valve-in-valve procedure 
may be performed. When a valve-in-valve procedure is required, as a general rule, the study device should 
be used. Since sufficient evidence has not been obtained for the safety and efficacy of the valve-in-valve 
procedures, a physician who performs implantation should carefully select the size and perform the 
implantation procedure. 
 
7.3 
Post-procedural Follow-up Observation 
All subjects for whom the THV was implanted and maintained at the time point when the subject left the 
operetaion room should undergo the 5-year post-procedural follow-up observation specified in the protocol. 
For study discontinuation subjects without implantation of the investigational valve for the reasons that the 
procedure was switched to surgery, or already approved TAVI bioprosthetic valve was implanted, 
participation in this trial should be discontinued at the time point, and follow-up observation will not be 
required thereafter. 
 
For the test/observation items and timing in the post-procedural follow-up observation, see Section 10. 
 
7.4 
Bailout Treatment Registry 
Patients in whom deployment of the THV by balloon dilatation at a nominal volume was impossible for a 
medical reason will be regarded as bailout cases, and these cases will be included in the bailout treatment 
registry at the end of study procedure. The bailout cases will be enrolled separately from the target sample 
size of this trial (30 subjects), and will not be included in the analysis set for the safety and efficacy 
evaluation of EWJ-003. The same post-procedural follow-up observation will be performed as that for 
subjects with successful valve implant procedure at a nominal volume, and the follow-up observation will 
be performed for up to 5 years post-procedure. 
 
In the continued access registry, irrespective of whether the THV was implanted at a nominal volume or not, 
subjects who received the study procedure will be included in this registry. 
 
 
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Figure 7-1: Bailout treatment registry treatment flow 
 
 
 
Informed consent
Screening
Case review
Enrollment
Study procedure
Dilatation at a nominal volume
Dilatation at a non-nominal volume
Bailout treatment registry
EWJ-003 analysis set 
(30 subjects)
Safety and efficacy evaluation  
(at 1 year post-procedure)
Follow-up until at 5 years post-procedure
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8 
CONCOMITANT THERAPY 
8.1 
Anticoagulation/Antiplatelet Therapy 
As a general rule, the principal investigator or subinvestigators should provide anticoagulation/antiplatelet 
regimen in accordance with Table 8-1. However, considering individual subject’s clinical circumstance 
including validity of contraindications for a subject, the dosage, concomitant drugs, timing of 
administration, and duration of administration should be decided, at the discretion of the primary physician. 
For example, if a subject with atrial fibrillation receives warfarin potassium, or a subject with obstructive 
arteriosclerosis or a subject with a stent implanted in the peripheral blood vessel or coronary artery 
(including bypass graft) is on an antiplatelet agent other than aspirin, taking continuous use into 
consideration, 
anticoagulation/antiplatelet 
therapy 
should 
be 
provided. 
Therefore, 
when 
anticoagulation/antiplatelet therapy different from those recommended in Table 8-1 (e.g., ticlopidine 
hydrochloride and clopidogrel sulfate) is given, the protocol deviation is not applicable.

Chronic dialysis patients, compared with non-dialysis patients, have a strong bleeding tendency, often 
leading to difficulty in hemostasis, patients on antiplatelet drugs and/or anticoagulant (excluding 
anticoagulant at dialysis) before the procedure, these drugs should be discontinued at least 14 days before 
the procedure as a general rule, so that the effect of these drugs fades away.
 
Table 8-1: 
Recommended anticoagulation/antiplatelet regimen 
Drug 
Pre-procedure 
At procedure 
Post-procedure 
Heparin 
None 
5000 IU/dose, then heparin will be 
given to achieve and maintain ACT 
 250 sec as needed 
None 
Aspirin 
None 
None 
75 - 100 mg/day, once daily 
continued indefinitely 
 
[Pre-procedural antiplatelet therapy] 
Considering bleeding risk, pre-procedural anticoagulation/antiplatelet therapy will not be given. However, 
if a platelet function inhibitory action is required, aspirin, etc. should be carefully administered in 
accordance with the package insert. 
 
[Anticoagulant therapy at procedure] 
After intravenous administration of heparin 5000 IU/dose, heparin will be given to achieve and maintain 
activated clotting time $&7VHFonds as needed throughout the course of the procedure. Monitor the 
ACT at regular intervals, and record it in the source document. 
 
[Post-procedural antiplatelet therapy] 
After the procedure, aspirin monotherapy will be given at a dose of 75 to 100 mg/day for an indefinite 
period after study procedure.


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<Rationales for the setting>
Considering bleeding risk related to the procedure, irrespective of the implantation approach, 
pre-procedural antiplatelet therapy will not be given. For the anticoagulant therapy during procedure, in 
addition to thromboprophylaxis, in order to inhibit enhancement of the blood coagulation system induced 
by damage on the vascular inner wall and prevent consumption of the blood coagulation factor, heparin will 
be administered. As for post-procedural antiplatelet therapy, compared with non-dialysis patients, dialysis 
patients have a higher trend toward bleeding, and therefore similarly to the antiplatelet therapy given in the 
advanced medical care at Osaka University Hospital, administration of aspirin single-agent for indefinite 
period was recommended. Aspirin is an agent that undergoes hepatic metabolism, and therefore the 
pharmacokinetics of these antiplatelet drugs is not affected in dialysis patients with impaired renal 
excretion. 
 
8.2 
Prophylactic Administration of Antibiotics 
An antibiotic agent will be administered to the subjects who undergo implantation procedure of the study 
device immediately before the start of the procedure. Regardless of the type of antibiotic agent, considering 
the use status of antibiotic agents at each study site, possible drug-resistant bacteria, and an impact on 
subject’s renal function, antibiotic agents should be chosen. If methicillin-resistance is suspected, consider 
the use of vancomycin. 

<Rationales for the setting>
In the subjects receiving implantation of the study device, incidence of endocarditis associated with 
infection may be fatal and therefore the subjects should be prophylactically treated for infections per the 
recommendations by the AHA[54] prior to the procedure. 
 
8.3 
Precautions for Concomitant Drugs 
The following concomitant drugs should be carefully used, and the concomitant use should be avoided as 
much as possible. When the concomitant use is necessary, concomitant use other than single use should be 
avoided. 
 
x 
Non-steroidal anti-inflammatory drug (indomethacin, etc.)
x 
Steroids, tacrolimus preparations, and other immunosuppressants 

<Rationales for the setting>
Since non-steroidal anti-inflammatory drugs may cause interactions with aspirin (enhancing), concomitant 
use other than single use in necessary cases should be avoided. Since steroids, tacrolimus preparations, and 
other immunosuppressants may affect the immune system, concomitant use other than single use in 
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necessary cases should be avoided. 
 
8.4 
Periprocedural Hemodialysis 
Perform periprocedural hemodialysis in accordance with the following recommendations: 
 
[Pre-procedural hemodialysis] 
x 
For hemodialysis patients, perform hemodialysis until achievement of this dry weight on the day 
before study procedure as a general rule. 
Do not change the anticoagulant therapy. 
x 
For peritoneal dialysis patients, continue peritoneal dialysis as usual until the day before study 
procedure. 
 
[Post-procedural hemodialysis] 
x 
Considering post-procedural hemodynamics, resume dialysis at the discretion of the investigator. 
x 
In case of the hemodialysis, it is recommended to use anticoagulant with shorter half-life (e.g. 
nafamostat mesilate) to reduce bleeding risk. 
x 
Do not change dialysis conditions until 1 year post-procedure as a general rule. However, the 
dialysis conditions may be changed if it is based on the medical judgement. 
 
8.5 
Other Drugs/Therapies 
Drugs or therapies previously used before procedure in the treatment of the primary disease should be 
discontinued as a general rule, unless they are used also for pre-procedural complication. Drugs or therapies 
used before procedure in the treatment of pre-procedural complication should be maintained as much as 
possible. This does not apply to the cases where it is used for an AE or aggravated primary disease. 

<Rationales for the setting>
Since treatments of the primary disease may affect the evaluation of this clinical trial, the use of these drugs 
or therapies should be discontinued as a general rule. If the same treatment is maintained from prior to the 
procedure, other treatments of complication may not affect the evaluation of this clinical trial, considering 
well-being of the trial subjects, these could be concomitantly used. 
 
8.6 
Precautions for Concomitant Drugs/Concomitant Therapy and Input Procedure 
in Electronic Case Report Forms 
8.6.1 Anticoagulant/antiplatelet drugs and antibiotics 
Observe anticoagulant/antiplatelet drug (excluding anticoagulant at dialysis) from 7 days prior to the day of 
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the procedure (counting the procedure day as Day 0) throughout the observation period, and for antibiotics 
from 7 days prior to the procedure day (counting the procedure day as Day 0) to hospital discharge (or 7 
days post-procedure, whichever earlier). The name, duration of treatment, reasons for treatment, route of 
administration, and dosage of the used anticoagulants/antiplatelet drugs and antibiotics should be entered in 
eCRF. However, the data on antibiotics will not be collected for the continued access registry. 
 
8.6.2 Blood purification 
Concerning periprocedural blood purification therapy, for dialysis given from immediately before the study 
procedure through to post-procedure hospital discharge (day of discharge or 7 days post-procedure, 
whichever earlier), the date of therapy, type of dialysis, dialysis condition, and anticoagulant used at 
dialysis should be entered in eCRF. Also at 1 year post-procedure, similarly to the periprocedural period, 
dialysis data should be collected to check the dialysis status. 
 
8.6.3 Other concomitant drug/therapy 
After the start of study procedure, the data on other drugs and therapies concomitantly used in the treatment 
of an AE and complication that can be a risk factor will be collected until 1 year post-procedure. Of the 
concomitant drugs, only for the cardiovascular agents applicable to the following therapeutic category, the 
name, duration of administration, reason for use, route of administration, and dosage should be entered in 
eCRFs, and for the concomitant therapies, the name, duration of concomitant use, and reason for 
concomitant use should be entered in eCRFs. However, for Continued Access Registry, these data may be 
collected as much as possible. 
 
<Concomitant cardiovascular drugs for which data will be collected> 
x 
Inotropic agent 
x 
Antiarrhythmic agent 
x 
Diuretic 
x 
Hypotensive agent 
ż 
Angiotensin-converting enzyme inhibitor (ACE-I) 
ż 
Angiotensin II receptor blocker (ARB) 
ż 
Renin inhibitor 
ż 
E-blocker 
ż 
D-blocker 
ż 
Į-ȕ-blocker 
ż 
Calcium-channel blocker (CCB) 
ż 
Aldosterone receptor antagonist 
x 
Capillary stabilizer 
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x 
Vasoconstrictor 
x 
Vasodilator 
ż 
Coronary vasodilator 
ż 
Peripheral vasodilator 
x 
Hyperlipidemia agent 
ż 
HMG-CoA reductase inhibitor (statin) 
 
 

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9 
STUDY ENDPOINTS 
9.1 
Primary Endpoints 
x 
Mortality at 1 year post-procedure 
 
<Rationales for the setting> 
Based on the fact that the study device EWJ-003 is clinically positioned as a device that enables us to treat 
chronic dialysis AS patients who have not been eligible for sAVR and have not had any radical treatments 
so far, it is important to evaluate whether or not improvement in the prognosis, the goal of the therapy, 
could be achieved for evaluation of the safety and efficacy of EWJ-003. Since the Valve Academic 
Research Consortium (VARC) guidelines recommend that the morality at 1 year post-procedure be set for 
the primary endpoint in clinical trials,[55] the mortality at 1 year post-procedure was set up for the primary 
endpoint for this clinical trial. 

9.2 
Secondary Endpoints 
9.2.1 Secondary safety endpoints 
x 
Composite endpoint: Post-procedure 30 days, 6 months, 1 year, and 2 to 5 years annually 
o 
Death and stroke 
 
x 
Single endpoints: Post-procedure 30 days, 6 months, 1 year, and 2 to 5 years annually 
ż 
Death (cardiovascular, non-cardiovascular) 
ż 
MI (periprocedural, spontaneous) 
ż 
Stroke (disabling, non-disabling) 
ż 
Bleeding (life-threatening or disabling, severe, mild) 
ż 
Vascular access site/access-related complications 
ż 
Severe vascular complications 
ż 
Conduction disorder/arrhythmia 
ż 
Conduction disorder requiring new pacemaker implantation 
ż 
Aortic valve re-intervention 
ż 
Coronary obstruction 
ż 
Endocarditis 
ż 
Valve explants 
ż 
Structural valve deterioration 
ż 
Nonstructural valve dysfunction 
 
 
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9.2.2 Secondary efficacy endpoints 
x 
Device success: 30 days after procedure 
x 
Length of post-procedural hospitalization/ICU stay: At discharge 
x 
NYHA classification: Post-procedure 30 days, 6 months, 1 year, and 2 to 5 years annually 
x 
Six-minute walk test: Post-procedure 30 days and 1 year 
x 
Quality of life (QOL) (EuroQOL, short form 12-item health survey [SF-12]): Post-procedure 30 days, 
6 months, 1 year, and 2 to 5 years annually 
 
9.2.3 Secondary valve performance endpoints 
x 
Echocardiography: Post-procedure 30 days, 6 months, 1 year, and 2 to 5 years annually 
ż 
Mean pressure gradient 
ż 
Peak gradient 
ż 
EOA 
ż 
EOAi 
ż 
Aortic valve regurgitation (paravalvular, transvalvular) 
ż 
LVEF 
ż 
Left ventricular mass 
ż 
Left ventricular mass index (LVMI) 
 
10 
TEST/OBSERVATION DATA COLLECTION 
10.1 Test/Observation Schedule 
All registered subjects in this clinical trial will receive the tests/observations shown in Section 10.2 
“Test/observation items”. Post-procedural follow-up observation will be performed at post-procedure 30 
days, 6 months, 1 year, and 2 to 5 years annually. 
 
The permissible time window for each test/observation period is as shown in Table 10-1 and Table 10-2, 
and the day of procedure is counted as Day 0. The time of the day of procedure is specified as between 0:00 
and 23:59, and 24:00 should be expressed as 0:00. If the procedure spans before and after 0:00, the day 
when the procedure was started should be counted as date of procedure (initial day). The time of the start 
and end of the procedure is the time when invasion such as incision was made on the access site and the 
time when closing the access site such as incision site was completed, respectively. 
 
The test/observation schedule is shown in Table 10-3. The test/observation schedule for the continued 
access registry is as shown in Table 10-4. 
 
 
 
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Table 10-1: Permissible time windows for the tests/observations  
<up to 6 months post-procedure> 
Test/observation 
timing 
Baseline a) 
Procedure b) 
Immediately 
after 
procedure 
Post-procedural follow-up observation 
Hospital 
discharge 
30 days 
post-procedure 
6 months 
post-procedure 
Reference date 
(time) 
- 
Day 0 
Up to 72 
hours after 
exiting the 
operation 
room 
7 days 
post-procedure 
or hospital 
discharge, 
whichever 
comes earlier 
30 days 
post-procedure 
182 days 
post-procedure 
Permissible time 
window 
Within 60 days 
pre-procedure 
- 
- 
± 2 days 
-7 days/+14 days 
± 30 days 
a) 
The 12-lead ECG should be performed within 48 hours prior to entering the operation room, clinical laboratory tests within 14 days prior 
to the procedure, and coronary angiography and aortofemoral blood vessel evaluation (CT, MRI, or X-ray) within 90 days pre-procedure 
(see Section 10.2.1 “Baseline”). For the continued access registry, except cases that may be clinically valid, coronary angiography 
should be performed within 1 year prior to the study procedure. 
b) Cardiac catheter test at procedure should be performed immediately before and after the procedure. 
 
 
Table 10-2: Permissible time windows for the tests/observations  
<at 1 year post-procedure and thereafter> 
Test/observation 
timing 
Post-procedural follow-up observation 
1 year 
post-procedure 
2 years 
post-procedure 
3 years 
post-procedure 
4 years 
post-procedure 
5 years 
post-procedure 
Reference date 
365 days 
post-procedure 
730 days 
post-procedure 
1095 days 
post-procedure 
1460 days 
post-procedure 
1825 days 
post-procedure 
Permissible time 
window 
± 30 days 
± 45 days 
± 45 days 
± 45 days 
± 45 days 
 
 
 
 
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Table 10-3: Schedule of Tests and Observations 
Timing 
 
 
 
 
 
 
 
Tests/observations 
Baseline 
(Within 60 days 
pre-procedure) 
During procedure 
Immediately after procedure 
(Within 72 hours 
pre-procedure) 
Discharge or 7 days 
post-procedure 
(± 2 days) 
30 days post-procedure 
(- 7 days, + 14 days) 
6 months post-procedure 
(± 30 days) 
1 year post-procedure 
(± 30 days) 
2 - 5 years post-procedure 
(± 45 days) 
Discontinued 
Unscheduled visit 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Patient background 
X 
 
 
 
 
 
 
 
 
 
Surgical risk assessment*1 
X 
 
 
 
 
 
 
 
 
 
NYHA classification of cardiac 
performance 
X 
 
 
X 
X 
X 
X 
X 
 
 
CCS status of stable angina 
X 
 
 
X 
X 
X 
X 
X 
 
 
Neurological assessment*2 
(NIHSS, mRS) 
X 
 
 
 
X 
X 
X 
 
 
 
Blood pressure 
X 
 
 
X 
X 
X 
X 
 
 
 
12-lead ECG 
X*3 
 
X 
X 
X 
X 
X 
 
 
 
Chest X-ray 
X 
 
X 
X 
X 
X 
X 
 
 
 
Head CT 
X 
 
 
 
X 
X 
X 
 
 
 
6-minute walk test  
X 
 
 
 
X 
 
X 
 
 
 
Clinical 
laboratory test 
Hematology 
X*4 
 
 
 
X 
X 
X 
 
 
 
Biochemistry 
X*4 
 
 
 
X 
X 
X 
 
 
 
Coagulation 
X*4 
 
 
 
X 
X 
X 
 
 
 
Cardiac enzyme 
X*4 
 
X 
X 
X 
X 
X 
 
 
 
Echocardiography 
X 
X*8 
 
X*11 
X*11 
X*11 
X*11 
X*11 
 
 
Cardiac CT 
X 
 
 
 
 
 
 
 
 
 
Coronary angiography 
X*5 
 
 
 
 
 
 
 
 
 
Aortofemoral imaging 
X*6 
 
 
 
 
 
 
 
 
 
Cardiac catheterization 
 
X*9 
 
 
 
 
 
 
 
 
QOL questionnaire 
(EuroQOL,SF-12) 
X 
 
 
 
X 
X 
X 
X 
 
 
Procedure information 
 
X 
 
 
 
 
 
 
 
 
Anticoagulant/antiplatelet drugs 
X*7 
X 
Antibiotic 
X*7 
X 
 
 
 
 
 
 
Blood purification 
X*10 
 
 
X 
 
 
 
Other concomitant medication/therapy 
 
X 
 
X*12 
X*12 
Adverse event/device deficiency 
 
X 
*1 
Calculate STS score, Logistic EuroSCORE, and EuroSCORE II. 
*2 㻌For patient who has suffered a stroke, mRS must be evaluated within 30 to 90 days and beyond 90 days as earlier as from the onset of 
stroke. 
*3 
Perform within 48 hours prior to entering the operating room. 
*4 
Perform within 14 days prior to the study procedure. 
*5 
Perform within 90 days prior to the study procedure. 
*6 
Perform CT, MRI, or X-ray within 90 days prior to the study procedure. 
*7 
Start assessment from 7 days pre-procedure. 
*8 
Measure the aortic annulus diameter, and perform observation items of cardiac catheterization according to the situation. 
*9 
Perform pre- and post-study procedure. May be performed by echocardiography according to the situation. 
*10 Assess dialysis information performed from the latest date prior to the study procedure to discharge (at discharge date or 7 days 
post-procedure, whichever came earlier). 
*11 Baseline BSA value must be used for calculation of EOAi and LVMI. 
*12 Assess other concomitant medication/therapy, excluding anticoagulation/antiplatelet, antibiotic, and hemodialysis, within 1 year 
post-procedure. 
 

Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 76 - 
Table 10-4: Schedule of Tests and Observations for Continued Access Registry 
*1 
Calculate STS score, Logistic EuroSCORE, and EuroSCORE II. 
*2 
For patient who has suffered a stroke, mRS must be evaluated within 30 to 90 days and beyond 90 days as earlier as from the onset of 
stroke. 
*3 
Subjects who developed stroke only. 
*4 
Perform within 48 hours prior to entering the operating room. 
*5 
Perform within 14 days prior to the study procedure. 
*6 
Except cases that may be clinically valid, perform within 1 year prior to the study procedure. 
*7 
Perform CT, MRI, or X-ray within 90 days prior to the study procedure. 
*8 
Start assessment from 7 days pre-procedure. 
*9 
Measure the aortic annulus diameter, and perform observation items of cardiac catheterization according to the situation. 
*10 Perform pre- and post-study procedure. May be performed by echocardiography according to the situation. 
*11 Assess dialysis information performed from the latest date prior to the study procedure to discharge (at discharge date or 7 days 
post-procedure, whichever came earlier). 
*12 Baseline BSA value must be used for calculation of EOAi and LVMI. 
*13 Subjects who were included in the continued access registry under Protocol ver. 5 will require no post-procedural QOL questionnaire. 
*14 Where possible, assess other concomitant medication/therapy, excluding anticoagulation/antiplatelet, antibiotic, and hemodialysis, within 1 
year post-procedure.  
 
Timing 
 
 
 
 
 
 
 
Tests/Observations 
Baseline 
(Within 60 days 
pre-procedure) 
During procedure 
Immediately after procedure 
(Within 72 hours 
pre-procedure) 
Discharge or 7 days 
post-procedure 
(± 2 days) 
30 days post-procedure 
(- 7 days, + 14 days) 
6 months post-procedure 
(± 30 days) 
1 year post-procedure 
(± 30 days) 
2 - 5 years post-procedure 
(± 45 days) 
Discontinued 
Unscheduled visit 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria for continued 
access registry 
X 
 
 
 
 
 
 
 
 
 
Patient background 
X 
 
 
 
 
 
 
 
 
 
Surgical risk assessment*1 
X 
 
 
 
 
 
 
 
 
 
NYHA classification of cardiac 
performance 
X 
 
 
X 
X 
X 
X 
X 
 
 
CCS status of stable angina 
X 
 
 
X 
X 
X 
X 
X 
 
 
Neurological assessment*2 
(NIHSS, mRS) 
X 
 
 
 
X 
X*3 
X*3 
 
 
 
Blood pressure 
X 
 
 
X 
X 
X 
X 
 
 
 
12-lead ECG 
X*4 
 
X 
X 
X 
X 
X 
 
 
 
Chest X-ray 
X 
 
X 
X 
X 
X 
X 
 
 
 
Head CT 
X 
 
 
 
X 
X*3 
X*3 
 
 
 
Clinical 
laboratory test 
Hematology 
X*5 
 
 
 
X 
X 
X 
 
 
 
Biochemistry 
X*5 
 
 
 
X 
X 
X 
 
 
 
Coagulation 
X*5 
 
 
 
X 
X 
X 
 
 
 
Cardiac enzyme 
X*5 
 
X 
X 
X 
X 
X 
 
 
 
Echocardiography 
X 
X*9 
 
X*12 
X*12 
X*12 
X*12 
X*12 
 
 
Cardiac CT 
X 
 
 
 
 
 
 
 
 
 
Coronary angiography 
X*6 
 
 
 
 
 
 
 
 
 
Aortofemoral imaging 
X*7 
 
 
 
 
 
 
 
 
 
Cardiac catheterization 
 
X*10 
 
 
 
 
 
 
 
 
QOL questionnaire 
(EuroQOL,SF-12) 
X 
 
 
 
X*13 
X*13 
X*13 
X*13 
 
 
Procedure information 
 
X 
 
 
 
 
 
 
 
 
Anticoagulant/antiplatelet drugs 
X*8 
X 
Blood purification 
X*11 
 
 
X 
 
 
 
Other concomitant medication/therapy 
 
X*14 
 
X*14 
X*14 
Adverse event/device deficiency 
 
X 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 77 - 
10.2 Tests/Observations 
10.2.1 Baseline 
For the baseline tests/observations, the following data will be collected from subject consent to before the 
study procedure. From the standpoint of protection of subjects, if any data are available on the tests 
performed within the permissible time windows specified in the protocol, the data obtained before informed 
consent and data used for screening may be used as baseline data. 
 
x 
Informed consent 
x 
Conformance to the inclusion/exclusion criteria 
x 
Patient background 
ż 
Demographic background 
Sex, date of birth, and age (calculated from the date of birth) 
ż 
Physical finding 
Height, weight, body surface area (BSA), and BMI 
* BSA and BMI will be calculated from height and weight in the following formulas. 
¾ BSA = 0.007184 u Weight [kg]0.425 u Height [cm]0.725 
¾ BMI = Weight [kg]/Height [m]2 
ż 
Clinical background 
Primary disease, risk factors (pre-procedural complication, past history, history of 
syncope not associated with atrioventricular block, number of hospitalization for AS in 
the past 6 months, and stroke in the past 12 months), type of dialysis (hemodialysis or 
peritoneal dialysis), the starting time of dialysis, duration of dialysis (to be calculated 
from the starting time of dialysis), and primary disease for introduction of dialysis 
x 
Surgical risk assessment 
After investigation/evaluation of surgical risks and risk score, evaluate patients who are not 
eligible for safe open surgical therapy as to whether or not the best therapy is treatment with 
EWJ-003. 
ż 
STS score [http://riskcalc.sts.org/stswebriskcalc/#/] 
ż 
Logistic EuroSCORE [http://www.euroscore.org/calcold.html] 
ż 
EuroSCORE II [http://www.euroscore.org/calc.html] 
* The results of risk score should be printed out and affixed to medical records, etc.㻌
x 
NYHA classification of cardiac performance (see Section 30 “GLOSSARY”) 
x 
Canadian Cardiovascular Society (CCS) status of stable angina (see Section 30 “GLOSSARY”) 
x 
Neurological examination 
ż 
National Institutes of Health Stroke Scale (NIHSS) (see Appendix 1) 
ż 
Modified Rankin Scale (mRS) (see Appendix 2) 
* Neurological assessment should be performed by a neurologist, neurosurgeon, or a physician 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 78 - 
who is able to perform appropriate assessment. 
x 
Blood pressure (systolic, diastolic) 
x 
12-lead ECG (to be performed within 48 hours prior to entering the operating room) 
x 
Chest X-ray 
x 
Head CT 
x 
Six Minute Walk Test (see Appendix 3) 
x 
Laboratory tests (to be performed within 14 days pre-procedure) 
ż 
Hematology 
Red blood cell count, hemoglobin, hematocrit, platelet count, white blood cell count, 
differential white blood cell count (neutrophil, lymphocyte, monocyte, eosinophil, 
basophil) 
ż 
Biochemistry 
Sodium, potassium, creatinine, urea nitrogen, albumin, total bilirubin, CRP, GOT(AST), 
GPT(ALT), LDH, hemoglobin A1c, glycated albumin, phosphate, calcium 
ż 
Coagulation 
Prothrombin time, activated partial thromboplastin time 
ż 
Cardiac enzyme 
CK and troponin, or CK-MB and troponin 
x 
Echocardiography 
Perform echocardiography in reference to the Echo Core Laboratory Procedure to 
measure/evaluate the following items. The resulted echocardiographic images should be 
submitted to the Echo Core Laboratory. 
[Measurements/endpoints] 
Cardiac output, aortic valve pressure gradient (mean/maximum), AVA, AVA index, aortic valve 
regurgitation (severity/regurgitation site), aortic annulus diameter*, maximum aortic flow 
velocity, LVEF, left ventricular mass, LVMI, valvular and paravalvular conditions 
* The aortic annulus diameter should be estimated from the left ventricular outflow tract 
(LVOT) dimension.㻌
x 
Cardiac CT 
[Measurements/endpoints] 
Aortic annulus diameter, aortic annulus area, distance from aortic annulus to coronary ostium 
x 
Coronary angiography (to be performed within 90 days pre-procedure) 
* If a subject has no hypersensitivity to contrast media, but contrast media cannot be used due 
to other disease, MRI may be used. 
x 
Aortofemoral vascular evaluation (to be performed within 90 days pre-procedure) 
Perform CT, MRI, or X-ray to evaluate from the aorta through to the femoral artery. 
x 
QOL questionnaire 
ż 
EuroQOL (see Appendix 4) 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 79 - 
ż 
SF-12 (Appendix 5) 
x 
Anticoagulant/antiplatelet drugs (to be investigated from 7 days prior to the procedure) 
x 
Antibiotics (to be investigated from 7 days prior to the procedure) 
x 
Blood purification㻌
Investigate the latest dialysis prior to the procedure. 
 
10.2.2 During procedure 
The test/observation during procedure will collect the data on the following items. 
 
x 
Echocardiography (perform observation items of cardiac catheter test according to the aortic 
annulus diameter and situation) 
x 
Cardiac catheter test (to be performed immediately before and after the procedure. It may be 
replaced with echocardiography according to the situation) 
[Measurements/endpoints] 
Aortic pressure (systolic/diastolic/mean), aortic valve pressure gradient (mean/maximum), 
AVA (immediately before procedure only), EOA (immediately after procedure only), aortic 
valve regurgitation (severity/regurgitation site) 
x 
Procedure information 
Date of procedure, delivery means, time of procedure, predilatation information, valve 
implantation information, maximum ACT, anesthesia procedure, X-ray status, contrast media 
status, evaluation of procedure, device information, aortic annulus diameter used for selection 
of THV size and measurement method 
x 
Anticoagulant/antiplatelet drugs 
x 
Antibiotic 
x 
Other concomitant drugs/therapies (to be investigated from right after the start of the study 
procedure) 
x 
AE/defect (to be investigated from right after the start of the study procedure) 
For a patient who has suffered a stroke, mRS must be evaluated within 30 to 90 days and beyond 
90 days as earlier as from the onset of stroke. 
 
10.2.3 Immediately after procedure 
The test/observation immediately after the procedure will collect the data on the following items until 72 
hours after exiting the operation room. 
 
x 
12-lead ECG 
x 
Chest X-ray 

Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 80 - 
x 
Cardiac enzyme test (CK and troponin, or CK-MB and troponin) 
x 
Anticoagulant/antiplatelet drugs 
x 
Antibiotic 
x 
Blood purification 
x 
Other concomitant medication/therapy 
x 
AE/device deficiency 
For a patient who has suffered a stroke, mRS must be evaluated within 30 to 90 days and beyond 
90 days as earlier as from the onset of stroke. 
 
10.2.4 Hospital discharge 
The tests/observation at hospital discharge will collect the data on the following items on the day of 
discharge or 7 days post-procedure, whichever comes earlier (± 2 days). 
 
x 
NYHA classification of cardiac performance (see Section 30 “GLOSSARY”) 
x 
CCS status of stable angina (see Section 30 “GLOSSARY”)㻌
x 
Blood pressure (systolic, diastolic) 
x 
12-lead ECG 
x 
Chest X-ray 
x 
Cardiac enzyme test (CK and troponin, or CK-MB and troponin) 
x 
Echocardiography 
Perform echocardiography in reference to the Echo Core Laboratory Procedure to 
measure/evaluate the following items. 
[Measurements/endpoints] 
Cardiac output, aortic valve pressure gradient (mean/maximum), EOA, EOAi*, aortic valve 
regurgitation (severity/regurgitation site), maximum blood flow rate, LVEF, left ventricular 
mass, LVMI* 
 
Baseline BSA values must be used for calculation of EOAi and LVMI. 
x 
Anticoagulant/antiplatelet drugs 
x 
Antibiotic 
x 
Blood purification 
x 
Other concomitant medication/therapy 
x 
AE/device deficiency 
For a patient who has suffered a stroke, mRS must be evaluated within 30 to 90 days and beyond 
90 days as earlier as from the onset of stroke. 
 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 81 - 
10.2.5 At 30 days post-procedural follow-up observation 
The tests/observation at 30 days post-procedure should be performed at 30 days post-procedural visit (-7 
days, +14 days) to collect the data on the following items. 
 
x 
NYHA classification of cardiac performance (see Section 30 “GLOSSARY”) 
x 
CCS status of stable angina (see Section 30 “GLOSSARY”) 
x 
Neurological examination 
ż 
NIHSS (see Appendix 1) 
ż 
mRS (see Appendix 2) 
* Neurological assessment should be performed by a neurologist, neurosurgeon, or a physician 
who is able to perform appropriate assessment.㻌
x 
Blood pressure (systolic, diastolic) 
x 
12-lead ECG 
x 
Chest X-ray 
x 
Head CT 
x 
Six-minute walk test (see Appendix 3) 
x 
Clinical laboratory test 
ż 
Hematology 
Red blood cell count, hemoglobin, hematocrit, platelet count, white blood cell count, 
differential white blood cell count (neutrophil, lymphocyte, monocyte, eosinophil, 
basophil) 
ż 
Biochemistry 
Sodium, potassium, creatinine, urea nitrogen, albumin, total bilirubin, CRP, GOT(AST), 
GPT(ALT), LDH, hemoglobin A1c, glycated albumin, phosphate, calcium 
ż 
Coagulation 
Prothrombin time, activated partial thromboplastin time 
ż 
Cardiac enzyme 
CK and troponin, or CK-MB and troponin 
x 
Echocardiography 
Perform echocardiography in reference to the Echo Core Laboratory Procedure to 
measure/evaluate the following items. The resulted echocardiographic images should be 
submitted to the Echo Core Laboratory. 
[Measurements/endpoints] 
Cardiac output, aortic valve pressure gradient (mean/maximum), EOA, EOAi*, aortic valve 
regurgitation (severity/regurgitation site), maximum blood flow rate, LVEF, left ventricular 
mass, LVMI* 
 
Baseline BSA values must be used for calculation of EOAi and LVMI. 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 82 - 
x 
QOL questionnaire 
ż 
EuroQOL (see Appendix 4) 
ż 
SF-12 (Appendix 5) 
x 
Anticoagulant/antiplatelet drugs 
x 
Other concomitant medication/therapy 
x 
AE/device deficiency 
For a patient who has suffered a stroke, mRS must be evaluated within 30 to 90 days and beyond 
90 days as earlier as from the onset of stroke. 
 
10.2.6 At 6 months post-procedural follow-up 
The tests/observation at 6 months post-procedural follow-up should be performed at 182 days 
post-procedural visit (± 30 days) to collect the data on the following items. 
 
x 
NYHA classification of cardiac performance (see Section 30 “GLOSSARY”) 
x 
CCS status of stable angina (see Section 30 “GLOSSARY”) 
x 
Neurological examination 
ż 
NIHSS (see Appendix 1) 
ż 
mRS (see Appendix 2) 
* Neurological assessment should be performed by a neurologist, neurosurgeon, or a physician 
who is able to perform appropriate assessment.㻌
x 
Blood pressure (systolic, diastolic) 
x 
12-lead ECG 
x 
Chest X-ray 
x 
Head CT 
x 
Clinical laboratory test 
ż 
Hematology 
Red blood cell count, hemoglobin, hematocrit, platelet count, white blood cell count, 
differential white blood cell count (neutrophil, lymphocyte, monocyte, eosinophil, 
basophil) 
ż 
Biochemistry 
Sodium, potassium, creatinine, urea nitrogen, albumin, total bilirubin, CRP, GOT(AST), 
GPT(ALT), LDH, hemoglobin A1c, glycated albumin, phosphate, calcium 
ż 
Coagulation 
Prothrombin time, activated partial thromboplastin time 
ż 
Cardiac enzyme 
CK and troponin, or CK-MB and troponin 
x 
Echocardiography 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 83 - 
Perform echocardiography in reference to the Echo Core Laboratory Procedure to 
measure/evaluate the following items. The resulted echocardiographic images should be 
submitted to the Echo Core Laboratory. 
[Measurements/endpoints] 
Cardiac output, aortic valve pressure gradient (mean/maximum), EOA, EOAi*, aortic valve 
regurgitation (severity/regurgitation site), maximum blood flow rate, LVEF, left ventricular 
mass, LVMI* 
 
Baseline BSA values must be used for calculation of EOAi and LVMI. 
x 
QOL questionnaire 
ż 
EuroQOL (see Appendix 4) 
ż 
SF-12 (Appendix 5) 
x 
Anticoagulant/antiplatelet drugs 
x 
Other concomitant medication/therapy 
x 
AE/device deficiency 
For a patient who has suffered a stroke, mRS must be evaluated within 30 to 90 days and beyond 
90 days as earlier as from the onset of stroke. 
 
10.2.7 At 1 year post-procedural follow-up observation 
The tests/observation at 1 year post-procedural follow-up should be performed at 365 days post-procedural 
visit (± 30 days) to collect the data on the following items. 
 
x 
NYHA classification of cardiac performance (see Section 30 “GLOSSARY”) 
x 
CCS status of stable angina (see Section 30 “GLOSSARY”) 
x 
Neurological examination 
ż 
NIHSS (see Appendix 1) 
ż 
mRS (see Appendix 2) 
* Neurological assessment should be performed by a neurologist, neurosurgeon, or a physician 
who is able to perform appropriate assessment.㻌
x 
Blood pressure (systolic, diastolic) 
x 
12-lead ECG 
x 
Chest X-ray 
x 
Head CT 
x 
Six-minute walk test (see Appendix 3) 
x 
Clinical laboratory test 
ż 
Hematology 
Red blood cell count, hemoglobin, hematocrit, platelet count, white blood cell count, 
differential white blood cell count (neutrophil, lymphocyte, monocyte, eosinophil, 

Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 84 - 
basophil) 
ż 
Biochemistry 
Sodium, potassium, creatinine, urea nitrogen, albumin, total bilirubin, CRP, GOT(AST), 
GPT(ALT), LDH, hemoglobin A1c, glycated albumin, phosphate, calcium 
ż 
Coagulation 
Prothrombin time, activated partial thromboplastin time 
ż 
Cardiac enzyme 
CK and troponin, or CK-MB and troponin 
x 
Echocardiography 
Perform echocardiography in reference to the Echo Core Laboratory Procedure to 
measure/evaluate the following items. The resulted echocardiographic images should be 
submitted to the Echo Core Laboratory. 
[Measurements/endpoints] 
Cardiac output, aortic valve pressure gradient (mean/maximum), EOA, EOAi*, aortic valve 
regurgitation (severity/regurgitation site), maximum blood flow rate, LVEF, left ventricular 
mass, LVMI* 
 
Baseline BSA values must be used for calculation of EOAi and LVMI. 
x 
QOL questionnaire 
ż 
EuroQOL (see Appendix 4) 
ż 
SF-12 (Appendix 5) 
x 
Anticoagulant/antiplatelet drugs 
x 
Blood purification 
Investigate the latest dialysis prior to the 1 year post-procedural follow-up visit. 
x 
Other concomitant medication/therapy 
x 
AE/device deficiency 
For a patient who has suffered a stroke, mRS must be evaluated within 30 to 90 days and beyond 
90 days as earlier as from the onset of stroke. 
 
10.2.8 Years 2 through 5 annual post-procedure visits 
The tests/observation at 2 to 5 years post-procedural follow-up should be performed within the permissible 
time windows shown in Section 10.1 “Test/observation schedule” to collect the data on the following items. 
 
x 
NYHA classification of cardiac performance (see Section 30 “GLOSSARY”) 
x 
CCS status of stable angina (see Section 30 “GLOSSARY”) 
x 
Echocardiography 
Perform echocardiography in reference to the Echo Core Laboratory Procedure to 
measure/evaluate the following items. The resulted echocardiographic images should be 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 85 - 
submitted to the Echo Core Laboratory. 
[Measurements/endpoints] 
Cardiac output, aortic valve pressure gradient (mean/maximum), EOA, EOAi*, aortic valve 
regurgitation (severity/regurgitation site), maximum blood flow rate, LVEF, left ventricular 
mass, LVMI* 
 
Baseline values must be used for calculation of EOAi and LVMI. 
x 
QOL questionnaire 
ż 
EuroQOL (see Appendix 4) 
ż 
SF-12 (Appendix 5) 
x 
Anticoagulant/antiplatelet drugs 
x 
AE/device deficiency 
 
10.2.9 At trial discontinuation 
At trial discontinuation, collect the data on the following items. If any AE is found at discontinuation, a 
follow-up investigation should be performed, and also the safety after discontinuation should be followed 
up as much as possible. For detailed subject’s trial discontinuation, see Sections 14.1 and 14.2. 
 
x 
Anticoagulant/antiplatelet drugs 
x 
Other concomitant drugs/therapies (until 1 year post-procedure) 
x 
AE/device deficiency 
For a patient who has suffered a stroke within 1 year post-procedure, mRS must be evaluated 
within 30 to 90 days and beyond 90 days as earlier as from the onset of stroke. 
 
10.2.10 Unscheduled visit 
If a subject made an unscheduled visit other than those specified in the protocol formedical necessity, 
collect the data on the following items. 
 
x 
Anticoagulant/antiplatelet drugs 
x 
Other concomitant drugs/therapies (until 1 year post-procedure) 
x 
AE/device deficiency 
For a patient who has suffered a stroke within 1 year post-procedure, mRS must be evaluated 
within 30 to 90 days and beyond 90 days as earlier as from the onset of stroke. 
 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 86 - 
10.3 Test/Observation Items for the Continued Access Registry 
10.3.1 Baseline 
For the baseline tests/observations, the following data will be collected from subject consent to before the 
study procedure. From the standpoint of protection of subjects, if any data are available on the tests 
performed within the permissible time windows specified in the protocol, the data obtained before informed 
consent and data used for screening may be used as baseline data. 
 
x 
Informed consent 
x 
Conformance to the inclusion/exclusion criteria for the continued access registry 
x 
Patient background 
ż 
Demographic background 
Sex, date of birth, and age (calculated from the date of birth) 
ż 
Physical finding 
Height, weight, BSA, and BMI 
* BSA and BMI will be calculated from height and weight in the following formulas. 
¾ BSA = 0.007184 u Weight [kg]0.425 u Height [cm]0.725 
¾ BMI = Weight [kg]/Height [m]2 
ż 
Clinical background 
Primary disease, risk factors (pre-procedural complication, past history, history of 
syncope not associated with atrioventricular block, number of hospitalization for AS in 
the past 6 months, and stroke in the past 12 months), type of dialysis (hemodialysis or 
peritoneal dialysis), the starting time  of dialysis, duration of dialysis (to be calculated 
from the starting time of dialysis), and primary disease for introduction of dialysis 
x 
Surgical risk assessment 
After investigation/evaluation of surgical risks and risk score, evaluate patients who are not 
eligible for safe open surgical therapy as to whether or not the best therapy is treatment with 
EWJ-003. 
ż 
STS score [http://riskcalc.sts.org/stswebriskcalc/#/] 
ż 
Logistic EuroSCORE [http://www.euroscore.org/calcold.html] 
ż 
EuroSCORE II [http://www.euroscore.org/calc.html] 
* The results of risk score should be printed out and affixed to medical records, etc.㻌
x 
NYHA classification of cardiac performance (see Section 30 “GLOSSARY”) 
x 
CCS status of stable angina (see Section 30 “GLOSSARY”) 
x 
Neurological examination 
ż 
NIHSS (see Appendix 1) 
ż 
mRS (see Appendix 2) 
* Neurological assessment should be performed by a neurologist, neurosurgeon, or a physician 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 87 - 
who is able to perform appropriate assessment. 
x 
Blood pressure (systolic, diastolic) 
x 
12-lead ECG (to be performed within 48 hours prior to entering the operating room) 
x 
Chest X-ray 
x 
Head CT 
x 
Laboratory tests (to be performed within 14 days pre-procedure) 
ż 
Hematology 
Red blood cell count, hemoglobin, hematocrit, platelet count, white blood cell count, 
differential white blood cell count (neutrophil, lymphocyte, monocyte, eosinophil, 
basophil) 
ż 
Biochemistry 
Sodium, potassium, creatinine, urea nitrogen, albumin, total bilirubin, CRP, GOT(AST), 
GPT(ALT), LDH, hemoglobin A1c, glycated albumin, phosphate, calcium 
ż 
Coagulation 
Prothrombin time, activated partial thromboplastin time 
ż 
Cardiac enzyme 
CK and troponin, or CK-MB and troponin 
x 
Echocardiography 
Perform echocardiography in reference to the Echo Core Laboratory Procedure to 
measure/evaluate the following items. The resulted echocardiographic images should be 
submitted to the Echo Core Laboratory. 
[Measurements/endpoints] 
Cardiac output, aortic valve pressure gradient (mean/maximum), AVA, AVA index, aortic valve 
regurgitation (severity/regurgitation site), aortic annulus diameter*, maximum aortic flow 
velocity, LVEF, left ventricular mass, LVMI, valvular and paravalvular conditions 
* The aortic annulus diameter should be estimated from the LVOT dimension.㻌
x 
Cardiac CT 
[Measurements/endpoints] 
Aortic annulus diameter, aortic annulus area, distance from aortic annulus to coronary ostium 
x 
Coronary angiography (except cases that may be clinically valid, perform within 1 year prior to 
the study procedure) 
* If a subject has no hypersensitivity to contrast media, but contrast media cannot be used due 
to other disease, MRI may be used. 
x 
Aortofemoral vascular evaluation (to be performed within 90 days pre-procedure) 
Perform CT, MRI, or X-ray to evaluate from the aorta through to the femoral artery. 
x 
QOL questionnaire 
ż 
EuroQOL (see Appendix 4) 
ż 
SF-12 (Appendix 5) 

Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 88 - 
x 
Anticoagulant/antiplatelet drugs (investigated from 7 days prior to the procedure) 
x 
Blood purification㻌
Investigate the latest dialysis prior to the procedure. 
 
10.3.2 During procedure 
The test/observation during procedure will collect the data on the following items. 
 
x 
Echocardiography (perform observation items of cardiac catheter test according to the aortic 
annulus diameter and situation) 
x 
Cardiac catheter test (to be performed immediately before and after the procedure. It may be 
replaced with echocardiography according to the situation) 
[Measurements/endpoints] 
Aortic pressure (systolic/diastolic/mean), aortic valve pressure gradient (mean/maximum), 
AVA (immediately before procedure only), EOA (immediately after procedure only), aortic 
valve regurgitation (severity/regurgitation site) 
x 
Procedure information 
Date of procedure, delivery means, time of procedure, predilatation information, valve 
implantation information, maximum ACT, anesthesia procedure, X-ray status, contrast media 
status, evaluation of procedure, device information, aortic annulus diameter used for selection 
of THV size and measurement method 
x 
Anticoagulant/antiplatelet drugs 
x 
Other concomitant drugs/therapies (to be investigated from right after the start of the study 
procedure) 
x 
AE/defect (to be investigated from right after the start of the study procedure) 
For a patient who has suffered a stroke, mRS must be evaluated within 30 to 90 days and beyond 
90 days as earlier as from the onset of stroke. 
 
10.3.3 Immediately after procedure 
The test/observation immediately after the procedure will collect the data on the following items until 72 
hours after exiting the operation room. 
 
x 
12-lead ECG 
x 
Chest X-ray 
x 
Cardiac enzyme test (CK and troponin, or CK-MB and troponin) 
x 
Anticoagulant/antiplatelet drugs 
x 
Blood purification 
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x 
Other concomitant medication/therapy 
x 
AE/device deficiency 
For a patient who has suffered a stroke, mRS must be evaluated within 30 to 90 days and beyond 
90 days as earlier as from the onset of stroke. 
 
10.3.4 Hospital discharge 
For the tests/observation at hospital discharge will collect the data on the following items on the day of 
discharge or 7 days post-procedure, whichever comes earlier (± 2 days). 
 
x 
NYHA classification of cardiac performance (see Section 30 “GLOSSARY”) 
x 
CCS status of stable angina (see Section 30 “GLOSSARY”)㻌
x 
Blood pressure (systolic, diastolic) 
x 
12-lead ECG 
x 
Chest X-ray 
x 
Cardiac enzyme test (CK and troponin, or CK-MB and troponin) 
x 
Echocardiography 
Perform echocardiography in reference to the Echo Core Laboratory Procedure to 
measure/evaluate the following items. 
[Measurements/endpoints] 
Cardiac output, aortic valve pressure gradient (mean/maximum), EOA, EOAi*, aortic valve 
regurgitation (severity/regurgitation site), maximum blood flow rate, LVEF, left ventricular 
mass, LVMI* 
 
Baseline BSA values must be used for calculation of EOAi and LVMI. 
x 
Anticoagulant/antiplatelet drugs 
x 
Blood purification 
x 
Other concomitant medication/therapy 
x 
AE/device deficiency 
For a patient who has suffered a stroke, mRS must be evaluated within 30 to 90 days and beyond 
90 days as earlier as from the onset of stroke. 
 
10.3.5 At 30 days post-procedural follow-up observation 
The tests/observation at 30 days post-procedure should be performed at 30 days post-procedural visit 
(-7 days, +14 days) to collect the data on the following items. 
 
x 
NYHA classification of cardiac performance (see Section 30 “GLOSSARY”) 
x 
CCS status of stable angina (see Section 30 “GLOSSARY”) 
Protocol 
 
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x 
Neurological examination 
ż 
NIHSS (see Appendix 1) 
ż 
mRS (see Appendix 2) 
* Neurological assessment should be performed by a neurologist, neurosurgeon, or a physician 
who is able to perform appropriate assessment.㻌
x 
Blood pressure (systolic, diastolic) 
x 
12-lead ECG 
x 
Chest X-ray 
x 
Head CT 
x 
Clinical laboratory test 
ż 
Hematology 
Red blood cell count, hemoglobin, hematocrit, platelet count, white blood cell count, 
differential white blood cell count (neutrophil, lymphocyte, monocyte, eosinophil, 
basophil) 
ż 
Biochemistry 
Sodium, potassium, creatinine, urea nitrogen, albumin, total bilirubin, CRP, GOT(AST), 
GPT(ALT), LDH, hemoglobin A1c, glycated albumin, phosphate, calcium 
ż 
Coagulation 
Prothrombin time, activated partial thromboplastin time 
ż 
Cardiac enzyme 
CK and troponin, or CK-MB and troponin 
x 
Echocardiography 
Perform echocardiography in reference to the Echo Core Laboratory Procedure to 
measure/evaluate the following items. The resulted echocardiographic images should be 
submitted to the Echo Core Laboratory. 
 
 
Protocol 
 
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[Measurements/endpoints] 
Cardiac output, aortic valve pressure gradient (mean/maximum), EOA, EOAi*, aortic valve 
regurgitation (severity/regurgitation site), maximum blood flow rate, LVEF, left ventricular 
mass, LVMI* 
 
Baseline BSA values must be used for calculation of EOAi and LVMI. 
x 
QOL questionnaire 
ż 
EuroQOL (see Appendix 4) 
ż 
SF-12 (Appendix 5) 
x 
Anticoagulant/Antiplatelet drugs 
x 
Other concomitant medication/therapy 
x 
AE/device deficiency 
For a patient who has suffered a stroke, mRS must be evaluated within 30 to 90 days and beyond 
90 days as earlier as from the onset of stroke. 
 
10.3.6 At 6 months post-procedural follow-up 
The tests/observation at 6 months post-procedural follow-up should be performed at 182 days 
post-procedural visit (± 30 days) to collect the data on the following items. 
 
x 
NYHA classification of cardiac performance (see Section 30 “GLOSSARY”) 
x 
CCS status of stable angina (see Section 30 “GLOSSARY”) 
x 
Neurological examination (to be performed only for patients diagnosed with a stroke after the 
procedure) 
ż 
NIHSS (see Appendix 1) 
ż 
mRS (see Appendix 2) 
* Neurological assessment should be performed by a neurologist, neurosurgeon, or a physician 
who is able to perform appropriate assessment.㻌
x 
Blood pressure (systolic, diastolic) 
x 
12-lead ECG 
x 
Chest X-ray 
x 
Head CT (to be performed only for patients diagnosed with a stroke after the procedure) 
x 
Clinical laboratory test 
ż 
Hematology 
Red blood cell count, hemoglobin, hematocrit, platelet count, white blood cell count, 
differential white blood cell count (neutrophil, lymphocyte, monocyte, eosinophil, 
basophil) 
ż 
Biochemistry 
Sodium, potassium, creatinine, urea nitrogen, albumin, total bilirubin, CRP, GOT(AST), 

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GPT(ALT), LDH, hemoglobin A1c, glycated albumin, phosphate, calcium 
ż 
Coagulation 
Prothrombin time, activated partial thromboplastin time 
ż 
Cardiac enzyme 
CK and troponin, or CK-MB and troponin 
x 
Echocardiography 
Perform echocardiography in reference to the Echo Core Laboratory Procedure to 
measure/evaluate the following items. The resulted echocardiographic images should be 
submitted to the Echo Core Laboratory. 
[Measurements/endpoints] 
Cardiac output, aortic valve pressure gradient (mean/maximum), EOA, EOAi*, aortic valve 
regurgitation (severity/regurgitation site), maximum blood flow rate, LVEF, left ventricular 
mass, LVMI* 
 
Baseline BSA values must be used for calculation of EOAi and LVMI. 
x 
QOL questionnaire 
ż 
EuroQOL (see Appendix 4) 
ż 
SF-12 (Appendix 5) 
x 
Anticoagulant/antiplatelet drugs 
x 
Other concomitant medication/therapy 
x 
AE/device deficiency 
For a patient who has suffered a stroke, mRS must be evaluated within 30 to 90 days and beyond 
90 days as earlier as from the onset of stroke. 
 
10.3.7 At 1 year post-procedural follow-up observation 
The tests/observation at 1 year post-procedural follow-up should be performed at 365 days post-procedural 
visit (± 30 days) to collect the data on the following items. 
 
x 
NYHA classification of cardiac performance (see Section 30 “GLOSSARY”) 
x 
CCS status of stable angina (see Section 30 “GLOSSARY”) 
x 
Neurological examination (to be performed only for patients diagnosed with a stroke after the 
procedure) 
ż 
NIHSS (see Appendix 1) 
ż 
mRS (see Appendix 2) 
* Neurological assessment should be performed by a neurologist, neurosurgeon, or a physician 
who is able to perform appropriate assessment.㻌
x 
Blood pressure (systolic, diastolic) 
x 
12-lead ECG 
Protocol 
 
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Jaunuary 6, 2020 
 
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x 
Chest X-ray 
x 
Head CT (to be performed only for patients diagnosed with a stroke after the procedure) 
x 
Clinical laboratory test 
ż 
Hematology 
Red blood cell count, hemoglobin, hematocrit, platelet count, white blood cell count, 
differential white blood cell count (neutrophil, lymphocyte, monocyte, eosinophil, 
basophil) 
ż 
Biochemistry 
Sodium, potassium, creatinine, urea nitrogen, albumin, total bilirubin, CRP, GOT(AST), 
GPT(ALT), LDH, hemoglobin A1c, glycated albumin, phosphate, calcium 
ż 
Coagulation 
Prothrombin time, activated partial thromboplastin time 
ż 
Cardiac enzyme 
CK and troponin, or CK-MB and troponin 
x 
Echocardiography 
Perform echocardiography in reference to the Echo Core Laboratory Procedure to 
measure/evaluate the following items. The resulted echocardiographic images should be 
submitted to the Echo Core Laboratory. 
[Measurements/endpoints] 
Cardiac output, aortic valve pressure gradient (mean/maximum), EOA, EOAi*, aortic valve 
regurgitation (severity/regurgitation site), maximum blood flow rate, LVEF, left ventricular 
mass, LVMI* 
 
Baseline BSA values must be used for calculation of EOAi and LVMI. 
x 
QOL questionnaire 
ż 
EuroQOL (see Appendix 4) 
ż 
SF-12 (Appendix 5) 
x 
Anticoagulant/antiplatelet drugs 
x 
Blood purification 
Investigate the latest dialysis prior to the 1 year post-procedural follow-up visit. 
x 
Other concomitant medication/therapy 
x 
AE/device deficiency 
For a patient who has suffered a stroke, mRS must be evaluated within 30 to 90 days and beyond 
90 days as earlier as from the onset of stroke. 
 
10.3.8 Years 2 through 5 annual post-procedure visits 
The tests/observation at 2 to 5 years post-procedural follow-up should be performed within the permissible 
time windows shown in Section 10.1 “Test/observation schedule” to collect the data on the following items. 
Protocol 
 
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Date of creation: 
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Jaunuary 6, 2020 
 
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x 
NYHA classification of cardiac performance (see Section 30 “GLOSSARY”) 
x 
CCS status of stable angina (see Section 30 “GLOSSARY”) 
x 
Echocardiography 
Perform echocardiography in reference to the Echo Core Laboratory Procedure to 
measure/evaluate the following items. The resulted echocardiographic images should be 
submitted to the Echo Core Laboratory. 
[Measurements/endpoints] 
Cardiac output, aortic valve pressure gradient (mean/maximum), EOA, EOAi*, aortic valve 
regurgitation (severity/regurgitation site), maximum blood flow rate, LVEF, left ventricular 
mass, LVMI* 
 
Baseline BSA values must be used for calculation of EOAi and LVMI. 
x 
QOL questionnaire 
ż 
EuroQOL (see Appendix 4) 
ż 
SF-12 (Appendix 5) 
x 
Anticoagulant/antiplatelet drugs 
x 
AE/device deficiency 
 
10.3.9 At trial discontinuation and unscheduled visits 
When a subject enrolled in continued access registry discontinues the trial, and if the subject made an 
unscheduled visit other than those specified in the protocol for necessity as specified in Section 10.2.9, 
collect the data in accordance with Section 10.2.10. 
 
 
 
 
 
Protocol 
 
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Date of creation: 
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11 
ADVERSE EVENT/DEVICE DEFICIENCY 
11.1 Definition of Adverse Events 
An AE is any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users, or other persons, whether or not related to the 
study device. However, for an event occurred in persons other than the subjects, it should be limited to an 
event suspected to be associated with the use of the study device.

The observation period for AEs will be from the start of the study procedure through to the final follow-up 
observation visit. A disease developed between the time of informed consent and the start of the study 
procedure, which has not recovered at the start of the study procedure, should be handled as a 
pre-procedural complication.
 
11.2 Definition of Serious Adverse Events 
An SAE is an event applicable to the followings, in accordance with the PMD Act Enforcement 
Regulations Article 274-2, irrespective of causal relationship to the study device. 
 
(a) Death 
(b) Those that may lead to death 
(c) Those requiring inpatient hospitalization or prolongation of existing hospitalization for treatment 
(d) Disability 
(e) Those that may lead to disability 
(f) Serious cases in accordance with those in (a) to (e) 
(g) Any congenital disease or abnormality in the offspring of a treated patient 
 
However, hospitalization without a newly developed AE or aggravated pre-procedural complication as 
shown in the followings is not regarded as an SAE, not requiring reporting to the sponsor. 
 
x 
Hospitalization for treatment scheduled before the procedure (e.g.: hospitalization for surgery for 
pre-procedural complication that became possible due to improvement in the heart condition)㻌
x 
Hospitalization for management (e.g.: regular checkup, hospitalization for examination, 
educational hospital admission)㻌
x 
Admission to a rehabilitation facility㻌
 
If an SAE is found, the investigators should take appropriate actions, and immediately report to the sponsor 
(see Section 11.5 “Serious Adverse Events Reporting”).
 

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11.3 Adverse Events Associated with Laboratory Test Abnormal Variations 
If any abnormal variations from baseline are found in the laboratory tests, blood pressure, and ECG as 
specified in the protocol, and if the value is applicable to the definition of SAE, or if the principal 
investigator or subinvestigators judges the value as an AE, the event should be handled as an AE. Also for a 
clinically important abnormal finding is found in the test items not specified in the protocol, and if the 
finding is applicable to the definition of SAE, or if the principal investigator or subinvestigators judges the 
finding as an AE, the finding should be handled as an AE. 
 
11.4 Device Deficiencies 
A device deficiency is defined as the failure of a device to meet its quality, safety, and performance 
specifications, such as damage and or malfunctioning, regardless of being associated with the design, 
supply, storage, or used. 
 
11.5 Serious Adverse Event Reporting 
If an SAE or defect that may cause an SAE is found after the start of the study procedure, the principal 
investigator or subinvestigators should take appropriate actions in accordance with the followings. 
 
(1) The principal investigator or subinvestigators should take appropriate actions for the subject, and 
regardless of the causal relationship to the study device, immediately report the SAE or defect that 
may cause an SAE to the sponsor orally, via telephone, e-mail, or FAX. 
(2) The investigator (if unavoidable, the subinvestigator under instructions from the investigator) should 
immediately report the details to the director of the study site and sponsor by forms such as “Report 
of serious adverse events”. 
(3) If an event that was assessed as non-serious at the time was reassessed as serious later by additional 
information, etc., the investigator should take the above-mentioned actions (1) to (2). 
 
After receiving the report from the principal investigator or subinvestigators, the sponsor should take the 
following actions. 
 
(4) If the sponsor is aware of any defect unforeseeable from the Investigational Devices Brochure among 
SAEs or failure that may cause an SAE, the sponsor should immediately report it to the investigators 
and directors of all study sites. 
(5) The sponsor will report a list of cases with an SAE that is suspected to be associated with the use of 
the study device or defect that may cause an SAE to the investigator and director of the study sites 
annually starting from the day of first notification of the study plan and within 3 months after the due 
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date of the annual reporting period. 
(6) In accordance with the PMD Act Enforcement Regulations Article 274-2, the sponsor should 
promptly report an SAE or defect that may cause an SAE to Minister of Health, Labour and Welfare. 
 
11.6 Records of Adverse Events 
In the event of an AE, it should be recorded in the eCRF in accordance with the followings. 
 
(1) The investigators should enter all AEs occurred during follow-up observation period in this clinical 
trial in the eCRFs. The investigators should enter the name of AEs. However, an extremely severe 
symptom is found in the diagnostic class, it should be entered as a separate event from the original 
diagnosis. If a definitive diagnosis cannot be clearly established, individual signs or symptoms should 
be recorded in the eCRF within 10 working days as a general rule. 
(2) The principal investigator or subinvestigators must confirm the outcome of the AE found in a subject, 
regardless of the causal relationship to the study device. 
(3) If an AE is found, the investigators should enter the followings in the eCRF. 
(a) Event:  
Enter the name of diagnosis as much as possible. If a definitive diagnosis cannot be clearly 
established, enter the signs or symptoms. 
(b) Date of onset: 
For subjective symptoms, enter the date of onset or exacerbation. For AEs based on the laboratory 
test abnormal variations, enter the date of consultation or test. 
(c) Severity: 
The severity of AEs will be assessed by the following 3 scales. 
Mild: 
With signs or symptoms that do not interfere with daily activities, or transient 
not requiring treatment with no secondary disorders 
Moderate: 
Interferes with daily activities, or requires symptomatic treatments 
Severe: 
With symptoms causing a significant pain, which enables to lead daily life, or 
requiring treatments 
(d) Severity: 
The severity of AEs will be assessed by the following classification. For definition of SAEs, see 
Section 11.2 “Definition of Serious Adverse Events”. 
1. 
Serious 
2. 
Non-serious 
(e) Measures taken for the study device: 
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Choose either one of the following 3 actions taken for the study device: 
1. 
No measures taken for the THV 
2. 
Valve explants 
3. 
Other action 
(f) Other measures taken: 
Record the other measures taken by the following classification: 
1. 
No 
2. 
Yes (measures taken) 
(g) Outcome: 
Choose either one of the following 6 outcomes for the AE: 
1. 
Recovered 
2. 
Resolving 
3. 
Not recovered 
4. 
Recovered with sequelae 
5. 
Death 
6. 
Unknown 
(h) Cause of death (only AEs with outcome of death): 
If the outcome of an AE is death, assess the cause of death by the following classification: See 
Section 30 “GLOSSARY - Death”. 
1. 
Cardiovascular death 
2. 
Non-cardiovascular death 
(i) Date of outcome (date of the clinical course was confirmed): 
Enter the date of the outcome was determined. For a death case enter the date of death, and for 
laboratory test abnormality enter the date of consultation or test as the date of outcome. If assessed 
as not recovered, regardless of whether or not related to the study device or study device 
implantation procedure, except for irreversible AEs or exacerbation of pre-existing complication, 
the event should be followed up until recovery as a general rule and make an additional report. If a 
persistent, irreversible AE, or exacerbation of pre-existing complication is determined to be 
unnecessary to perform follow-up investigation until recovery, enter the assessment in the 
comment field of the eCRF. 
(j) Causal relationship to the study device and study procedure: 
Assess the causal relationship to the study device or study procedure by the following 
classification: 
Definitely related: 
Applicable to any one of the following a) to c) 
a) 
Has a temporal relationship 
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b) 
The AE abates upon completion of device application or 
implantation procedure 
c) 
The AE cannot be clearly explained by the subject’s 
condition or pre-procedural complication 
Possibly related: 
There may be a temporal relationship between the AE and the study 
device or implantation procedure, or the subject’s condition can be 
reasonably explained. 
Possibly unrelated: 
The temporal relation is unlikely between the AE and the study device 
or implantation procedure. 
Unrelated: 
There is no relation between the AE and the study device or 
implantation procedure 
 
Except for events assessed as “Unrelated”, handle AEs as with the relationship to the study device 
or study procedure. 
(k) Reason for the assessment result of “Unrelated” to the study device or study procedure: 
For AEs that were assessed as “Unrelated” to the study device or study procedure, enter the reason 
for the assessment result by the following classification: 
1. 
An event associated with physiological factors 
2. 
A pre-existing event associated with the primary disease or exacerbation of 
complication 
3. 
A transient and accidental event 
4. 
An event associated with concomitant drug or concomitant therapy 
5. 
Other 
(l) Comment: 
Enter the rationales for the judgment of the causal relationship of AEs to the study device or study 
procedure and the rationales for the judgement of abnormal laboratory test variations as an AE.. 
 
11.7 Follow-up Investigation of Adverse Events 
The investigators must follow up AEs until recovery as a general result or disease condition is stabilized, 
except for the following cases, and must report the additional information on the disease condition resulted 
from the follow-up investigation to the sponsor. 
 
x 
The principal investigator or subinvestigators judges that the outcome of the AE cannot be 
recorded because the AE is permanent with no prospect of recovery, etc. 
x 
The AE is exacerbation of pre-existing complication. 
x 
The subject is lost to follow-up. 

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x 
The principal investigator or subinvestigators judges that a follow-up investigation until recovery 
is unnecessary. 
 
AEs sustained at the end of the clinical trial or discontinuation of the trial, except for the above-mentioned 
cases, should be followed up until recovery or the disease condition is stabilized. 
 
 
 
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12 
MONITORING OF THE CLINICAL TRIAL BY DATA MONITORING 
COMMITTEE 
To ensure the safety of the subjects and ensure the ethical and scientific validity of the conduct of this 
clinical trial, Data Monitoring Committee (DMC) independent from the study organization including the 
sponsor and study sites will evaluate the intermediate data during the trial. The DMC consists of at least 3 
members, including physicians with expertise in the present disease area and study treatment and a clinical 
statistician, monitors as to whether the clinical trial is conducted safely and appropriately, and give advice 
and recommendations to the sponsor for changes to the protocol and as to whether the trial should be 
continued or not. The monitoring of this clinical trial by the DMC will be continued until the end of the 
enrollment in the continued access registry, and may be extended as needed. For DMC opening 
requirements and detailed activities and operating procedure, see “EWJ-003 Data Monitoring Committee 
Procedure.” 
 
When provision of information including autopsy records, etc. is requested by the DMC, the study sites 
should respond as much as possible. 
 
13 
EVALUATION BY THIRD-PARTY JUDGMENT ORGANIZATION 
13.1 Clinical Event Adjudication Committee 
To avoid bias among study sites and physicians, and to ensure consistent and objective evaluation, the 
major clinical events reported by the study sites will be assessed by Clinical Event Committee (CEC) that is 
independent from the study organization including the sponsor and study sites. The CEC consists of at least 
1 member with expertise in this present disease area and study treatment, and at least 1 member with 
expertise in neurological disease area, and as shown below, performs review and adjudication of all death 
cases and cases with stroke occurred in all enrolled subjects in this clinical trial (including continued access 
registry) up to 1 year post-procedure. For CEC opening requirements and detailed activities and operating 
procedure, see “EWJ-003 Clinical Event Adjudication Procedure.” 
 
x 
Death 
For all death cases reported by the study sites within 1 year post-procedure, the CEC will adjudicates the 
cause of death (cardiovascular or non-cardiovascular death) and the causal relationship to the study device 
and study procedure, in accordance with VARC-2 guideline[56] (see Section 30 “GLOSSARY”). 
 
x 
Stroke 
For all stroke cases reported by the study sites within 1 year post-procedure, the CEC will adjudicates the 
events (disabling stroke or non-disabling stroke) and the causal relationship to the study device and study 
procedure, in accordance with VARC-2 guideline[56] (see Section 30 “GLOSSARY”). 
 
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The study sites must submit source documents required for event adjudication by CEC of all death cases 
and cases with stroke occurred up to 1 year post-procedure via the monitor as much as possible. The source 
documents required for event adjudication are as shown in Table 13-1, but not limited to those. When 
provision of additional information is requested by the CEC, the study sites should respond as much as 
possible. 
 
Table 13-1: Source documents required for event adjudication by CEC 
Time of death 
Time of stroke onset 
x 
Death certificate 
x 
Autopsy record* 
x 
Discharge record 
x 
Head neuroimaging (head CT/MRI)* 
x 
Medical record 
x 
Medical record by a neurologist/neurosurgeon 
x 
mRS 
* When available 
 
13.2 Echo Core Laboratory 
To avoid bias among study sites and physicians, and to ensure consistent and objective evaluation, the 
echocardiographic parameters including EOA will be measured and evaluated by an echocardiography core 
laboratory that is independent from the study organization including the sponsor and study sites. The 
echocardiography core laboratory will appropriately measure/evaluate the echocardiographic parameters 
including EOA of all enrolled subjects in this clinical trial (including the continued access registry), using 
the echocardiographic imaging data at baseline, 30 days post-procedure, 6 months post-procedure, and 1 to 
5 years post-procedure annually. For details, see the “Echo Core Laboratory Procedure.” 
 
The study sites should provide the echocardiographic imaging data (CD-ROM or DVD) at baseline, 30 
days post-procedure, 6 months post-procedure, and 1 to 5 years post-procedure annually to the Echo Core 
Laboratory via the monitor. 
 
 
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14 
SUBJECT TREATMENT DISCONTINUATION 
14.1 Subject Treatment Discontinuation 
Enrolled subjects will continuously participate in the clinical trial until all follow-up observations specified 
in the protocol are completed. However, the following subjects should discontinue the trial.

x 
A subject or the legal representative requests discontinuation of the participation in the clinical 
trial. 
x 
The principal investigator or subinvestigators judges that continued trial will be a disadvantage 
for subject’s health condition.
x 
The study procedure has not been started.
x 
When the subject is exiting the operation room, the investigational valve has not been implanted. 
x 
The investigational valve was removed. 
x 
The subject died. 
x 
Continued participation in the clinical trial was deemed difficult. 
x 
The sponsor requests (continued trial was determined to be a disadvantage in the subjects). 
 
14.2 Subject Treatment Discontinuation Procedure 
When a subject discontinues participation in the clinical trial, the following procedure should be used. 
 
(1) The investigators should enter the date of discontinuation, reason for discontinuation, AE incidence 
status, and drug therapy status in the eCRFs. To ensure the safety of discontinued subjects, all possible 
measures should be taken, appropriate treatment should be given, and also for the safety after 
discontinuation, perform follow-up investigation as much as possible. 
(2) If a subject discontinued the trial due to a safety issue arise from an incidence of AE or worsened 
disease, the investigators enter it in the eCRF in accordance with Section 11 “ADVERSE EVENTS.” 
(3) If an AE is found at the time of discontinuation, the investigators should perform a follow-up 
investigation of the AE. 
(4) The investigators should promptly inform the sponsor of the subject’s treatment discontinuation. 
 
14.3 Follow-up Investigation of Subjects with Missing Visits 
If a subject miss the follow-up observation as specified in the protocol because the subject failed to visit, 
the investigators should contact the subject as much as possible to investigate the subject’s health condition 
(confirmation of survival, the presence or absence of an AE). In such a case, enter the contact means, date 
of contact, subject’s condition, and the reason for missing visit in the eCRF. When after trying to contact to 
the subject, but the subject could not be reached, enter the fact, date of contact, contact means the eCRF. 
 
 

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15 
STATISTICAL ANALYSIS 
15.1 Safety and Efficacy Analysis of EWJ-003 
In this clinical trial, the safety and efficacy of EWJ-003 will be evaluated in subjects for whom the 
investigational valve was dilated at a nominal volume. Subjects in the bailout treatment registry in whom 
the THV could not be dilated at a nominal volume will not be included in the analysis set (see Section 15.2 
“Bailout Treatment Registry Statistical Analysis”). Also subjects enrolled in the continued access registry 
will not be included in the analysis set for the safety and efficacy evaluation of EWJ-003 (see Section 15.3 
“Statistical Analysis of the Continued Access Registry”). 
 
15.1.1 Analysis sets 
15.1.1.1 Intent-to-treat analysis set 
Regardless of whether or not the study procedure was given, or whether or not the study device was 
implanted, the intent-to-treat (ITT) analysis set is defined as an analysis population consists of all subjects 
enrolled in this clinical trial. 
 
15.1.1.2 As-treated analysis set 
A subject population consisting of subjects who were enrolled in this clinical trial and implantation of the 
study device was initiated is defined as as-treated (AT) analysis set. The time when invasion such as 
incision was made on the access site is regarded as the start of the study procedure. The primary endpoint 
and secondary safety and efficacy endpoints will be analyzed in the AT analysis set. 
 
15.1.1.3 Valve implant analysis set 
The subject population consisting for all subjects in whom the THV was implanted, and when the subject 
exited the operation room the implanted THV was maintained is defined as valve implant (VI) analysis set. 
Subjects for whom the investigational valve was not implanted, including subjects switching to surgery, and 
TAVI bioprosthetic valve other than the investigational valve was implanted, will not be included in the VI 
analysis set. As for subjects who received a valve-in-valve procedure, cases with additional investigational 
valve implantation will be included in the VI analysis set, while cases with additional TAVI bioprosthetic 
valve other than the investigational valve will be excluded from the VI analysis set. The secondary valve 
performance endpoints based on the echocardiographic evaluation will be analyzed in the VI analysis set. 
 
15.1.2 Statistical analysis plan and statistical method 
Mortality at 1 year post-procedure, the primary endpoint, will be analyzed in the AT analysis set to verify 
the non-inferiority of EWJ-003 therapy to the standard therapy. The non-inferiority test will be performed 
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using one-sided Fisher’s exact test, and at one-sided significant level of 0.05 if the 95% CI upper limit for 
the mortality at 1 year post-procedure is lower than the PG (45%), non-inferiority of EWJ-003 therapy to 
the standard therapy would be verified. 
 
No statistical tests will be conducted for the secondary endpoints, but evaluate by descriptive statistics. The 
secondary valve performance endpoints based on the echocardiographic evaluation will be analyzed in the 
VI analysis set, and other secondary endpoints. Other data including subject background and baseline 
characteristics, and procedure information, etc. will be summarized by descriptive statistics. 
 
All statistical analyses will be performed for, in addition to the entire analysis sets, each approach of TF, TA, 
and TAo. For continuous variables, the number of measurements, mean, standard deviation, median, 
quartile, minimum, maximum, and 95% CI of the mean will be calculated. On the other hand, for 
categorical variables, the number of samples (n), percentage (%), and for binary variables 95% CI will be 
calculated. For the primary endpoint and secondary safety and efficacy endpoints, the cumulative incidence 
will be calculated by Kaplan-Meier estimates as needed. 
 
The detailed statistical analysis plan and statistical method are included in the Statistical Analysis Plan. 
 
15.2 Bailout Treatment Registry Statistical Analysis 
In this clinical trial, subjects enrolled in the bailout treatment registry will not be included in the analysis 
set for the safety and efficacy evaluation of EWJ-003. The bailout treatment registry will be analyzed 
separately as sub-analysis, which will primarily confirm the safety. In this sub-analysis, no statistical tests 
will be conducted. 
 
15.3 Statistical Analysis of the Continued Access Registry 
Subjects enrolled in the continued access registry will not be included in the analysis set for the safety and 
efficacy evaluation of EWJ-003. The continued access registry will be analyzed separately as sub-analysis, 
which will primarily confirm the safety. In this sub-analysis, no statistical tests will be conducted. 
 
15.4 Creation/Changes to Statistical Analysis Plan 
The person in charge of statistical analysis should create the Statistical Analysis Plan describing the 
statistical analysis plan and method for this clinical trial. 
 
When the statistical analysis plan is to be changed, the sponsor will examine the validity of the change and 
impact on the evaluation in this clinical trial to decide whether or not the change should be made. When the 
statistical analysis plan should be changed, a revision history should be created describing the changes 
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made and reasons for the changes, and the Statistical Analysis Plan should be revised. 
 
All deviations from the Statistical Analysis Plan should be described in the Study Report. 
 
 
 
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16 
ELECTRONIC CASE REPORT FORM 
16.1 Procedure for Electronic Case Report Form Creation and Precautions 
(1) The investigators should create eCRFs using electronic data capture (EDC) system. 
(2) The investigators should create an eCRF per subject. 
(3) The appropriately trained investigator, subinvestigator, and/or study staff should enter the data that 
were collected in accordance with the protocol in the eCRFs. The eCRFs may be completed by, in 
addition to the investigator, those appointed in “List of subinvestigators/study staff. ” 
(4) The sponsor will provide an explanation of entry and correction, in the eCRFs in accordance with 
“Guide for input into case report forms (eCRFs)”, to the investigator, subinvestigator, and/or study 
staff. 
(5) The investigators should create an eCRF per subject after the end of observation as soon as possible 
(as a general rule within 10 working days), and submit it to the sponsor. 
(6) The investigator should check the accuracy and validity of the data, and place name and a seal or sign 
the CRFs to be submitted to the sponsor. 
(7) The sponsor will retain the original CRFs submitted by the investigator. The study site or investigator 
should retain a copy of the submitted CRFs. 
 
16.2 Changes or Corrections to Electronic Case Report Forms 
(1) For changes/corrections before placing the name and seal or signature, the relevant sites should be 
changed or corrected. However, for changes/corrections to an important content (considerations 
concerning informed consent, changes to abnormal variations, name of AEs and causality), reasons 
for changes/corrections should be described in the applicable field. 
(2) For changes/corrections after placing the name and seal or signature, in addition to (1), place the 
name and a seal or sign again after the changes/corrections. 
 
16.3 Inconsistency Between Electronic Case Report Form and Source Document 
If any inconsistency is found between eCRF and source document, the investigator should create 
documents describing the contents and reasons for inconsistency. The investigator should place the name 
and a seal or sign the created document, and submit it to the sponsor. The investigator should retain a copy 
of the document.
 
 
 

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17 
PROTOCOL DEVIATIONS OR MODIFICATION 
The principal investigator or subinvestigators must not make any changes or deviate from this protocol 
without prior written agreement with the sponsor and written approval based on the IRB’s review. However, 
this is not applicable if it is medically evitable to eliminate immediate hazards to the subjects or only 
changes to the administrative matters in this clinical trial. The principal investigator or subinvestigators 
must record all protocol deviations whatever the reason may be. Of protocol deviations, deviations from the 
protocol to eliminate immediate hazards to the subjects or for other medically unavoidable reasons, the 
investigator must create records to explain the reasons and immediately submit the records to the sponsor 
and director of the study site. The principal investigator or subinvestigators may make any changes or 
deviate from this protocol without prior written agreement with the sponsor and written approval based on 
the IRB’s review, if it is for medically unavoidable reasons such as to eliminate immediate hazards to the 
subjects. In such a case, if the deviation or change, and reasons and revision of the protocol are appropriate, 
the investigator must submit the proposal to the sponsor, director of the study site, and to the IRB via the 
director of the study site as soon as possible, and obtain a written agreement of the director of the study site 
and written agreement from the sponsor via the director of the study site. For any changes that may 
significantly affect the conduct of the clinical trial or may increase hazards to the subject, the investigator 
must promptly submit a report to the sponsor, director of the study site, and IRB via director of the study 
site. 
 
18 
TRIAL DISCONTINUATION/SUSPENSION AND TERMINATION 
18.1 Discontinuation/Suspension of the Entire Trial 
In the following cases, the sponsor will discuss with medical advisors to decide whether or not the entire 
clinical trial should be discontinued or suspended. 
 
x 
Continued participation in the clinical trial is deemed difficult due to an incidence of 
unpredictable SAE. 
x 
Occurrence of significant disease that may interfere with continued clinical trial, disorder, or 
death is reported. 
 
Discontinuation or suspension of the entire clinical trial should be carried out in accordance with the 
following procedure. 
 
(1) If discontinuation or suspension of the entire clinical trial is decided, the sponsor will immediately 
notify all directors of the study sites and the regulatory authority of the discontinuation or suspension 
and its reason in writing. 
(2) When the sponsor decides and notifies discontinuation or suspension of the entire clinical trial, the 
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director of the study site should promptly notify the investigator and IRB in writing, and provide a 
written explanation about the discontinuation or suspension. 
(3) If discontinuation or suspension of the entire clinical trial is decided, the investigator should promptly 
notify, and provide the subjects with appropriate medical care and take other necessary measures. 
(4) When this clinical trial is discontinued or suspended, the study sites should return the study materials 
(study device, etc.) to the sponsor. 
 
18.2 Discontinuation/Suspension at Individual Study Sites 
In the following cases, the study sites should discontinue or suspend the clinical trial. 
 
x 
The investigator judges that the clinical trial should be discontinued. 
x 
The director of the study site or IRB judges that the clinical trial should be discontinued. 
x 
The sponsor judges that a violation of the J-GCP, protocol, or clinical trial contract by the study 
site hindered proper conduct of the clinical trial. 
 
Discontinuation or suspension of the clinical trial at individual study sites should be carried out in 
accordance with the following procedure. 
 
(1) Discontinuation or suspension decided by the investigator 
If the investigator discontinues or suspends this clinical trial at the his/her discretion, the investigator 
should promptly notify the director of the study site of discontinuation or suspension and reasons in 
writing. When the investigator decides and notifies discontinuation or suspension of the clinical trial, 
the director of the study site should promptly notify the IRB and sponsor of discontinuation or 
suspension and reasons in writing. 
(2) Discontinuation or suspension decided by the director of the study site or IRB 
The director of the study site should promptly notify the sponsor, investigator, and IRB, of the 
decision of discontinuation or suspension at the discretion of the director or IRB in writing. 
(3) Discontinuation or suspension decided by the sponsor 
When the sponsor decides and notifies discontinuation or suspension of the clinical trial, the director 
of the study site should promptly notify the investigator and IRB in writing, and provide a written 
explanation about the discontinuation or suspension. 
 
In any of the above cases, the sponsor will promptly notify all directors of the study sites and the regulatory 
authority of the discontinuation or suspension and its reason in writing. If discontinuation or suspension of 
the clinical trial is decided, the investigator should promptly notify, and provide the subjects with 
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appropriate medical care and take other necessary measures. The study sites should return the study 
materials (study device, etc.) to the sponsor. 
 
18.3 Termination of the Clinical Trial 
When the number of enrolled subjects in this clinical trial reached the target number of subjects specified in 
the protocol, and at the time point when the last subject completed follow-up observation at 5 years 
post-procedure or when this clinical trial is prematurely discontinued, the entre clinical trial is considered to 
be completed. However, in this clinical trial, study report will be created at the time point when the data on 
the EWJ-003 analysis set up to 1 year post-procedure have been collected, which should be attached to the 
approval application for the purpose of the expanded indications of EWJ-003, and therefore even before the 
last subject completes follow-up observation at 5 years post-procedure, acquisition of marketing approval 
for EWJ-003 may be regarded as completion of this clinical trial. In such a case, this clinical trial will be 
switched to a post-marketing clinical trial after acquisition of the marketing approval, and will be continued 
until completion of follow-up observation at 5 years post-procedure by the last subject. (See Section 28 
“CONSIDERATION AFTER MARKETING APPROVAL”). 
 
Completion of this clinical trial at study site should be carried out in accordance with the following 
procedure. 
 
(1) When the clinical trial is completed at the study site, the investigator should promptly notify the 
director of the study site of completion of the trial in writing, and report the summary of the trial 
results in writing based on the regulations of the study site. 
(2) When the investigator notifies completion of the clinical trial, the director of the study site should 
promptly notify the IRB and sponsor in writing, and report the summary of the trial results based on 
the submitted report by the investigator. 
(3) The sponsor will carry out the procedure for completion of the clinical trial at the study site. The 
investigator and director of the study site should carry out the procedure for completion of the clinical 
trial in accordance with the regulations of the study site. 
(4) When this clinical trial is completed, the study site should return all the study materials (study device, 
etc.) to the sponsor. 
 
19 
RECORD RETENTION 
19.1 Study Site 
The record keeping manager appointed by the director of the study site will maintain essential documents 
concerning the clinical trial to be retained in the study site as specified in the J-GCP for either of the 
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following period (1) or (2), whichever comes later. 
 
(1) The date of marketing approval of the study device (or 3 years following the date that the 
Sponsor notified the decision not to attach the documents of the study results as specified in the 
J-GCP Article 32-3 to the marketing approval application form as specified in the PMD Act 
Article 23-2-5 Section 3) 
(2) Three years after discontinuation or completion of the clinical trial. 
 
However, if the record retention period provided above becomes difficult for the reason of the study site or 
extended per request by the sponsor, the sponsor and the study sites will discuss the duration and method of 
retention. 
 
The investigator must retain the trial-related documents and records in accordance with the instructions 
given by the director of the study site. The records subject to storage include letters to the sponsor, 
documents for the meetings, and communications via telephone about important considerations related to 
the trial. 
 
19.2 Sponsor 
The sponsor will maintain all study records to be retained as specified in the J-GCP for either of the 
following period (1) or (2), whichever comes later: 
 
(1) Five years after the day of marketing approval for the medical device related to the study device 
in this clinical trial (or, 3 years after the day when discontinuation of the development of the 
device was decided). 
(2) Three years after discontinuation or completion of the clinical trial. 
 
If retention of the trial-related records to be retained by the founder of IRB and director of the study site 
becomes unnecessary, the sponsor will notify the founder of IRB and director of the study site. 
 
20 
TRAINING 
The investigators must complete the training course provided by the sponsor. The training course includes 
trainings for the protocol, eCRFs, and study device, and the investigators must not perform the study 
procedure before completion of these trainings. The subjects for each training program are as shown in 
Table 20-1. 
 

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Table 20-1: Training subjects 
Training program 
Training subjects 
Training for the protocol 
All investigators, subinvestigators, and study staff 
Training for eCRFs 
Investigators, subinvestigators and/or study staff who will 
enter the data in eCRFs 
Training for the study device 
Investigators, subinvestigators, and study staff, who will be 
engaged in the study procedure 
 
Since the TF system, the study device, already has been approved in Japan, if completed the training for the 
transfemoral system prior to the use in clinical practice, re-training would not be required. As for the 
training for the TA/TAo systems, all investigators, subinvestigators, and study staff must complete the 
training course before performing the study procedure using the relevant system. Records of training will 
be documented and retained by the sponsor. 
 
 
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21 
DIRECT ACCESS TO SOURCE DOCUMENTS 
21.1 Identification of Source Documents 
Source documents are records required for reproduction and evaluation of the course of the trial, such as 
subject’s medical records, the study device use records, etc. Of the data recorded in eCRFs, records of the 
following items in the eCRFs may be handled as source documents. 
 
(1) Descriptions of AEs (severity, seriousness, causality, outcome, cause of death, treatments given, and 
comments) 
(2) Descriptions of defects (name of defect, detailed information on defect) 
(3) Date and reason for discontinuation 
(4) Follow-up investigation of subjects with missing visits 
(5) Descriptions of concomitant drug/therapy 
(6) Clinical decisions and views of the principal investigator or subinvestigators 
 
21.2 Procedure for Direct Access 
The director of the study site and investigator should accept and cooperate in monitoring and audits by the 
sponsor as well as an investigation by the IRB and regulatory authority. In such cases, upon requests by the 
monitor, auditor, IRB, and regulatory authority, provide all trial-related records including source documents 
for direct access. The sponsor will discuss with the investigator and director of the study site about the 
direct access procedure, timing, and items to be reviewed, and then directly access to the documents for 
review. 
 
22 
CLINICAL TRIAL QUALITY CONTROL AND QUALITY 
ASSURANCE 
22.1 Quality Control 
In order to ensure that the clinical trial, data generation, and reporting are conducted in compliance with the 
J-GCP and protocol, quality control of the clinical trial should be performed by the monitor and personnel 
in charge of quality control and data management at each stage of the trial. 
 
22.1.1 Clinical trial monitoring 
In order to ensure that attempts are made for protection of subjects’ rights, retention of the safety, and 
improved welfare, the trial is conducted in compliance with the latest protocol and J-GCP, and the trial data 
reported by the principal investigator or subinvestigators are accurate and complete and can be verified 
based on the trial-related records including source documents, the monitor should visit the study sites in 
accordance with the pre-specified procedure and directly access to the source documents to perform 
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monitoring of the clinical trial. 
 
22.2 Quality Assurance 
In order to confirm that the clinical trial was conducted in compliance with the J-GCP, standard operating 
procedure, protocol, and pre-specified other plans and procedures, the quality of the clinical trial should be 
assured by the auditor of the sponsor. The auditor should be independent from monitoring and quality 
control of the clinical trial, perform an audit in accordance with the pre-specified audit plan and procedure, 
and confirm proper conduct of the clinical trial, including reliability of the data, to assure the quality of the 
clinical trial. 
 
23 
STUDY DEVICE MANAGEMENT 
The study sites and sponsor should appropriately control the study device in accordance with the following 
considerations. 
 
(1) Provision of study device control procedure 
The sponsor will provide the study sites with study device control procedure that specifies handling of 
the study device, records, management, and storage, without delay after conclusion of the contract. 
(2) Delivery of the study device 
After conclusion of the contract between the study site and sponsor, the sponsor will deliver the study 
device to the study site. 
(3) Storage, recovery, control records of the study device, and confirmation of unused device 
The study device should be stored and controlled by the director of the study site or study device 
manager appointed by the director of the study site in accordance with the study device control 
procedure. The director of the study site or study device manager should carry out the storage, 
recovery, control records of the study device, and confirmation of unused device in accordance with 
the followings. 
 
(a) 
The study device must be appropriately stored and controlled in accordance with the study 
device control procedure. 
(b) 
In order to understand the use status of the study device and progress of the clinical trial, 
create a study device log for recording. The study device log includes the date, number of 
device, manufacturing number or manufacturing code, expiration date, product number of the 
device, and subject ID code. 
(c) 
Any expired unused device must be returned to the sponsor. Also any study device with 
trouble or deficiency should be returned to the sponsor as much as possible. 
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(4) Consistency check on the control records of the study device and input in the eCRFs 
The investigator and study device manager should check the consistency between the contents of 
study device log and eCRFs, and if any inconsistency is found, the cause should be investigated 
immediately, and take necessary measures. Corrections should be made so as to the correction history 
can be seen. Also check the contents of the study device log, and if any inconsistency is found, take 
necessary measures. 
 
 
 

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24 
ETHICAL CONSIDERATIONS AND REGULATORY 
REQUIREMENTS 
24.1 Compliance with J-GCP 
This clinical trial will be conducted in compliance with the PMD Act, ethical principles that have their 
origin in the Declaration of Helsinki, the J-GCP, ministerial ordinances partially amending J-GCP and the 
relating regulations, and this protocol. 
 
24.2 Creation of Written Patient Information and Informed Consent Form 
(1) The investigator, with the cooperation of the sponsor, should create the written patient information 
and informed consent form. Creation and revision of the written patient information should be carried 
out in compliance with the ethical principles based on the J-GCP. For the written patient information, 
use plain terms so that subjects can easily understand. 
(2) The written patient information and informed consent form should include the followings: 
 
(a) 
That the clinical trial involves research. 
(b) The purpose of the trial. 
(c) 
The name, job title, and contact place of the principal investigator or subinvestigators. 
(d) The trial procedures to be followed (experimental aspects of the trial, subject inclusion criteria, 
and exclusion criteria). 
(e) 
The reasonably expected benefits and risks or inconveniences to the subject. 
(f) 
The alternative procedure(s) or course(s) of treatment that may be available to the subject, and 
their important potential benefits and risks. 
(g) The expected duration of the subject’s participation in the trial. 
(h) That the subject’s participation in the trial is voluntary and that the subject may refuse to 
participate or withdraw from the trial, at any time. By refusing to participate or withdrawing 
from the trial, the subject will not get a penalty or loss of benefits to which the subject is 
otherwise entitled. 
(i) 
Handling of the study device in case where the subject withdraws from the trial after 
participation in the trial. 
(j) 
That the monitor, auditor, IRB, and regulatory authority will be granted direct access to the 
subject’s original medical records. In such a case, the subject’s confidentiality will be protected. 
By signing a written informed consent form, the subject is authorizing such access. 
(k) If the results of the trial are published, the subject’s identity will remain confidential. 
(l) 
The person(s) to contact for further information regarding the trial and the rights of trial subjects, 
and whom to contact in the event of trial-related injury. 
(m) The compensation and treatment available to the subject in the event of trial-related injury. 
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(n) The approximate number of subjects involved in the trial. 
(o) That the subject will be informed in a timely manner if information becomes available that may 
be relevant to the subject’s willingness to continue participation in the trial. 
(p) The foreseeable circumstances or reasons under which the subject’s participation in the trial may 
be terminated. 
(q) The anticipated expenses, if any, to the subject for participating in the trial. 
(r) 
The anticipated payment, if any, to the subject for participating in the trial (arrangement of 
prorated payment, etc.) 
(s) 
The subject’s responsibilities. 
 
24.3 Changes to the Protocol, Written Patient Information, and Informed Consent 
Form 
If any changes are to be made to the protocol, the sponsor will discuss with the investigator, promptly 
revise the protocol, and submit the revised protocol to the director of the study sites to gain an approval of 
the IRB. The investigator must not conduct the clinical trial under the revised protocol without an approval 
of the IRB. 
 
If any important information becomes available that affects the subject’s consent to participation in the trial, 
or if revision of the protocol results in changes to the written patient information and informed consent 
form, the investigator must revise the written patient information and informed consent form based on the 
new information, and gain an approval of the IRB before use of the revised documents. The principal 
investigator or subinvestigators must provide the subject with an explanation using the revised written 
patient information, and obtain written informed consent to continued participation in this clinical trial 
voluntarily signed by the subject. In such cases where the subject is difficult to give written reconsent, the 
subject may continue the study participation by obtaining consent from the legal representative. 
 
24.4 Institutional Review Board 
Prior to the conduct of this clinical trial, the IRB must review and approve whether the study site is suitable 
for the conduct of the trial, based on the protocol, written patient information and informed consent form, 
study device investigator’s brochure, and other necessary documents, from the standpoints of ethical, 
scientific, and medical validity. Changes to the protocol, written patient information, and informed consent 
form must be approved by the IRB prior to the application of the changes. 
 
If the duration of the trial exceeds 1 year, the study site must be reviewed by the IRB as to whether or not 
the trial should be continued at least once per year, and must be approved by the IRB. Also cases where a 
serious, unforeseeable defect was reported, whether or not the trial should be continued at the study site 
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should be reviewed. 
 
24.5 Considerations Concerning Subject’s Privacy 
(1) The investigators should enter the subject’s ID code in the eCRFs, with no medical record number. If 
other documents/materials have expressions by which the subject can be personally identified, such as 
subject’s name, the expressions will be removed before submission of the documents/materials to the 
sponsor. 
(2) The principal investigator or subinvestigators should provide the subject with the information that 
when the monitor, auditor, IRB, and regulatory authority directly access to the trial-related records, 
when the trial-related records are used for marketing approval application for the study device, and 
when the trial results are published, the confidentiality of the subject will be protected. 
 
24.6 Compensation Available to the Subjects 
The sponsor will prepare the compensation system in case of subject’s health injury. In the event of 
trial-related health injury, based on the sponsor’s compensation system, medical expenses, medical 
allowance, and compensation will be paid. However, this does not apply if the damage is willful or gross 
negligence of the study site, or subject’s deliberate damage. 
 
24.7 Payment to Reduce Financial Burden on the Subjects 
As for the payments to reduce financial burden on the subjects for participation in the trial, based on the 
contract with each study site, the sponsor will pay to the study site at the pre-specified time point. 
 
25 
AGREEMENT TO PROTOCOL 
The investigator and sponsor will sign the written agreement in the protocol to certify the agreement on the 
contents of the protocol, and agreement on the compliance with the protocol. 
 
26 
USE OF STUDY RESULTS OR PUBLICATION POLICY 
(1) Unpublished information provided by the sponsor, including all information on the study device and 
other academic data concerning the clinical use, components, performance, and principle of the study 
device should be kept confidential. The principal investigator or subinvestigators must use the above 
information only for the purpose of this clinical trial, and must not use for other purpose without prior 
written approval by the sponsor. 
(2) By signing the written agreement in the protocol, the investigator agrees with the sponsor to use the 
trial results for marketing approval application in Japan, publishing, and for the information for 
medical experts. 
 
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27 
SCHEDULED TRIAL DURATION 
Scheduled trial duration: 
September 2016 to September 2025* 
<EWJ-003 analysis set/bailout treatment registry> [End of subject enrollment] 
Scheduled trial duration: September 2016 to December 2022 
Scheduled duration of subject enrollment: 
September 2016 to October 2017 (for 14 months) 
<Expanded clinical trial registry> 
Scheduled trial duration: January 2018 to September 2025 
Scheduled duration of subject enrollment: 
January 2018 to July 2020 (for 2 years and 6 months)** 
 
* 
For this clinical trial, at the time point when the collection of data on the EWJ-003 analysis set up to 
1 year post-procedure is completed, a study report will be created, which will be attached to the 
approval application form for the expanded indications of EWJ-003. Therefore, this clinical trial may 
be completed by acquisition of marketing approval of EWJ-003 prior to completion of the last subject 
follow-up observation at 5 years post-procedure. 
** Subject entry into the continued access registry will be started after completion of subject entry into 
the EWJ-003 analysis set, and the subject enrollment will be continued until acquisition of marketing 
approval for EWJ-003. 
 
28 
CONSIDERATION AFTER MARKETING APPROVAL 
This clinical trial will be completed at acquisition of marketing approval of the study device and will be 
switched to post-marketing clinical trial after marketing approval. Therefore, "clinical trial" in this clinical 
protocol and CRFs will be replaced with "post-marketing clinical trial" as needed. Additionally, "Japan 
Ministerial Ordinance on Good Clinical Practice for Medical Devices (Ordinance of the Ministry of Health, 
Labour and Welfare No. 36 of 2005)" shall be deemed to be replaced with "Japan Ministerial Ordinance on 
Good Clinical Practice for Medical Devices (Ordinance of the Ministry of Health, Labour and Welfare No. 
36 of 2005) and Japan Ministerial Ordinance on Good Post-marketing Study Practice for Medical Devices 
(Ordinance of the Ministry of Health, Labour and Welfare No. 38 dated March 23, 2005)." (However, this 
section does not replace them.) 
 
For the procedure to be followed at completion of the trial by acquisition of marketing approval for the 
study device, see Section 18.3. 
 
 

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29 
GENERAL STUDY ORGANIZATION 
Study sites 
Name: Osaka University Hospital 
Address: 
 
Contact to: 
 
 
Name: Keio University Hospital 
Address:
 
Contact to:
 
 
Sponsor 
Name: Edwards Lifesciences Corporation 
Address: 
 
Contact to: 
 
 
Contract Research Organization 
Name:
 
Address: 
 
Contact to: 
 
 
For the details see Attachment 1 “General Study Organization.” 
 
 
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30 
GLOSSARY 
The definitions of terms used in this clinical trial are listed below: 
 
Term 
Definition 
Reference/rationale 
Legally acceptable 
representative 
A legally acceptable representative is who excersise parental 
authority over the subject, may also be the spouse, the guardian 
or the equivalent. 
J-GCP 
Adverse event 
An adverse event (AE) is any untoward medical occurrence, 
unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users, or 
other persons, whether or not related to the study device. 
However, for an event occurred in persons other than the 
subjects, it should be limited to an event suspected to be 
associated with the use of the study device.

In this clinical trial, any events developed between the start of 
the study procedure and the final follow-up observation (when 
the trial is discontinued, until the time of discontinuation) will 
be regarded as AEs, and events occurred between the time of 
informed consent and the start of the study procedure, which 
have not recovered at the start of the study procedure, should be 
handled as pre-procedural complications. 
J-GCP 
Serious adverse event 
A serious adverse event (SAE) is an event applicable to the 
followings, irrespective of causal relationship to the study 
device. 
 
(a) Death 
(b) Those that may lead to death 
(c) Those requiring inpatient hospitalization or prolongation of 
existing hospitalization for treatment 
(d) Disability 
(e) Those that may lead to disability 
(f) Serious cases in accordance with those in (a) to (e) 
(g) Any congenital disease or abnormality in the offspring of a 
treated patient 
 
However, hospitalization without a newly developed AE or 
aggravated pre-procedural complication as shown in the 
followings is not included in SAEs. 
 
x Hospitalization for treatment scheduled before the 
procedure 
(e.g.: 
hospitalization 
for 
surgery 
for 
pre-procedural complication that became possible due to 
improvement in the heart condition) 
x Hospitalization for management (e.g.: regular checkup, 
hospitalization for examination, educational hospital 
admission) 
x Admission to a rehabilitation facility 
Pharmaceutical 
and Medical 
Device Act 
Enforcement 
Regulation 
Access site 
The site where a guidewire, catheter, or sheath was inserted, 
including the artery or vein, left ventricular apex, and aorta. 
 
Access-related 
complication 
An adverse clinical course that may have occurred in 
association with all access sites used during the study 
procedure. 
 
Access 
site/access-related 
complications 
Access site/access-related complications are classified by the 
severity into severe vascular complications or mild vascular 
complications. 
VARC-2 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 122 - 
Term 
Definition 
Reference/rationale 
 
x Severe vascular complications 
ż Aortic dissection, aortic rupture, aortic annulus rupture, 
left 
ventricular 
perforation, 
apical 
aneurysm/pseudoaneurysm 
ż Access 
site 
or 
access-related 
vascular 
injury 
(dissociation, 
stenosis, 
perforation, 
rupture, 
arteriovenous 
fistula, 
pseudoaneurysm, 
hematoma, 
irreversible nerve injury, compartment syndrome, 
unsuccessful percutaneous closure device) that caused 
death, life-threatening or severe hemorrhage, visceral 
ischemia, or neurological disorder 
ż Embolization of the distal blood vessel (excluding the 
cerebral blood vessels) requiring surgery, or leading to 
amputation or irreversible peripheral organ damage 
ż Unscheduled peripheral arterial intervention or surgery 
related to death, severe hemorrhage, visceral ischemia, or 
neurological disorder 
ż Hypoperfusion of blood flow determined by the subject’s 
symptoms, physical findings and/or lower extremity 
angiography, or newly found ipsilateral limb ischemia 
diagnosed by no perfusion 
ż Surgery for access-site related nerve injury 
ż Nerve injury related to a permanent access site 
x Mild vascular complications 
ż Access 
site 
or 
access-related 
vascular 
injury 
(dissociation, 
stenosis, 
perforation, 
rupture, 
arteriovenous 
fistula, 
pseudoaneurysm, 
hematoma, 
unsuccessful percutaneous closure device) that does not 
cause death, life-threatening or severe hemorrhage, 
visceral ischemia, or neurological disorder 
ż Embolization of the distal blood vessel treated with 
embolectomy and/or thrombectomy, without amputation 
or irreversible peripheral organ damage 
ż Unscheduled peripheral arterial intervention or surgery 
not applicable to the definition of severe vascular 
complications. 
ż Vascular repair (surgery, ultrasound-guided compression 
method, transcatheter arterial embolization, stent-graft 
placement) was performed or required 
Unsuccessful 
percutaneous 
closure 
device 
Hemostasis of the arteriotomy site using a percutaneous closure 
device failed, and an alternative measure (excluding manual 
compression or auxiliary peripheral balloon angioplasty) was 
taken. 
VARC-2 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 123 - 
Term 
Definition 
Reference/rationale 
Aortic stenosis (AS) 
Aortic stenosis is a condition of blood inflow from the left 
ventricle to the ascending aorta associated with aortic valve 
stenosis, and when the following criteria (a) and (b) were met, it 
is classified as severe. 
 
(a) 0HDQ SUHVVXUH JUDGLHQW   PP+J RU DRUWLF IORZ
YHORFLW\PV 
(b) $9$FP2 RU$9$LQGH[FP2/m2 
 
<Severity classification of AS> 
 
Guideline 
Mild 
Moderate 
Severe 
Maximum aortic flow velocity 
(m/s) 
< 3.0 
3.0 - 3.9 
 4.0 
Mean systolic pressure gradient 
(mmHg) 
< 25 
25 - 39 
 40 
AVA (cm2) 
> 1.5 
1.1 - 1.5 
 1.0 
AVA index (cm2/m2) 
--- 
--- 
 0.6 
 
ACC/AHA, 
Guidelines 
for 
Surgical 
and 
Interventional 
Treatment 
of 
Valvular 
Heart 
Disease 
Aortic 
valve 
regurgitation 
It is an index that reflects the total volume of blood leaked into 
the left ventricle, including both transvalvular regurgitation and 
paravalvular regurgitation. The severity of aortic valve 
regurgitation will be assessed in accordance with the 
followings: 
 
<Severity classification of aortic valve regurgitation> 
 
Mild 
Moderate 
Severe 
Semi-quantitative evaluation 
Diastolic retrograde wave of the 
descending aorta 
None or 
proto- 
diastole 
Middle part 
of a diastole 
Significant, 
for the 
entire 
diastolic 
phase 
Range of paravalvular 
regurgitation (%) 
< 10 
10 - 29 
 30 
Quantitative evaluation 
Regurgitation volume (mL/beat) 
< 30 
30 - 59 
 60 
Regurgitation rate (%) 
< 30 
30 - 49 
 50 
Effective regurgitant orifice area 
(cm2) 
0.10 
0.10 - 0.29 
 0.30 
 
VARC-2 
Aortic 
valve 
regurgitation 
At the Echo Core Laboratory, the severity of aortic valve 
regurgitation will be assessed in accordance with the 
followings: 
 
<Severity classification of aortic valve regurgitation> 
7-grade evaluation 
Corresponding 
4-grade evaluation Regurgita- 
tion volume 
(mL/beat) 
Regurgita- 
tion rate 
(%) 
Effective 
regurgitant 
orifice area 
(mm2) 
ASE 
VARC-2 
None 
0 
None/ 
negligible 
Unable to quantitate/undetectable 
Negligible 
1 
Mild 
2 
Mild 
< 15 
< 15 
< 5 
Mild - Moderate 
15 - 29 
15 - 29 
5 - 9 
Moderate 
3 
Moderate 
30 - 44 
30 - 39 
10 - 19 
Moderate - Severe 
45 - 59 
40 - 49 
20 - 29 
Severe 
4 
Severe 
 60 
 50 
 30 
 
 

Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 124 - 
Term 
Definition 
Reference/rationale 
Aortic 
valve 
incompetence 
A condition where the aortic valve does not close properly, with 
blood regurgitation from the aortic valve into the left ventricle, 
and the severity will be assessed in accordance with the 
followings: 
 
<Severity classification of aortic valve incompetence> 
 
Mild 
Moderate 
Severe 
Qualitative evaluation 
Aortographic grade 
I 
II 
III - IV 
Color Doppler jet area 
< 25% of 
LVOT 
 
> 65% of 
LVOT 
vena contracta width (cm) 
< 0.3 
0.3 - 0.6 
> 0.6 
Quantitative evaluation (catheter or echo) 
Regurgitation volume (RVol) 
(mL/beat) 
< 30 
30 - 59 
 60 
Regurgitation rate (%) 
< 30 
30 - 49 
 50 
Effective regurgitant orifice area 
(cm2) 
0.10 
0.10 - 0.29 
 0.30 
 
ACC/AHA, 
Guidelines 
for 
Surgical 
and 
Interventional 
Treatment 
of 
Valvular 
Heart 
Disease 
Prosthetic valve stenosis 
When meeting both of the following criteria (a) and (b), and 
meeting either one of (a) or (b) and (c), it is regarded as 
significant stenosis. 
 
(a) 0D[LPXP DRUWLF IORZ YHORFLW\   PV RU PHDQ
SUHVVXUHJUDGLHQWmmHg 
(b) (2$FP2 ZKHQ%6$FP2RUFP2 
(when BSA < 1.6 cm2) 
(c) Aortic flow velocity coefficient by continuous wave 
'RSSOHUPHWKRG 0.35 
 
 
Normal 
Mild 
Moderate/
Severe 
Quantitative evaluation [blood flow dependent] 
Maximum aortic flow velocity 
(m/s) 
< 3.0 
3 - 4 
> 4 
Mean pressure gradient (mmHg) 
< 20 
20 - 40 
> 40 
Quantitative evaluation [blood flow independent] 
Aortic flow velocity coefficient 
by continuous wave Doppler 
method* 
> 0.35 
0.35 - 0.25 
< 0.25 
EOA (cm2) 
>%6$FP2] 
> 1.1 
1.1 - 0.8 
< 0.8 
EOA (cm2) 
[BSA < 1.6 cm2] 
> 0.9 
0.9 - 0.6 
< 0.6 
* When the LVOT > 2.5 cm, the significant stenosis criterion is < 0.20. 
VARC-2 
As-treated analysis set 
A subject population consisting of subjects who were enrolled 
in this clinical trial and implantation of the study device was 
initiated is defined as as-treated (AT) analysis set. 
 
Bleeding 
Bleeding can be classified into life-threatening or disabling, 
severe, and mild by severity. 
 
x Life-threatening or disabling bleeding 
When applicable to any one of the followings: 
ż Fatal bleeding (BARC Type 5) 
ż Bleeding of major organs (BARC Types 3b and 3c, 
including 
intracranial 
hemorrhage, 
intramedullary 
hemorrhage, 
intraocular 
hemorrhage, 
pericardial 
bleeding requiring pericardial puncture, and muscle 
hemorrhage with compartment syndrome. 
ż Hypovolemic shock or bleeding that induced severe 
VARC-2 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 125 - 
Term 
Definition 
Reference/rationale 
hypotension requiring vasoconstrictors or surgery. 
ż $GHFUHDVHLQKHPRJORELQ g/dL, or apparent bleeding 
with transfusion of whole blood preparation or red cell 
SURGXFWXQLWV* (BARC Type 3b) 
x Severe bleeding (BARC Type 3a) 
Not applicable to the definition of life-threatening or 
disabling bleeding, and any one of the following is observed: 
ż %OHHGLQJZLWKDGHFUHDVHLQKHPRJORELQJG/ 
ż Bleeding with transfusion of 2 or 3 units whole blood 
preparation or red cell product 
ż Bleeding causing hospitalization or a permanent injury 
ż Bleeding requiring surgery 
 
x Mild bleeding (BARC Type 2 or 3a, severity dependent) 
Not applicable to the definition of life-threatening or 
disabling bleeding or severe bleeding, and all bleedings 
assessed as of clinical significance (e.g.: access site 
hematoma) 
 
* Considering a predicted increase in hemoglobin of 1 g/dL per unit of general 
red cell preparation, the reduced hemoglobin level may be estimated 
CCS status of stable 
angina 
Class 1: 
No limits to physical activities. Ordinary physical 
activity does not cause angina, such as walking and 
climbing stairs. Angina with strenuous or rapid or 
prolonged exertion at work or recreation. 
Class 2: 
Slight limitation of ordinary activity. Angina with 
walking or climbing stairs rapidly, walking uphill, 
walking or stair climbing after meals, or in cold, or 
in wind, or under emotional stress, or only during the 
1 to 2 hours after awakening. Or walking more than 
two blocks on the level and climbing more than two 
flight of ordinary stairs at a normal pace and in 
normal conditions. 
Class 3: 
Marked limitation of ordinary activity. Angina with 
walking one or two blocks (80 m - 160 m) on the 
level and climbing one flight of stairs in normal 
conditions and at normal pace. 
Class 4: 
Inability to carry on any physical activity without 
discomfort. Anginal symptoms may be present at 
rest. 
CCS 
Cancer 
Refers to a condition caused by an uncontrolled division of 
abnormal cells conditions, and is characterized by invasion into 
the surrounding tissues, and can progress to distant metastasis. 
Cancer is classified into benign and malignant, and in this 
clinical trial, if a subject has a history of malignant cancer, enter 
as a subject with a history of cancer at baseline in the eCRF. 
 
Cardiac tamponade 
Newly 
occurred 
pericardial 
effusion 
associated 
with 
hemodynamic instability and a clear causal relationship to the 
study procedure. 
VARC-2 
Conduction 
disorder/arrhythmia 
The following data on conduction disorder/arrhythmia will be 
collected: 
 
x Conduction disorder at baseline, paroxysmal or persistent 
atrial 
fibrillation/flutter, 
and 
permanent 
pacemaker 
implantation 
x New or aggravated conduction disorder related to the 
implanted valve 
VARC-2 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 126 - 
Term 
Definition 
Reference/rationale 
ż First degree atrioventricular (A-V) block 
ż Second degree A-V block (Mobitz type I or II) 
ż Third degree A-V block 
ż Incomplete right bundle branch block 
ż Right bundle branch block 
ż Defect intraventricular conduction 
ż Left bundle branch block 
ż Left anterior hemiblock (LAH) 
ż Left posterior hemiblock (LPH) 
ż Block requiring permanent pacemaker implantation 
x Persistent or transient advanced A-V block 
When advanced A-V block is observed at every test, it is 
regarded as persistent. 
x New permanent pacemaker implantation 
The indications of permanent pacemaker implantation and the 
number of days after the procedure should be accurately 
recorded. 
x Newly found atrial fibrillation/flutter 
x Newly found arrhythmia with hemodynamic instability or 
requiring treatments 
Switching to surgery 
Refers to cases with switching to open heart surgery by 
sternotomy due to a procedure-related complication during the 
study procedure. 
VARC-2 
Coronary obstruction 
During the study procedure or post-procedure newly found 
prosthetic valve, native cusp, lump lime, or partial or total 
occlusion at the coronary ostium associated with dissociation in 
the angiogram or echocardiography findings. 
VARC-2 
Death 
Death 
is 
classified 
into 
cardiovascular 
death 
or 
non-cardiovascular death by the cause of death. 
x Cardiovascular death 
When applicable to the followings, it is regarded as 
cardiovascular death: 
ż Death directly associated with the heart (e.g.: myocardial 
infarction, cardiac tamponade, worsened heart failure) 
ż Death associated with blood vessels other than the 
coronary artery (e.g.: neurological event, pulmonary 
embolism, aortic aneurysm rupture, dissecting aneurysm, 
and other vascular disease) 
ż All study procedure-related deaths, including deaths 
related to procedural complication and treatments for the 
procedural complication. 
ż All deaths related to the investigational valve, including 
deaths from structural valve deterioration, non-structural 
dysfunction, and other valve-related AEs. 
ż Sudden death and unwitnessed death 
ż Death with unknown cause 
x Non-cardiovascular death 
It is apparent that the major cause of death is a disease other 
than the above (e.g.: trauma, cancer, suicide) 
VARC-2 
Device deficiency 
A device deficiency is defined as the failure of a device to meet 
its quality, safety, and performance specifications, such as 
damage and or malfunctioning, regardless of being associated 
with the design, supply, storage, or used. 
J-GCP 
Valve malposition 
Valve malposition includes moved valve, valve embolism, and 
implantation at an unintended site. For definition of events, see 
respective section. 
VARC-2 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 127 - 
Term 
Definition 
Reference/rationale 
Moved valve 
After a prosthetic valve was placed in an appropriate position, 
the valve moved upward or downward in the aortic annulus 
from the implanted site, with or without a causal relationship to 
the study procedure. 
VARC-2 
Valve embolism 
The prosthetic valve moved during or after implantation, and no 
longer stay in the annulus. 
VARC-2 
Implantation 
at 
an 
unintended site 
A prosthetic valve being persistently implanted at the site other 
than the aortic root. 
VARC-2 
Device success 
No operative death (death within 30 days post-procedure or 
death during hospital stay), the investigational valve was 
implanted at an appropriate anatomical position, and all 
intended performance of the investigational valve as shown in 
the followings were achieved. 
x No prosthetic valve - patient mismatch 
x Mean pressure gradient < 20 mmHg or maximum aortic 
flow velocity < 3 m/s 
x 1RPRGHUDWHDRUWLFYDOYHUHJXUJLWDWLRQ 
VARC-2 
Dry weight 
The body fluid volume is proper, without excessive decrease in 
blood pressure during dialysis, and body weight with less 
burden on the cardiovascular system in a long-term basis.㻌
Guidelines for 
evaluation and 
treatment of 
cardiovascular 
complication in 
hemodialysis 
patients 
Dialysis conditions 
The dialysis conditions are as shown below: 
x Number of dialysis per week (times/week) 
x Duration of dialysis (hours) 
x Blood flow (mL) 
x Quantity of dialysate flow (mL) 
x Removal method (filtration or diffusion) 
x Dialyzer membrane type and membrane area 
x With or without High Performance Membrane (HPM) 
dialyzer 
Guidelines for 
maintenance 
hemodialysis: 
Blood 
prescription 
Embolism 
Free blood clots or lesional substance in blood in the systemic 
circulation or pulmonary circulation. 
All embolic events occurred under the circumstances with no 
infections immediately after perioperative period (at complete 
recovery from loss of consciousness by general anesthesia). 
Embolic events in the peripheral vascular system are embolisms 
recorded as surgery, autopsy, or clinically, and symptoms 
associated with total or partial occlusion of the peripheral artery 
(except cerebral artery). Conscious patients with myocardial 
infarction should be excluded. Unless coronary artery embolism 
was caused by myocardial infarction is evident by surgery, 
autopsy, or clinical investigation, also patients with myocardial 
infarction after perioperative period should be excluded. If it 
was evident that an embolus consists of non-thrombotic 
substances (for example, arteriosclerosis, myxoma), it would be 
excluded. 
STS 
Endocarditis 
When applicable to any one of the followings: 
x Duke diagnostic criteria 
x A histological or bacteriological test during re-operation 
reveals an abscess secondary to infection, paravalvular 
regurgitation and/or verruca 
x An autopsy reveals an abscess related to the implanted 
valve and/or verruca 
 
VARC-2 

Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 128 - 
Term 
Definition 
Reference/rationale 
<Duke diagnostic criteria> 
I. Clinical criteria 
Meeting 2 major criteria, or 1 major criterion and 3 minor 
criteria, or 5 minor criteria. 
(Major diagnostic criteria) 
1. 
Positive blood culture for typical infective endocarditis 
organisms 
A. Any one of the followings was found from 2 separate 
blood cultures 
i. Streptococcus viridans, Streptococcus bovis, HACEK 
group 
ii. Staphylococcus aureus or Enterococcus was detected, with 
no other infection focus 
B. Positive blood culture corresponding persistent infective 
endocarditis defined as followings: 
i. Two or more SRVLWLYH FXOWXUHV IURP VDPSOHV GUDZQ  
hours apart 
ii. All 3 or a majority of 4 separate positive blood cultures 
ILUVWDQGODVWVDPSOHGUDZQKRXUDSDUW 
2. 
Endocardial have been affected applicable to A or B 
below: 
A. Echocardiogram positive for infective endocarditis with 
any one of the followings 
i. Oscillating intracardiac mass on valve or supporting 
structures, in the path of regurgitant jets, or on implanted 
material in the absence of an alternative anatomic 
explanation 
ii. Abscess 
iii. New partial dehiscence of prosthetic valve 
B. New valve incompetence (deterioration of existing noise 
or change alone is not adequate) 
(Minor diagnostic criteria) 
1. 
Predisposition: Predisposing heart condition or intravenous 
drug use 
2. 
)HYHU& 
3. 
Vascular phenomena: Major vascular emboli, septic 
infarction, infective mycotic aneurysms, intracranial bleed, 
conjunctival hemorrhages, Janeway lesions 
4. 
Immunologic 
phenomena: 
Glomerulonephritis, 
Osler 
nodes, Roth spots, rheumatoid factor 
5. 
Microbiological evidence: Positive blood culture but does 
not meet a major criterion as noted above or serological 
evidence of active infection with organism consistent with 
endocarditis 
6. 
Echocardiographic findings: Consistent with endocarditis 
but do not meet a major criterion as noted above 
 
II. Pathological criteria 
Microorganism: 
Demonstrated by culture or histology in a 
vegetation or in a vegetation that has 
embolized, or in an intracardiac abscess: 
Pathologic 
lesions: 
Vegetation 
or 
intracardiac abscess present confirmed by 
histology showing active endocarditis. 
Enrolled subjects 
Enrollment in this clinical trial should be completed by the 
document describing the patient’s eligibility finally determined 
by case review. Enrollment in the continued access registry 
should be completed by the start of the study procedure (at the 
 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 129 - 
Term 
Definition 
Reference/rationale 
time point when an invasion such as an incision is made on the 
access site). 
Bailout subjects 
Patients in whom deployment of the THV by balloon dilatation 
at a nominal volume was impossible for a medical reason will 
be regarded as bailout cases. 
 
Valve explants 
Removal of the implanted investigational valve for any reason. 
(See “Re-operation”) 
STS/AATS 
Length of 
post-procedural 
hospitalization 
A period from the day of study procedure to hospital discharge. 
 
Study procedure 
Study procedure refers to the procedure using the study device 
specified in the protocol for this clinical trial. The time of the 
start of the study procedure is the time after a subject’s entering 
the operation room when invasion such as incision was made on 
the access site, and the time when closing the access site such as 
incision site was completed should be regarded as the end of 
study procedure. 
 
Infections 
Known infections that require intravenous administration of 
antibiotics for reasons other than prophylactic use or prolonged 
hospitalization. 
 
Intent-to-treat (ITT) 
analysis set 
Regardless of whether or not the study procedure was given, or 
whether or not the study device was implanted, the 
intent-to-treat (ITT) analysis set is defined as an analysis 
population consists of all subjects enrolled in this clinical trial. 
 
Past medical history 
History of a disease, disorder, etc. that had developed before the 
start of the study procedure and resolved at the start of the study 
procedure. 
 
Mitral valve tissue 
damage or dysfunction 
Damage to the mitral valve tissue (chorda tendineae, papillary 
muscles, or cusp) or dysfunction (limitation posed by the 
investigational valve) newly found during or after the study 
procedure in the angiogram or echocardiography findings. 
VARC-2 
Mitral valve 
incompetence 
A condition where the mitral valve does not close properly at 
systole, with blood regurgitation from the left ventricle to the 
left atrium, and the severity will be assessed in accordance with 
the followings: 
<Severity classification of mitral valve incompetence> 
 
Mild 
1+ 
Moderate 
2+ 
Moderate - 
Severe 
3+ 
Severe 
4+ 
Color flow jet 
Transvalvular 
and small (< 4 
cm2 or < 10% 
of the left atrial 
area) 
Transvalvular 
and 
moderate 
(4 - 6 cm2 or < 
10 - 30% of the 
left atrial area) 
Transvalvular 
and large (> 6 
cm2 to < 8 cm2 
or > 30% to < 
40% of the left 
atrial area), or 
aberrant 
reaching the 1st 
pulmonary vein 
Transvalvular 
DQG ODUJH  
cm2 RU  
of the left atrial 
area), aberrant 
reaching 
the 
2nd pulmonary 
vein 
Pulmonary 
venous 
blood flow 
Systole 
predominant 
Diastole 
predominant 
Entire diastole 
Systolic 
regurgitation 
Regurgitation volume 
(mL/beat) 
< 30 
30 - 44 
45 - 59 
 60 
Regurgitation fraction 
(%) 
< 30 
30 - 39 
40 - 49 
 50 
Effective regurgitant 
orifice area (cm2) 
< 0.20 
0.20 - 0.29 
0.30 - 0.39 
 0.40 
Vena contracta width 
< 0.5 cm 
 0.5 cm 
 
 
ASE 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 130 - 
Term 
Definition 
Reference/rationale 
mRS 
A commonly used international scale as the prognosis rating 
scale for daily activities of patients with stroke. 
(see Appendix 2 “Modified Rankin Scale (mRS)”) 
0 
No symptoms at allᴾ
1 
No significant disability despite symptoms; 
able to carry out all usual duties and activities 
2 
Slight disability; 
unable to carry out all previous activities, but able to look 
after own affairs without assistance 
3 
Moderate disability; 
requiring some help, but able to walk without assistanceᴾ
4 
Moderately severe disability; 
unable to walk without assistance and unable to attend to 
own bodily needs without assistanceᴾ
5 
Severe disability; 
bedridden, incontinent and requiring constant nursing care 
and attentionᴾ
6 
Dead 
 
Myocardial Infarction 
When meeting any one of the followings, it is defined as 
myocardial infarction. 
 
x Periprocedural myocardial infarction (within 72 hours 
post-procedure) 
When meeting both of the following criteria, it is regarded as 
periprocedural myocardial infarction. 
ż Newly developed ischemic symptoms (chest pain, 
shortness of breath, etc.) or signs (ventricular arrhythmia, 
newly developed or worsened heart failure, new ST 
change, unstable hemodynamics, newly developed 
abnormal Q-ZDYHOHDGVQHZLPDJLQJLQIRUPDWLRQRI
normal myocardial loss, or regional wall abnormal 
motion). 
ż CK-MB within 72 hours post-procedure > 5 times the 
upper range limit (URL), or troponin > 15 times. 
 
x Idiopathic myocardial infarction (72 hours post-procedure) 
When meeting any one of the following criteria, it is regarded 
as idiopathic myocardial infarction. 
ż Elevation of CK-MB or troponin over the reference 
standard, together with at least one of the following 
findings: 
• Symptoms of ischemia 
• ECG changes indicative of new ischemia (ST-T 
changes, LBBB) 
• Newly developed abnormal Q-ZDYHDWVHTXHQWLDO
2 leads 
• Imaging evidence of a new loss of viable 
myocardium or new wall motion abnormality. 
ż Unexpected sudden death including cardiac arrest 
(developing 
symptoms 
primarily 
suggestive 
of 
myocardial ischemia, with new ST elevation or new 
LBBB, and/or death before blood sampling or 
development of myocardial biomarker in blood, with a 
newly developed clot by angiogram and autopsy. 
ż Pathological findings of acute myocardial infarction 
VARC-2 
NIHSS 
Neurological severity scale for stroke developed by National 
Institutes of Health (NIH). 
(see Appendix 1 “NIHSS”) 
NIH 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 131 - 
Term 
Definition 
Reference/rationale 
Non-structural 
dysfunction 
Although abnormality is not of the prosthetic valve itself 
(namely the valve structure is normal), abnormality leading to 
stenosis regurgitation. Non-structural dysfunction includes 
pannus formation, proliferation of own tissues, engulfed suture, 
paravalvular regurgitation, inappropriate sizing or implantation 
position, residual leakage or obstruction after implantation of 
the valve, and clinically significant hemolytic anemia. 
(see “Paravalvular regurgitation”) 
STS/AATS 
NYHA classification of 
cardiac performance 
Classification of cardiac performance developed by New York 
Heart Association, which classifies the severity of heart failure 
into 4 classes based on the subjective symptoms. 
 
<NYHA classification of cardiac performance> 
Class I 
No limitations of physical activities. Ordinary physical 
activity does not cause undue fatigue, palpitations, 
dyspnea, or angina pectoris. 
Class II 
Slight limitation of physical activity. Asymptomatic at 
rest. Ordinary physical activity results in fatigue, 
palpitations, dyspnea, or angina pectoris. 
Class III 
Marked limitation of physical activity. Asymptomatic 
at rest. Less than ordinary physical activity leads to 
fatigue, palpitations, dyspnea, or angina pectoris. 
Class IV 
Inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or angina 
pectoris present at rest. These symptoms may be 
exacerbated by a slight exertion. 
NYHA 
Paravalvular 
regurgitation 
All blood leakages around the prosthetic valve associated with 
the gap between the prosthetic valve and native annulus. 
 
Paravalvular regurgitation can be classified as follows: 
 
Total regurgitation: 
Moderate to severe paravalvular 
dysfunction clearly observed by 
echocardiography. 
Mild regurgitation: 
Paravalvular regurgitation classified as 
aortic valve regurgitation < 3+ and not 
requiring surgical intervention. 
Severe regurgitation: $RUWLFYDOYHUHJXUJLWDWLRQDQG
requiring surgical intervention. 
 
(also see “Non-structural dysfunction) 
STS/AATS 
Pre-procedural 
complication 
Defined as any complication developed before the start of the 
study procedure and the symptoms sustained or under treatment 
at the start of the study procedure. 
 

Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 132 - 
Term 
Definition 
Reference/rationale 
Prosthesis-patient 
mismatch (PPM) 
Prosthesis-patient mismatch (PPM) is an index to show a 
relationship between the implanted prosthetic valve and cardiac 
output originally required for the subject. When the aortic flow 
velocity coefficient by continuous wave Doppler method is 
QRUPDO!EXW(2$L%0,LWLVUHJDUGHGDV
hemodynamically significant prosthesis-patient mismatch. 
 
 
Not 
significant 
Moderate 
Severe 
EOAi (cm2/m2) 
[BMI < 30 kg/cm2] 
> 0.85 
0.85 - 0.65 
< 0.65 
EOAi (cm2/m2) 
[BMI  30 kg/cm2] 
> 0.70 
0.90 - 0.60 
< 0.60 
 
VARC-2 
Re-hospitalization 
Re-hospitalized due to AS symptoms and/or post-procedural 
complication. 
 
If the post-procedural hospital stay exceeds 30 days, in-hospital 
Day 31 is statistically regarded as re-hospitalization. 
 
Re-intervention 
All interventions including repair, correction, or replacement of 
the already operated valve. 
STS/AATS 
Stroke/transient 
ischemic attack 
<Stroke/transient ischemic attack diagnostic criteria> 
Acute onset of a local or general neurological disorder, with at 
least one of the followings: changes in the conscious level, 
hemiplegia, hemiparesis, numbness, sensory loss affecting one 
side of the body, dysphasia or aphasia, hemianopia, amaurosis 
fugax, and other neurological signs or symptoms consistent with 
stroke. 
 
Stroke: 
Local oUJHQHUDOQHXURORJLFDOGLVRUGHUVXVWDLQVKRXUVRU
even < 24 hours new hemorrhage or infarction is found by head 
neuroimaging, or a neurological disorder resulted in death. 
 
Transient ischemic attack: 
Local or general neurological disorder sustains < 24 hours, with 
no new hemorrhage or infarction by head neuroimaging. 
 
As for clinical findings, the absence of causes other than stroke 
that can be easily identified (brain tumor, trauma, infection, 
hypoglycemia, peripheral lesion, influence of drug, etc.) must 
have been determined by a neurologist or together with a 
neurologist*. Definitive diagnosis should be made by at least 
one of the followings: 
 
x Diagnosis by a neurologist or neurosurgeon 
x Head neuroimaging (CT scan or brain MRI); however 
stroke may be diagnosed only by the clinical findings 
 
* Do not report non-local encephalopathy as stroke, unless findings of cerebral 
infarction are present based on the head neuroimaging (CT scan or brain 
MRI). 
 
<Stroke classification> 
Ischemic: 
Acute angiopathy at the local brain, spinal cord, 
or retina associated with infarction in the central 
nervous system tissues 
Hemorrhagic: Acute angiopathy at the local or general brain or 
spinal cord associated with hemorrhage in the 
cerebral parenchyma, cerebral ventricle, or 
VARC-2 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
- 133 - 
Term 
Definition 
Reference/rationale 
subarachnoid 
 
If the information is inadequate for determining ischemic or 
hemorrhagic, classify as cause unknown. 
 
<Definition of stroke> 
Stroke is classified into disabling or nondisabling. 
 
 
x Disabling stroke 
At 90 days after the onset of D VWURNH P56   DQG
H[DFHUEDWLRQLQWKHP56IURPEHIRUHWKHRQVHW 
 
x Non-disabling stroke 
At 90 days after the onset of a stroke, mRS < 2, and no 
H[DFHUEDWLRQLQWKHP56IURPEHIRUHWKHRQVHW 
Structural valve 
deterioration 
All changes in the functions of the implanted valve resulted 
from abnormality specific to the valve that may lead to stenosis 
RU UHJXUJLWDWLRQ H[DFHUEDWLRQ   RI 1<+$ FODVVLILFDWLRQ RI
cardiac performance). 
 
Structural 
valve 
deterioration 
includes 
dysfunction 
or 
degradation of the implanted valve, while infection or 
thrombosis confirmed by re-operation, autopsy, or laboratory 
tests is not included. Structural deterioration means substantial 
change in the valve, including wear, damage, calcification, 
rupture of the cusp, and fraying of the joining thread for the 
components (e.g.: cusp). 
STS/AATS 
Valve thrombosis 
All thrombi adhered to the implanted valve or around the valve 
that obstruct part of the blood flow paths, or interfere with valve 
functions, or are large enough to be treated. Valve-related 
thrombus observed at autopsy of a death case that was assessed 
as unrelated to the study device will not be regarded as valve 
thrombosis. 
VARC-2 
Unplanned use of 
artificial heart-lung 
machines 
Cases for which artificial heart-lung machines were used 
unplanned for circulatory assistance during study procedure. 
VARC-2 
Valve implant analysis 
set 
The subject population consisting for all subjects in whom the 
THV was implanted, and when the subject exited the operation 
room the implanted THV was maintained is defined as valve 
implant (VI) analysis set. Subjects for whom the investigational 
valve was not implanted, including subjects switching to 
surgery, and TAVI bioprosthetic valve other than the 
investigational valve was implanted, will not be included in the 
VI analysis set. As for subjects who received a valve-in-valve 
procedure, 
cases 
with 
additional 
investigational 
valve 
implantation will be included in the VI analysis set, while cases 
with additional TAVI bioprosthetic valve other than the 
investigational valve will be excluded from the VI analysis set. 
 
Valve-in-valve 
procedure 
Implantation of a new prosthetic valve in the already implanted 
prosthetic valve during or after the study procedure due to 
inappropriate implantation position and/or valve function. 
VARC-2 
Ventricular septal 
perforation 
New ventricular septal perforation newly found during or after 
the study procedure by angiogram or echocardiography 
findings. 
VARC-2 
Protocol 
 
Edition number: 
Date of creation: 
Ver. 6.2 
Jaunuary 6, 2020 
 
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31 
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